Medical Literature

CHAEN has commissioned a yearly search as a service to researchers and clinicians with the hopes that they will freely use the results for various endeavours including but not limited improving patient care, fostering research, and increasing education and awareness of HAE. The results are presented as originally identified [i.e. without bias]. The full search strategy is listed below. CHAEN provides this a service free of charge and endeavours to make this as useful as possible. As such, we would appreciate any constructive criticism to help improve the utility of the literature searches.

Search Strategy

The following search strategy was used to identify English language comparison studies addressing hereditary angioedema in Ovid MEDLINE.

  1. angioedemas, hereditary/ or hereditary angioedema type iii/ or “hereditary angioedema types i and ii”/
  2. (“hereditary angio$” or “inherited angio$” or “familial angio$”).mp.
  3. hereditary C1 inhibitor deficiency.mp.
  4. or/1-3
  5. (“clinical trial” or random$ or placebo).mp.
  6. 4 and 5
  7. limit 4 to (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or randomized controlled trial)
  8. 6 or 7
  9. limit 8 to (english language and humans)
  10. limit 9 to (case reports or comment or editorial or letter or news)
  11. 9 not 10

    A case of hereditary angioneurotic oedema, successfully treated with epsilon-aminocaproic acid. Studies on C’1 esterase inhibitor, C’1 activation, plasminogen level and histamine metabolism.

    Lundh B, Laurell AB, Wetterqvist H, White T, Granerus G. 9/1968 Clinical & Experimental Immunology

    A patient with clinical and laboratory findings characteristic of hereditary angioneurotic oedema was investigated. The patient was observed for a period of 5 weeks, during which he had four attacks. ε-Aminocaproic acid (EACA) was then given continuously for 5 months, during which time the patient had no attacks. Attacks reappeared on withdrawal of EACA. Trans-4-(aminomethyl) cyclohexane carboxylic acid (AMCA®) was found to be equally effective in later therapeutic trials. C’1 esterase inhibitor was found in low concentration in defibrinated plasma also during attacks. ε-Aminocaproic acid (EACA) produced no significant change of the inhibitor content. C’1 esterase inhibitor disappeared on incubation of defibrinated plasma from the patient at 37°C for 40 min, and C’1 esterase was generated. The generation time of C’1 esterase increased with increasing the concentration of EDTA in the test solution. The C’1 esterase inhibitor content of defibrinated plasma from the patient, varied with the C’1 esterase generation time, the coefficient of correlation being higher in plasma sampled before treatment with EACA. Plasminogen and α2-macroglobulin were within the normal ranges, also during attacks. EACA markedly depressed the plasminogen level, which rapidly returned to normal on withdrawal of the drug. The studies on histamine metabolism revealed no significant changes with the exception of the urinary excretion of histamine, which was moderately increased towards the end of the period studied. On the days the patient received EACA the urine never contained 1-methylimidazole-5-acetic acid which was present in all the other specimens of urine examined. The basal gastric acid secretion was increased. Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578990/

    Hereditary angio-oedema treated with E-aminocaproic acid

    Champion RH, Lachmann PJ. 10/1969 British Journal of Dermatology

    SUMMARY.— Two brothers with hereditary angio-oedema have been studied, the only 2 cases among 227 patients with angio-oedema seen in 10 years. The absence of the inhibitor of the activated first component of complement in their serum confirmed the diagnosis. In a double blind trial their symptoms were partially controlled by ε – aminocaproic acid, although there were no consistent changes in the serum complement levels.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.1969.tb15938.x/abstract (small fee)

    Treatment of familial angio-oedema

    Owen RM. 3/1969 Lancet

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673669919862 (small fee)

    Use of a kallikrein inhibitor in the treatment of urticaria and hereditary angioneurotic edema

    Juhlin L, Michaelsson G. 1/1969 Acta Dermato Venereologica

    Volume 49(1): pages: 37-44

    Not available online.

    Vascular reactions in hereditary angioneurotic edema

    Juhlin L, Michaelsson G. 1/1969 Acta Dermato Venereologica

    Issue: 49(1): pages: 20-25.

    Not available online.

    Hereditary angioneurotic edema. Report of a large kindred with defect in C’1 esterase inhibitor and review of the literature.

    Dennehy JJ. 7/1970 Annals of Internal Medicine

    Jul;73(1):55-59.

    Of 39 individuals in a family with hereditary angioneurotic edema, 11 are clinically affected in 4 generations, with 2 deaths from laryngeal edema; those still living have abnormally low levels of C′1 esterase inhibitor. Five children have the biochemical defect but as yet no symptoms. Four members of the family have symptoms suggestive of the disease but have normal sera; they may have other illnesses. Two patients have shown marked improvement with testosterone treatment. The known biologic reactions involved are discussed, the recent literature is reviewed, and a previously unnoticed historical reference is added.

    Available online at: http://annals.org/article.aspx?articleid=684591 (small fee)

    Family study of hereditary angio-oedema

    Beck IP, Sassman M, Wills D. /1971 Q.J.Med.

    40(160):563-564

    Not available online.

    Family study of hereditary angio-oedema

    Beck IP, Sassman M, Wills D. 10/1971 Q.J.Med.

    Oct;40(160):563-564.

    Not available online.

    Hereditary angio-oedema

    Bedford S. 10/1971 Proceedings of the Royal Society of Medicine

    Oct;64(10):1049-1050.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1812730/

    Hereditary angio-oedema: a review with particular reference to pathogenesis and treatment.

    Hadjiyannaki K, Lachmann PJ. 6/1971 Clinical & Experimental Allergy

    Jun;1(2):221-233.

    “Hereditary angio-oedema (HAE) is a rare disease associated with, and caused by, an inherited deficiency of the inhibitor of the activated first component of complement (C1-inhibitor). The disease is readily diagnosed in the laboratory by measuring C1-inhibitor levels.

    Very uncharacteristically for an inherited deficiency, genetic transmission is as an autosomal dominant. The patients are therefore heterozygotes and their deficiency is incomplete; many having up to 20% of the normal amount of inhibitor.

    It appears most probable that attacks are precipitated by exhaustion of local inhibitor as a result of its consumption by any of the plasma enzymes (plasmin. kininogenase, P.F./Dil as well as C1)with which the inhibitor can react. Thus, conditions associated with increased generation of any of these enzymes may predispose to relapse in HAE. In the absence of all inhibitor C1 activation proceeds autocatalytically and reacting with its substrates C4 and C2 produces a kinin-like peptide from C2 which appears to be the main mediator of the disease.

    Attacks of the disease have been successfully treated by replacement of inhibitor using fresh frozen plasma as source. Effective prophylactic treatment has been obtained with ɛ-aminocaproic acid and its derivatives. These drugs inhibit the activation of the plasma proteases with which the inhibitor reacts and will thus produce an ‘inhibitor sparing’ effect in addition to themselves inhibiting CT activation.”

    Available online at: http://onlinelibrary.wiley.com/wol1/doi/10.1111/j.1365-2222.1971.tb03021.x/abstract (small fee)

    Hereditary angioneurotic oedema in three families. Symptomatic heterogeneity, complement analysis and therapeutic trials.

    Blohme G, Ysander L, Korsan-Bengtsen K, Laurell AB. 3/1972 Acta Medica Scandinavica

    Mar;191(3):209-219.

    Not available online.

    Tranexamic acid therapy in hereditary angioneurotic edema

    Sheffer AL, Austen KF, Rosen FS. 8/1972 The New England Journal of Medicine

    Aug 31;287(9):452-454.

    Available online at: http://www.nejm.org/doi/pdf/10.1056/NEJM197208312870907 (small fee)

    Treatment of hereditary angioneurotic oedema with tranexamic acid. A random double-blind cross-over study.

    Blohme G. 10/1972 Acta Medica Scandinavica

    Acta Med.Scand. 1972 Oct;192(4):293-298.

    Five patients with hereditary angioneurotic oedema (HANE) have been treated, in a random double-blind cross-over study, with tranexamic acid (trans-AMCHA). Three patients have reacted positively to the treatment. The positive effect in these cases has been so obvious that a specific effect of trans-AMCHA seems probable even if it cannot be definitely ruled out that spontaneous variations have been the cause of this effect. Therapeutic trials with fibrinolytic inhibitors should be made on patients with HANE.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.0954-6820.1972.tb04818.x/abstract (small fee)

    A family study of hereditary angioneurotic oedema

    Beck P, Willis D, Davies GT, Lachmann PJ, Sussman M 4/1973 Q.J.Med.

    Apr;42(166):317-339.

    Hereditary angioneurotic oedema is a rare condition inherited as an autosomal dominant and characterized by episodic circumscribed oedema of the skin, subcutaneous tissues, or mucous membranes. Life may be threatened when the pharynx or larynx are involved and oedema of the intestinal mucous membrane, presenting as colicky abdominal pain and vomiting, may lead to unnecessary surgical intervention. The condition is due to deficiency of the functional inhibitor of the activated first component of complement. Consumption of the inhibitor by activation of other plasma esterase systems permits spontaneous activation of the initial stages of the complement system and leads to the appearance of a kinin derived from the second component of complement which causes oedema by increasing vascular permeability.

    Four patients in three generations of a family with hereditary angioneurotic oedema are presented with special reference to attacks of abdominal colic. The clinical and radiological appearances and serological changes are described before, during, and after treatment by transfusion of fresh-frozen plasma. It was confirmed that this, by replacing the inhibitor, is highly effective in terminating attacks without significant side-effects. It was also confirmed by a controlled trial that epsilon-aminocaproic acid acts prophylactically by reducing the frequency and severity of attacks of oedema.

    Available online at: http://qjmed.oxfordjournals.org/content/42/2/317 (small fee)

    Familial angiooedema treated with epsilon aminocaproic acid

    Williamson DM. 5/1973 British Journal of Clinical Practice

    May;27(5):193-195.

    Not available online.

    Hereditary angio-neurotic oedema. Genealogical and immunological studies.

    Ohela K, Rasanen JA, Wager O. 6/1973 Annals of Clinical Research

    Jun;5(3):174-180.

    Not available online.

    Hereditary angio-oedema (HAO)

    Felix RH. 5/1973 Proceedings of the Royal Society of Medicine

    May;66(5):437-438.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1644953/

    Hereditary angioneurotic oedema

    7/1973 Lancet

    Jul 7;2(7819):41.

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673673919727 (small fee)

    Hereditary angioneurotic oedema

    5/1973 Lancet

    May 12;1(7811):1044-1045.

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673673906752 (small fee)

    Hereditary angioneurotic oedema

    Agostoni A, Martignoni GC. 8/1973 Lancet

    2(7824):325

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673673908313 (small fee)

    Hereditary angioneurotic oedema

    Brackertz D, Kueppers F. 9/1973 Lancet

    2(7830):680

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673673925191 (small fee)

    Hereditary angioneurotic oedema

    Calvert GD, Kilpatrick D, McQueen EG, Houston IB, Kilpatrick JA, Veale AM. 10/1973 N.Z.Med.J.

    Oct 24;78(501):337-342.

    Not available online.

    Hereditary angioneurotic oedema

    Keller MF. 6/1973 Lancet

    Jun 16;1(7816):1381-1382.

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673673916966 (small fee)

    Possible therapy in hereditary angioneurotic edema (HAE)

    Brackertz D, Kueppers F. 6/1973 Klin.Wochenschr.

    51(12):620-622

    The symptomatic therapy of hereditary angioneurotic edema with tranexamic acid and suramin in two patients is reported. The first patient responded well to tranexamic acid (Cyclocapron®) but not to suramin. In the second patient, attacks of edema could apparently be better prevented with suramin.

    Available online at: http://link.springer.com/article/10.1007/BF01468576 (small fee)

    Tranexamic acid in hereditary angioneurotic edema–a progress report

    Lundh B. 1/1973 The New England Journal of Medicine

    Jan 4;288(1):53.

    Available online at: http://www.nejm.org/doi/pdf/10.1056/NEJM197301042880123 (small fee)

    Hereditary angioneurotic edema. Treatment with epsilon-aminocaproic acid during surgery.

    Johns ME, Vanselow MA, Boles R. 5/1974 Archives of Otolaryngology

    May;99(5):388-389.

    Not available online.

    Letter: Hereditary angioneurotic oedema

    Erill S, Cabezas R, VAusina 2/1974 Lancet

    Feb 2;1(7849):169.

    Available online at: http://www.sciencedirect.com/science/article/pii/S0140673674924647 (small fee)

    Long-term therapy of hereditary angioedema (HAE). Preventive management with fluoxymesterone and oxymetholone in severely affected males and females.

    Davis PJ, Davis FB, Charache P. 12/1974 Johns Hopkins Med.J.

    Dec;135(6):391-398.

    Not available online.

    Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema

    Pence HL, Evans R, Guernsey LH, Gerhard RC. 5/1974 Journal of Allergy & Clinical Immunology

    May;53(5):298-302.

    A case is reported for the first time of a patient with hereditary angioneurotic edema who had oral surgery and teeth extractions while being treated with epsilon aminocaproic acid (EACA). The mechanism of action and possible further use of this medication for similar clinical situations are discussed.

    Available online at: http://www.jacionline.org/article/0091-6749%2874%2990109-2/abstract

    Therapy in hereditary angioneurotic oedema

    Gwynn CM. 8/1974 Archives of Disease in Childhood

    Aug;49(8):636-640.

    “Two branches of a family suffering from hereditary angioneurotic oedema underwent trials of therapy of ε-amino caproic-acid (EACA) to ascertain the optimum dosage required to alleviate symptoms without giving rise to unpleasant side effects.

    It was found that children under 11 years tolerated 3 g/day and patients over 11 years 6 g/day without side effects, but with incomplete control of symptoms in some of the patients. However, if the dose was doubled for a period of less than 4 days during times of expected and experienced trauma, better control was achieved and unpleasant muscle cramps were not experienced. These doses, though effective, were much smaller than those used in previous studies.”

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1648996/

     

    A study of complement functions in a family with hereditary angioneurotic edema

    Casali P, Rugarli C, Zanussi C. 11/1975 Bollettino dell Istituto Sieroterapico Milanese

    Nov 20;54(5):405-408.

    A study of some complement functions was performed in two patients affected with hereditary angioneurotic edema (HAE) – mother and daughter – from a Southern Italy family (Apulia) and in three of their relatives. A decreased level of the C1 esterase plasma inhibitor was found in both the patients, who were treated with tranexamic acid with a slight, but definite improvement. However, the disease could not be traced beyond two generations in the pedigree and a couple of ascendants was found who were free from HAE both from the clinical standpoint and from that of the laboratory evaluation of complement functions. The possibility that HAE arose in the family through a mutational event is discussed.

    Not available online.

    Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery

    Jaffe CJ, Atkinson JP, Gelfand JA, Frank MM. 6/1975 Journal of Allergy & Clinical Immunology

    Jun;55(6):386-393

    Six patients with hereditary anagioedema (HAE) undergoing 7 episodes of dental surgery received transfusions with fresh frozen plasma one day before surgery. Although the morbidity observed in these patients following similar procedures had been high, no significant complications of surgery were noted with this therapy. Thus, fresh frozen plasma infusion appears to provide a safe and effective method of prophylaxis in patients with HAE. Following infusion of fresh frozen plasma, serum levels of C4 esterase inhibitor (C1EI) rose transiently, and then fell to preinfusion levels within 1 to 12 days. In all but one patient the rise in C4 was greater than could be accounted for by the amount of C4 infused. In no patient did the level of C1EI or C4 rise to within the normal range. The data raise the question of the role of C1EI in the pathogenesis of angioedema in these patients.

    Available online at: http://www.jacionline.org/article/0091-6749%2875%2990077-9/abstract

    Hereditary angioneurotic oedema

    Levi L. 7/1975 Klinische Wochenschrift

    Jul 15;53(14):679-684

    Three families with hereditary angioneurotic oedema (HANE) are described. Serum CI-INH and C4 immunochemical determinations were performed on 23 members of the families: in 6 persons low CI-INH and C4 levels were found with typical symptoms of HANE, and in one asymptomatic subject. Normal ranges of both proteins for adults, children and newborns are given for comparative purposes. The importance of the early diagnosis and treatment is emphasized.

    Not available online.

    Observations on the ultrastructure of lesions induced in human and guinea pig skin by C 1 esterase and polypeptide from hereditary angioneurotic edema (HANE) plasma

    Willms K, Rosen FS, Donaldson VH. 7/1975 Clinical Immunology & Immunopathology

    Jul;4(2):174-188.

    Intradermally injected preparations of purified Cls̄ and polypeptide from plasma of persons with hereditary angioneurotic edema (HANE) induced venular lesions with ultrastructural changes of the endothelium similar to changes induced by histamine (1). Treatment of test animals with an antihistaminic did not block increased vascular permeability about injections of HANE polypeptide or bradykinin. Animals depleted of C3 demonstrated decreased change in vascular permeability about injections of Cls̄, but responses to histamine, bradykinin and HANE polypeptide were not blocked. Patients with HANE excreted larger amounts of histamine in their urine than normals; this increase was most pronounced as an epidsode of edema was subsiding.

    Available online at: http://www.sciencedirect.com/science/article/pii/0090122975900537 (small fee)

    The relationship between hemolytic and immunodiffusion methods for measurement of C4 in patients with immunologic disorders

    Yam P, Petz LD, Cooper NR. 9/1975 American Journal of Clinical Pathology

    Sep;64(3):351-357

    A comparison of radial immunodiffusion and functional (hemolytic) assays for C4 revealed a highly significant correlation between the two methods in patients with a variety of immunologic disorders. Immunodiffusion technics are more convenient than hemolytic assays for most clinical laboratories. C4 assays are useful for the presumptive diagnosis of hereditary angioneurotic edema, whereas C3 is usually normal in such patients. C4 is usually more sensitive than C3 in a variety of immunologic disorders, although in some patients the opposite is true, especially in hypocomplementemic nephritis.

    Not available online.

    Hereditary angioedema: modification of clinical manifestations with androgens

    Davis PJ, Davis FB, Charache P. 12/1976 Birth Defects: Original Article Series

    12(6):283-287.

    HAE is an autosomal dominant trait of decreased levels or function of circulating and tissue C’1 esterase inhibitor. The clinical illness is characterized by disabling episodes of peripheral, oropharyngeal and gut-wall edema. Long-term fluoxymesterone treatment of 5 affected males (393 patient-months) and oxymetholone treatment of 6 affected females (204 patient-months) has significantly decreased the frequency of attacks of edema without substantive side effects.

    Not available online.

    Hereditary angioedema: the clinical syndrome and its management

    Frank MM, Gelfand JA, Atkinson JP. 5/1976 Annals of Internal Medicine

    May;84(5):580-593

    Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C1 esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 30%.

    Available online at: http://annals.org/article.aspx?articleid=690279 (small fee)

    Letter: Hereditary angioedema and heparin therapy

    Colman RW. 9/1976 Annals of Internal Medicine

    Sep;85(3):399-400.

    Available online at: http://annals.org/article.aspx?articleid=690529 (small fee)

    The effect of synthetic androgens in hereditary angioneurotic edema: alteration of C1 inhibitor and C4 levels

    Rosse WF, Logue GL, Silberman HR, Frank MM. 1/1976 Trans.Assoc.Am.Physicians

    1976;89:122-132.

    Not available online.

    Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities.

    Gelfand JA, Sherins RJ, Alling DW, Frank MM. 12/1976 The New England Journal of Medicine

    Dec 23;295(26):1444-1448

    Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality.

    Available online at: http://www.nejm.org/doi/full/10.1056/NEJM197612232952602 (small fee)

    Danazol in the treatment of hereditary angio-neurotic oedema

    Blackmore WP. 5/1977 J.Int.Med.Res.

    5(Suppl 3):38-43.

    Not available online.

    Methyltestosterone therapy in hereditary angioedema

    Sheffer AL, Fearon DT, Austen KF. 3/1977 Annals of Internal Medicine

    Mar;86(3):306-308

    In a double-blind study of four patients with hereditary angioedema, the efficacy of methyltestosterone (taken daily in 10-mg linguet form) in preventing attacks was shown. There were 19 episodes during 11.8 months of placebo administration, compared with only four attacks during the 46 months of cumulative methyltestosterone treatment (P less than 0.001). The mean serum C4 protein level was twice as high in all patients when they were taking the drug (176 +/- 36 mug/ml) as compared with the placebo (84 +/- 21 mug/ml), and rose to normal range in three of four patients.

    Available online at: http://annals.org/article.aspx?articleid=690932 (small fee)

    Obesity in children. Environment or genes? New treatment for hereditary angioedema.

    11/1977 The Journal of the American Medical Association

    238(19):2009-2010

    Available online at: http://jama.jamanetwork.com/article.aspx?articleid=356438 (small fee)

    Participation of Hageman factor dependent pathways in human disease states

    Colman RW, Wong PY. 12/1977 Thrombosis & Haemostasis

    Dec 15;38(4):751-775.

    Abnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of C1 esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders. [References: 179].

    Not available online.

    Tranexamic acid: preoperative prophylactic therapy for patients with hereditary angioneurotic edema

    Sheffer AL, Fearon DT, Austen KF, Rosen FS. 7/1977 Journal of Allergy & Clinical Immunology

    Jul;60(1):38-40.

    Short-term therapy of 96-hr duration with tranexamic acid was prophylactically effective as defined by the absence of attacks of angioedema in 14 patients with hereditary angioedema undergoing 10 dental and 4 general surgical procedures. Eight of the 14 patients had previously undergone dental extractions without prophylactic therapy with antifibrinolytic agents and each had experienced one or more attacks of angioedema. Seven of these 8 patients had a cumulative experience of 13 episodes of laryngeal edema after dental extractions and the eighth had a bout of cutaneous angioedema. Although the number of dental extractions conducted without prophylactic antifibrinolytic therapy cannot be accurately defined in retrospect, the prominence of laryngeal edema in this circumstance is striking when compared with the absence of attacks in the presence of prophylaxis with tranexamic acid. Methyltestosterone and impeded androgens are now known to be effective prophylaxis for spontaneous and, presumably, postoperative attacks when employed chronically because their administration is associated with correction of the biochemical defect of hereditary angioneurotic edema, but their chronic administration to children and women of childbearing age requires further definition because of their potential pituitary suppressive action. Tranexamic acid prophylaxis makes it possible to offer to untreated patients with hereditary angioneurotic edema dental work and other operative procedures that in the past were withheld or conducted with considerable risk.

    Available online at: www.jacionline.org/article/0091-6749(77)90080-X/

    Hepatic function and fibrinolysis in patients with hereditary angioedema undergoing long-term treatment with tranexamic acid

    Agostoni A, Marasini B, Cicardi M, Martignoni G, Uziel L, Pietrogrande M. 8/1978 Allergy

    33(4):216-221

    Prophylactic treatment with antifibrinolytic agents, epsilon-aminocaproic and tranexamic acid, reduces the incidence and severity of attacks in patients with hereditary angioedema. Long-term effectiveness or risk of antifibrinolytic agents has not been established. Sixteen patients needing continuous prophylaxis because of frequency and severity of attacks were treated with tranexamic acid. In four patients this treatment was ineffective and the drug was withdrawn after 2 months. A remission or reduction in the frequency or severity of attacks was observed in 12 patients treated for a period ranging from 8 to 34 months. Hepatic tests and blood fibrinolytic activity were not influenced by long-term oral treatment with tranexamic acid.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1978.tb01537.x/abstract (small fee)

    Plasma kinin activation in tranexamic acid treated patients with hereditary angioneurotic edema

    Laurberg G. 7/1978 Archives of Dermatological Research

    Jul 28;262(2):153-156

    Plasma kinin formation after in vitro activation of factor XII in the coagulation system was examined in 4 patients with hereditary angioneurotic edema. Compared to controls activationcurves showed a steeper increase and higher maximum levels. Administration of tranexamic acid to the patients resulted in partial normalisation of plasma kinin activation.

    Available online at: http://link.springer.com/article/10.1007%2FBF00455384 (small fee)

    Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the forth and second components of complement

    Pitts JS, Donaldson VH, Forristal J, Wyatt RJ. 10/1978 Journal of Laboratory & Clinical Medicine

    Oct;92(4):501-507

    Serum concentrations of antigenic and functional C1-INH increased in patients in whom remissions from attacks of HANE were induced with danazol. The levels of C4 were directly related to serum concentrations of C1-INH antigens up to a concentration of about half the C1-INH found in normal plasma; at this point, the C4 concentrations were in the normal range and no longer correlated well with C1-INH concentration. Serum C2 levels correlated less well with C1-INH concentration. In normal serum there was a poor correlation between C1-INH, C4, and C2 levels, suggesting that C1-INH is normally present in excess of the amount needed for normal C4 levels. The increments in serum C1-INH were related to the dose of danazol.

    Not available online.

    Specific functional and immunologic assay of plasma plasminogen in hereditary angioedema, in hereditary angioedema treated with tranexamic acid, and in normal subjects

    Spragg J. 2/1978 Journal of Immunology

    Feb;120(2):592-596

    Plasma plasminogen levels were determined by a specific esterolytic assay and a radial immunodiffusion assay, both of which were standardized on a weight basis by using highly purified plasminogen diluted in plasminogen-free plasma. In thirteen normal individuals the functional and antigenic levels were 275 +/- 61 microgram/ml and 285 +/- 61 microgram/ml, respectively (r = 0.95), whereas in 58 plasmas from individuals with hereditary angioedema the levels were 272 +/- 58 microgram/ml and 265 +/- 64 microgram/ml, respectively (r = 0.89). In two patients treated with tranexamic acid either acutely or chronically, both the functional and antigenic plasminogen levels were diminished.

    Available online at: http://www.jimmunol.org/content/120/2/592.full.pdf+html (small fee)

    The second component of complement (C2) as an index of hereditary angioneurotic edema

    Sobel AT, Moisy M, Belghiti D, Gabay Y, Lagrue G. 11/1978 J.Clin.Lab.Immunol.

    Nov;1(3):179-181

    Measurements of C2 hemolytic activity were performed in the sera of 13 patients with Hereditary Angioneurotic Edema. Prior to treatment, C2 values correlated with the severity of the disease in each patient. During androgen therapy with Danazol, C2 measurements reflected the clinical benefit of the drug more accurately than C4 levels, thus explaining the effectiveness of low drug doses. This study also suggests that breakdown products of C2 may play an essential role in the pathogenesis of the edema.

    Not available online.

    Treatment of hereditary angioedema

    Marasini B, Cicardi M, Martignoni GC, Agostoni A. 8/1978 Klinische Wochenschrift

    Aug 15;56(16):819-823

    The purpose of this study was to report the results of different treatments in 20 patients with hereditary angioedema. Effectiveness of tranexamic acid in preventing swellings was evaluated in 15 patients: in all but 3 subjects tranexamic acid was effective without serious side effects. 15 severe attacks of edema were managed with intravenous infusions of either kallikrein inhibitor (8 cases) or concentrate of C1 esterase inhibitor (7 cases). In only 1 case was the kallikrein inhibitor unsuccessful. C 1 esterase inhibitor concentrate proved highly effective in the treatment of acute attacks (the result was lacking in one patient because of too low dosage of the drug). No side effects were observed with both treatments, but improvement was more rapidly achieved with infusion of C1 esterase inhibitor. The serum levels of C4 and C1 esterase inhibitor and the activity of C 1 esterase inhibitor before and after long-term prophylaxis and acute attacks treatment were investigated.

    Available online at: http://link.springer.com/article/10.1007%2FBF01489716 (small fee)

    Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema

    Sheffer AL, Fearon DT, Austen KF. 10/1979 Journal of Allergy & Clinical Immunology

    Oct;64(4):275-280

    Daily therapy and alternate-day therapy with the attenuated androgen oxymetholone were compared in patients with hereditary angioedema (HAE). Fifteen of 16 patients who experienced at least monthly attacks of HAE without treatment were asymptomatic on administration of 5 mg oxymetholene daily. When 13 of the patients who had been maintained asymptomatically on 5 mg oxymetholone daily were advanced to a treatment schedule of 5 mg every other day, seven attacks occurred during a cummulative 50 mo of therapy. The adverse effects that occurred with daily oxymetholone therapy largely subsided when the patients received alternate-day therapy, while a significant mean rise in C4 protein and function occurred only on daily therapy. Statistically significant mean increases in serum levels of C1INH occurred with daily therapy and were maintained with alternate-day therapy. Clinical benefit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise C1INH to the lower limit of normal. The finding that alternate-day therapy diminished the side effects of the drug while affording a substantial reduction in the incidence and severity of attacks indicates the feasibility of this therapeutic approach.

    Available online at: www.jacionline.org/article/0091-6749(79)90144-1/

    Diagnosis and management of hereditary angioedema (HAE)

    Atkinson JP 6/1979 Annals of Allergy, Asthma & Immunology

    In summary, HAE is a dominantly inherited form of angioedema which is manifested by nonpainful, nonerythematous, nonpruritic and nonpitting swelling of the extremities, face, gastrointestinal and respiratory tracts unaccompanied by urticaria. These patients have deficient activity of the C1 INH and the laboratory diagnosis can be easily made by finding low C4 and C1 inh levels during an attack. Effective and specific therapy is now available that prevents the clinical syndrome and corrects the serologic hallmarks of the disease. [References: 21].

    42(6):348-352

    Not available online.

     

    Effect of sex hormones on the complement-related clinical disorder of hereditary angioedema

    Frank MM. 11/1979 Arthritis & Rheumatism

    Nov;22(11):1295-1299.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1002/art.1780221118/abstract (small fee)

    Hereditary angioneurotic edema

    Donaldson VH. 11/1979 Disease-A-Month

    Nov;26(2):1-37.

    Available online at: http://www.diseaseamonth.com/article/S0011-5029%2879%2980015-2/pdf (small fee)

    Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications.

    Gadek JE, Hosea SW, Gelfand JA, Frank MM. 7/1979 The Journal of Clinical Investigation

    Jul;64(1):280-286

    Hereditary angioedema (HAE), an auto-somal dominant disorder characterized by attacks of episodic edema is associated with decreased functional levels of the C1 esterase inhibitor. Approximately 85% of patients have lowered antigen levels of a normal inhibitor protein. 15% of patients have normal or elevated antigenic levels of functionless protein. We have examined the response to danazol therapy of patients with the variant HAE phenotypes possessing the abnormal protein in an effort to determine if these patients possess a normal structural C1 inhibitor allele. Four patients with a variant HAE phenotype were treated successfully with danazol. In two patients, distinguished by the presence of a functionless, albumin-bound, C1 inhibitor (phenotype 2), phenotypic analysis of the danazol response by bidirectional immunoelectrophoresis revealed the appearance of the normal C1 inhibitor gene product during danazol therapy. This relatively cathodal C1 inhibitor peak appears in conjunction with the development of nearly normal functional activity. All of the functional C1 inhibitory activity which appeared in the phenotype 2 treatment serum was associated with the electrophoretically normal inhibitor. This normal protein could be separated from the functionless inhibitor protein by immunoadsorption and molecular sieve chromatography. Danazol therapy of the two patients with an electrophoretically normal, functionless C1 inhibitor (phenotype 3) also resulted in a clinical remission associated with development of a significant increment in functional serum C1 inhibitory activity and C1 inhibitor protein. These findings demonstrate that these two HAE phenotypic variants are heterozygous for the normal serum C1 inhibitor, a finding which was not apparent before phenotypic analysis of this serum during danazol therapy. These data provide strong evidence for a basic similarity between the common form of HAE and its phenotypic variants. They also suggest that a structural gene lesion may result in the abnormalities of serum C1 inhibitor function and disease expression in all three of these HAE phenotypes.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC372115/

    The treatment of hereditary angio-oedema with low dose androgenic drugs [proceedings]

    Warin AP, Gatecliff M, Greaves MW, Warin RP, Williamson DM. 7/1979 British Journal of Dermatology

    Jul;101(Suppl 17):18-19.

    Not available online.

     

    Urticaria and angioedema. Common clinical problems.

    Hill JS. 4/1979 Postgrad.Med.

    Apr;65(4):83-86

    The cause of urticaria and angioedema often is difficult to ascertain. In most cases the conditions are transient, but a chronic idiopathic form does occur and may be intractable. Acute urticaria and angioedema usually result from an IgE-mediated mechanism; success in treatment depends on recognition of the underlying factor. Chronic urticaria may ultimately necessitate use of corticosteroids. Hereditary angioedema is easily differentiated from idiopathic angioedema by the family history and absence of pruritus.

    Not available online.

    Danazol therapy in hereditary angioedema

    Sweet LC, Jackson CE, Yanari SS, Yott JB 1/1980 Henry Ford Hospital Medical Journal

    1980;28(1):31-35

    Not available online.

    Danazole in the treatment of hereditary angioedema

    Hosea SW, Frank MM. 5/1980 Drugs

    May;19(5):370-372

    Danazol is an effective agent for the prophylaxis of the recurrent attacks of mucocutaneous and visceral swelling which occur in patients with hereditary angioedema (HAE). Danazol apparently increases the synthesis of the inhibitor of the first component of complement which is partially deficient in these heterozygous individuals. The efficacy of danazol in this condition appears to be limited only by the occurrence of adverse effects. [References: 6].

    Available online at: http://link.springer.com/article/10.2165%2F00003495-198019050-00007 (small fee)

    Hereditary angio-oedema: its pathogenesis and management

    Ballogh Z, Whaley K. 7/1980 Scottish Medical Journal

    Jul;25(3):187-195

    Hereditary angio-oedema is a genetically-determined disease. Usually the disease is due to a deficiency of C1-inhibitor or less commonly to the production of a functionally inactive molecule. The pathogenesis and clinical features of the disease are reviewed, and discussed in relation to the homeostatic role of C1 inhibitor. Finally the therapeutic approach to the disease is described and the scientific bases for the newer therapeutic discussed.

    Available online at: http://scm.sagepub.com/content/25/3/187.abstract (small fee)

    Hereditary angioneurotic edema and its correction with androgen therapy

    Rosen FS, Beyler A. 1/1980 Birth Defects: Original Article Series

    1980;16(1):499-507.

    Not available online.

    Long-term therapy of hereditary angioedema with danazol

    Hosea SW, Santaella ML, Brown EJ, Berger M, Katusha K, Frank MM. 12/1980 Annals of Internal Medicine

    Dec;93(6):809-812

    We treated 69 patients who had hereditary angioedema with danazol to alleviate attacks of mucocutaneous angioedema involving the skin, oropharynx, and gastrointestinal tract, and we documented the continued efficacy of danazol for long-term treatment (1 to 6 years) of hereditary angioedema. Significant dose-related, adverse reactions occurred, including weight gain, myalgias, headaches, microscopic hematuria, abnormal liver function tests, anxiety, altered libido, alopecia, dizziness, and nausea. Alterations in menstrual function were consistently observed. About 10% of patients noted masculinizing side effects, such as acne, hirsutism, and voice deepening. We recommend downward titration of danazol dosage to achieve control of attacks and minimize adverse reactions. Periodic monitoring of patients on long-term danazol therapy is essential to avoid undesirable toxicity.

    Available online at: http://annals.org/article.aspx?articleid=694440 (small fee)

    The use and misuse of androgens

    Wilson JD, Griffin JE 12/1980 Metabolism: Clinical & Experimental

    Because testosterone is rapidly metabolized by the liver, it is necessary either to administer androgens by injection in the form of testosterone esters that are absorbed slowly into the circulation or to administer by mouth derivatives that are slowly metabolized by the liver. The later derivatives, however, have deleterious side effects that limit their usefulness. Long-acting parenteral androgen esters are the treatment of choice in the replacement therapy of male hypogonadism. Because these esters must be hydrolyzed to the free hormone prior to exerting their cellular actions the effectiveness of therapy can be monitored by following plasma testosterone levels. All known effects of the endogenous hormone can be duplicated except for the induction and maintenance of normal spermatogenesis. Androgens have been tried in a variety of clinical situations other than male hypogonadism in the hopes that the nonvirilizing actions would outweigh any detectable side effects. The only disorders in which a salutary effect has been documented are hereditary angioneurotic edema and some patients with anemia due to failure off the bone marrow. [References: 224].

    Dec;29(12):1278-1295

    Available online at: http://www.sciencedirect.com/science/article/pii/0026049580901596 (small fee)

    Treatment of acute attacks of hereditary angioedema with C1-inhibitor concentrate

    Agostoni A, Bergamaschini L, Martignoni G, Cicardi M, Marasini B. 5/1980 Annals of Allergy, Asthma & Immunology

    May;44(5):299-301

    Attacks of laryngeal edema in patients with hereditary angioedema (HAE) have been successfully treated with the infusion of C1-inhibitor (C1-INH) concentrate. No side effects were observed.

    Not available online.

    treatment of hereditary angio-oedema by low dose attenuated androgens: disassociation of clinical response from levels of C1 esterase inhibitor and C4

    Warin AP, Greaves MW, Gatecliff M, Williamson DM, Warin RP 10/1980 British Journal of Dermatology

    Nine patients with hereditary angio-oedema (H.A.E.) with a deficiency of C1 esterase inhibitor (C1 INH), have been treated with low dose attenuated androgenic drugs, with complete control of their disease. The C1 esterase inhibitor and C4 levels became normal in only one patient. It is concluded that H.A.E. can be controlled in the absence of correction of the reduced levels of C1 INH and C4. The mode of action of these drugs appears to be more complex than is generally realized.

    Oct;103(4):405-409

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.1980.tb07263.x/abstract;jsessionid=DFB26512DE1D68FF737BF433A7477538.f02t02 (small fee)

    Treatment of hereditary angioneurotic oedema with Danazol

    van Royen EA, Hannema A, Cormane RH, Pondman KW 1/1980 The Netherlands Journal of Medicine (MJM)

    1980;23(5):185-190

    Not available online.

    Clinical and biochemical effects of stanozolol therapy for hereditary angioedema

    Sheffer AL, Fearon DT, Austen KF 9/1981 Journal of Allergy & Clinical Immunology

    Stanozolol, an inexpensive anabolic steroid with a 30:1 anabolic:androgenic ratio, was administered to 12 male and 15 female patients with biochemically proven hereditary angioedema over a 2-yr period to obtain a systematic assessment of the relationship between drug dosage and clinical response, incidence of side effects, and amelioration of complement abnormalities. All 27 patients attained the minimal effective dose, ranging from 0.5 to 2 mg daily, which controlled the frequency and intensity of symptoms with minimal side effects. At daily maintenance doses of 2, 1, and 0.5 mg the frequencies of attacks per weeks of therapy were 1/14.6, 1/7.2, and 1/8.2 wk, respectively. Side effects with maintenance therapy included menstrual abnormalities and virilization in four females and elevation of serum creatinine phosphokinase (CPK) in five males. In six patients on maintenance doses of stanozolol, serum levels of testosterone, free thyroxin (T4), and thyroxin binding globulin (TBG) (four males), and of estradiol, progesterone, T4, and TBG (two females) were normal. Slightly low serum levels of progesterone and TBG were found in two females who had normal menstrual cycles. Statistically significant elevations above pretherapy levels of serum inhibitor to the activated first component of complement function and C4 protein and function occurred when patients were on maintenance therapy, but these measurements remained below the lower limit of normal range. Higher doses of stanozolol (4 mg/day), which caused greater immunochemical responses, were unnecessary for control of clinical disease and were unjustified for chronic therapy because of more frequent side effects.

    Sep;68(3):181-187

    Available online at: http://www.jacionline.org/article/0091-6749%2881%2990181-0/abstract

    Danazol and other androgens for hereditary angioedema

    9/1981 Medical Letter on Drugs & Therapeutics

    Sep 18;23(19):83-84.

    Not available online.

    Hormone binding globulin levels in patients with hereditary angiooedema during treatment with Danazol

    Schwarz S, Tappeiner G, Hintner H. 06/1981 Clinical Endocrinology (Oxf)

    Five patients with hereditary angiooedema were treated with Danazol for periods up to 10 months. This therapy resulted in normalization of serum levels of the inhibitor of the first complement component and disappearance of clinical disease symptoms in all patients. Although a variety of hormones were measured, only those of the pituitary-gonadal axis altered during treatment: a moderate decrease in leuteinizing hormone levels and a sharp fall of testosterone in adult men were observed. In all patients, however, both sex hormone binding globulin and thyroxine binding globulin concentrations were considerably suppressed during Danazol therapy. However, levels of corticosterone binding globulin and thyroxine binding globulin concentrations were considerably suppressed during Danazol therapy. However, levels of corticosterone binding globulin remained unchanged. The fraction of endogenous testosterone not bound to sex hormone binding globulin invariably increased. The possible relevance of these findings to the understanding of the mode of action of Danazol both in these patients and in general, are discussed.

    1981 Jun;14(6):563-570

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.1981.tb02966.x/pdf (small fee)

     Acute upper airway obstruction in the adult. 1. Causative disease processes.

    Boster SR, Martinez SA. 12/1982 Postgrad.Med.

    1982 55-7; Dec;72(6):50-52

    Infectious processes that can cause acute upper airway obstruction in adults include Ludwig’s angina, retropharyngeal infection, acute epiglottis, diphtheria, tetanus, and peritonsillar abscess. They are uncommon but potentially lethal. Ludwig’s angina in particular quickly progresses to airway obstruction. In most cases, the mainstays of management are antibiotics, surgical drainage, and if necessary, airway maintenance by tracheostomy, cricothyrotomy, or nasotracheal or endotracheal intubation. Hereditary angioneurotic edema causes episodes of laryngeal edema that may lead to suffocation. In an acute episode the airway must be maintained by endotracheal intubation.

    Not available online.

     Hereditary angioedema: an appraisal of 104 cases

    Cicardi M, Bergamaschini L, Marasini B, Boccassini G, Tucci A, Agostoni A. 7/1982 American Journal of the Medical Sciences

    Jul-Aug;284(1):2-9

    One hundred and four patients affected by hereditary angioedema belonging to 31 families have been studied. Twenty-two percent had the variant form related to the deficiency of the functional activity of serum C1 esterase inhibitor. The remaining 78% of patients had the predominant form, characterized by low antigenic levels and low functional activity of serum C1 esterase inhibitor. Attacks of swelling affected the subcutaneous tissue in 86% of patients; the upper airways in 76% of patients, and the bowel mucose in 75% of patients. Before treatment was available the mortality rate was 56%. One or more attacks a month were present in 46% of cases. The infusion of C1 inhibitor concentrate promptly reversed 14 severe attacks without any side effect. Twenty-nine patients were given long term prophylactic treatment with androgen derivatives with full success. Tranexamic acid reduced the frequency of swelling of 70% of the patients.

    Available online at: http://journals.lww.com/amjmedsci/Abstract/1982/07000/Hereditary_Angioedema__An_Appraisal_of_104_Cases_.1.aspx (small fee)

    Effect of treatment with 17 alpha-alkylated androgens on C4 conversion products in hereditary angioedema studied by crossed immunoelectrophoresis

    Bergamaschini L, Cicardi M, Tucci A, Agostoni A. 7/1982 Journal of Clinical Pathology

    Jul;35(7):728-731

    During agarose electrophoresis C4 in the normal human serum is converted into cleavage products of Beta 1 and Beta 2 mobility. By contrast in the serum of untreated patients with hereditary angiodema C4 gives only one Beta 2 peak on crossed immunoelectrophoresis. The normal C4 electrophoretic pattern is restored in serum of patients treated with stanazolol but not with danazol despite the same C1-esterase inhibitor (C1 INH) activities and C4 serum concentration. We suggest that stanazolol besides having specific effect on C1 INH activity can interfere with other protease inhibitors affecting C1 activation.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC497765/

     

    Hereditary angioneurotic edema and HLA types in two Danish families

    Eggert J, Zachariae H, Svejgaard E, Svejgaard A, Kissmeyer-Nielsen F. 7/1982 Archives of Dermatological Research

    July;273(3-4):347-348

    HLA types were determined in 19 patients and 9 healthy members of 2 Danish families with hereditary angioneurotic edema. The study revealed no connections between hereditary angioneurotic edema and the HLA system.

    Available online at: http://link.springer.com/article/10.1007%2FBF00409265 (small fee)

    The C1 esterase inhibitor and hereditary angioedema

    Frank MM. 4/1982 Journal of Clinical Immunology

    Apr;2(2):65-68.

    Available online at: http://link.springer.com/article/10.1007/BF00916888 (small fee)

     Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives

    Cicardi M, Bergamaschini L, Tucci A, Agostoni A, Tornaghi G, Coggi G, et al. 9/1983 Journal of Allergy & Clinical Immunology

    Sep;72(3):294-298

    17 alpha-Alkylated androgens are highly effective in preventing attacks in HAE patients. These drugs, however, seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumors. In order to assess the risk-benefit balance of the long-term therapy with androgen derivatives, a follow-up investigation was performed in 13 HAE patients. The results of this study indicate that long-term treatment (15 to 47 mo) with low doses of danazol or stanozolol does not induce significant hepatic damage detectable by laboratory tests or liver biopsy. However, the limited number of patients, although in a rather long period of observation, still suggests a careful control and the use of minimal effective doses.

    Available online at: http://www.jacionline.org/article/0091-6749%2883%2990034-9/abstract

    C1 INH concentrate in the therapy of hereditary angioedema

    Bergamaschini L, Cicardi M, Tucci A, Gardinali M, Frangi D, Valle C, et al. 2/1983 Allergy

    Feb;38(2):81-84.

    Ten acute attacks were managed in nine patients with hereditary angioedema by means of the infusion of a C1 INH concentrate produced on large scale. No side effects were observed.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1983.tb01590.x/abstract (small fee)

    Effect of dehydroepiandrosterone on hereditary angioedema

    Koo E, Feher KG, Feher T, Fust G. 7/1983 Klinische Wochenschrift

    Jul 15;61(14):715-717

    Hereditary angioneurotic edema (HAE) is a complement-related clinical disorder with a deficiency of the C1 esterase inhibitor protein. Eight patients with severe attacks of the disease were treated with the adrenal “androgen” dehydroepiandrosterone sulphate (DS). Steroid therapy for 3-28 months resulted in dramatic improvement in their clinical state and a moderate increase in the serum concentration of C1 inhibitor. There was a significant increase in the serum level of either unconjugated dehydroepiandrosterone (D) or of DS during treatment.

    Available online at: http://link.springer.com/article/10.1007%2FBF01487618 (small fee)

    Epsilon-amino-caproic acid in the treatment of Osler’s hereditary angioneurotic edema

    Fernandez M, Dieguez I, Neffen H, Oehling A. 1/1983 The Journal of Clinical Investigation

    Jan-Feb;11(1):19-23

    This clinical entity described for the first time by Osler in 1888 presented a great therapeutic problem during many decades because of its severity. Landerman and later on Donaldson and Evans established the pathogenic mechanisms of this disease finding a deficiency in the inhibitor of the first activated component of complement, an alpha 2 aminoglycoprotein, to be the mechanism responsible of the same. More concretely, alterations in the plasmin, kinin and kallikrein systems are those that will lead to a change in vascular permeability with resultant tissue alterations. Four cases of hereditary angioneurotic edema are studied in female patients aged between 15 and 50 years and with family history consistent with angioneurotic familiar edema in which there were six cases of death due to edema of the glottis. Once the diagnosis had been made the patients were subjected to treatment with EACA at doses of 2.5 gm every 6 hours. The determinations of complement were similar in the four cases, with marked decreases in C4 and C1 inhibitor with a decrease in total complement in three cases. Regarding secondary effects, vomiting was found only in one cases, which as the dose was reduced did not necessitate termination of treatment. In summary, considering the results obtained in the cases above, we believe that due to its good tolerance and moderate cost, epsilon-amino-caproic acid at the abovementioned dosage is an excellent pharmacological agent in the treatment of Osler’s hereditary angioneurotic edema.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423402/

    Hereditary angioedema

    Berman BA, Ross RN. 2/1983 Cutis

    Feb;31(2):124.

    Not Available online.

    Hereditary angioedema

    Brickman CM, Hosea SW. 4/1983 International Journal of Dermatology

    Apr;22(3):141-147.

    Available online at:http://onlinelibrary.wiley.com/doi/10.1111/j.1365-4362.1983.tb03351.x/abstract (small fee)

    Immunodiffusion assay of C1 inhibitor function in serum: prospective analysis in angioedema-urticaria

    Yelvington M, Prograis LJ Jr, Pizzo CJ, Curd JG 9/1983 American Journal of Clinical Pathology

    An immunodiffusion assay for detecting C1 inhibitor function in human serum was described recently by Ziccardi and Cooper. In our present study, the applicability of this assay for C1 inhibitor deficiency or C1 inhibitor dysfunction was evaluated. Of the 39 patients evaluated, all eight patients with the common (C1 inhibitor deficiency) form of hereditary angioedema and all three patients with the variant (dysfunctional C1 inhibitor) form of hereditary angioedema were identified correctly. Treatment of patients with hereditary angioedema with stanozolol or danocrine increased their serum C1 inhibitor concentrations and normalized the immunodiffusion assay for C1 inhibitor function. In addition, the assay allowed the correct identification of three patients with the acquired form of C1 inhibitor deficiency, because the sera of these patients exhibited a distinctive pattern. The 25 samples from patients (chronic angioedema, chronic urticaria, or hypocomplementemic vasculitis) without C1 inhibitor deficiency had normal assays.

    Sep;80(3):309-313

    Not available online.

    The management of hereditary angioedema

    Agostoni A. 1/1983 Ricerca in Clinica e in Laboratorio

    Jan-Mar;13(1):55-59.

    Our experience in managing 120 cases of hereditary angioedema is reported. Forty-two severe episodes of mucous or subcutaneous edema were successfully managed using CI-INH concentrate. A prophylactic treatment was done with two classes of drugs: antifibrinolytic agents (tranexamic acid) and 17α-alkylated androgen derivatives.

    Available online at: http://link.springer.com/article/10.1007%2FBF02904745 (small fee)

    C1 inhibitor functional activities in hereditary angioedema plasma of patients under therapy with attenuated androgens

    Spath PJ, Wuthrich B, Butler R 1/1984 Dermatologica

    The effects of therapy with danazol or stanozolol on complement component C4 and on C1 inhibitor concentrations and functions in 6 patients suffering from the common form of hereditary angioedema are described. Whereas the mean C4 concentration was found within the normal range, the therapy with attenuated androgens resulted in a subnormal mean of C1 inhibitor concentration, but an almost normal mean of functional activity.

    169(5):301-304

    Available online at: https://www.karger.com/Article/Pdf/249616 (small fee)

    Cold enhancement of blood coagulation: observations on the role of C1(-)-inhibitor

    Donaldson VH. 1/1984 Acta Pathologica, Microbiologica, et Immunologica Scandinavica

    Supplement ;284:41-47

    The effect of incubation at 4 degrees C upon the one stage prothrombin times and the Thrombotest times of plasma from normal people, females taking oral contraceptive agents (O.C.A.’s) or in the third trimester of pregnancy, and patients with hereditary angioneurotic edema (H.A.N.E.) was measured to determine if enhancement of coagulant activity was regularly associated with reduced amounts of C1(-)- inhibitor (C1(-)-INH) in the plasma. Cold-enhanced coagulant activity was not always found in H.A.N.E. plasmas, markedly deficient in C1(-)- INH, and when found, the addition of purified C1(-)-INH to the plasma did not always prevent its development in vitro. Females taking O.C.A.’s regularly demonstrated cold-enhanced plasma coagulant activity in this series, as did pregnant females tested, as reported by others. The relation of C1(-)-INH levels in plasma to the cold-enhanced plasma coagulant activity was imperfect. In plasma obtained during pregnancy, but not exposed to 4 degrees C, C1(-)-INH levels were low despite minimal shortening of the Thrombotest time. Thus, these observations suggest that reduced levels of C1(-)-INH in plasma was not directly related to the tendency to generate enhanced coagulant activity at 4 degrees C. Other factors must be critical to the development of this activity, and the failure to block its development in C1(-)-INH deficient plasmas by adding purified C1(-)-INH at venesection suggests that events which initiate the development of this property may have occurred in vivo.

    Not available online.

    Inhibition of the complement activation by an adrenal androgen, dehydroepiandrosterone

    Hidvegi T, Feher GK, Feher T, Koo E, Fust G. 1/1984 Complement

    ;1(4):201-206

    The effect of dehydroepiandrosterone (DEA), an adrenal androgen successfully used for preventing attacks in hereditary angioneurotic edema (HANE) patients was studied on the activation of classical and alternative complement pathway. The steroid inhibited both the spontaneous and immune activation of the classical complement pathway (CP), the former effect, however, was found to be more marked than the latter one. DEA exerted its inhibiting effect most probably by interfering with the internal activation of C1. Because DEA rendered HANE patients symptom free but induced only a slight increase in their serum C1-INH level, our present findings suggest that inhibition of CP activation may have a significance in the therapeutic effect of DEA and possibly of other androgens as well.

    Not available online.

    Interaction between C1-INA, coagulation, fibrinolysis and kinin system in hereditary angioneurotic edema (HANE) and urticaria

    Bork K, Witzke G, Artmann K, Benes P, Bockers M, Kreuz W. 9/1984 Archives of Dermatological Research

    Sept;276(6):375-380.

    The C1-inactivator plays an important rol.e not only in the initial phases of the complement system, but also in those of the coagulation, fibrinolysis and kinin systems. The present study was concerned with the reciprocal influence of decreased C1-inactivator levels in patients with hereditary angioneurotic edema (HANE, HAE). In 13 HANE-I patients there were significantly increased levels of the coagulation factors XII, XI, V, of plasminogen and of alpha 2-antiplasmin, while the factors IX and VII were decreased. Conversely, it emerged that in patients with markedly raised prephase factor levels, angioneurotic edema occurred in the presence of normal or only slightly decreased C1-inactivator levels. However, the ratio between factor XI and C1-INA activity was significantly higher than in normal and urticaria patients. Factor XII, HMWK, XI, VIII and V levels were significantly raised in 10 patients with frank chronic urticaria, while factor VII was lowered. Numerous other factors and inhibitors of the coagulation, fibrinolysis and kinin systems were, however, normal or showed no significant differences.

    Available online at: http://link.springer.com/article/10.1007/BF00413358 (small fee)

    Studies of four Japanese families with hereditary angioneurotic edema: simultaneous activation of plasma protease systems and exogenous triggering stimuli

    Kodama J, Uchida K, Yoshimura S, Katayama Y, Kushiro H, Yutani C, et al. 11/1984 Blut

    Nov;49(5):405-418

    Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C 1-inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme.

    Available online at: http://link.springer.com/article/10.1007%2FBF00319889 (small fee)

    The catabolism of C1(-)-inhibitor and the pathogenesis of hereditary angio-edema

    Lachmann PJ, Rosen FS. 1/1984 Acta Pathologica, Microbiologica, et Immunologica Scandinavica

    Supplement 1984;284:35-39

    A sufficient explanation for the observations that HAE is a dominantly transmitted disease and that the hemizygotes have levels of the normal protein of only in the region of 15%-20% of normal can be given by proposing that a substantial proportion of the catabolism of C1(-)-esterase inhibitor involves the prior formation of a complex with one of the enzymes with which the inhibitor reacts. This part of the catabolism will be largely independent of inhibitor concentration, i.e. of zero order, and for this reason occurs similarly in normals and in hemizygotes. Estimates of the extent of this zero order metabolism can be obtained from turnover data with normal and dysfunctional C1(-)-inhibitor and the results are consistent with the observed levels. In the form of the disease associated with the dysfunction protein the dysfunctional protein makes up more than 85% of the total protein found for the same reason. The extent of the enzyme inhibitor complex dependent catabolism (RO) can be determined in vivo by simultaneous turnovers of dysfunctional and normal inhibitor and gives a measure of the extent of activation of this group of enzymes. The value of this technique in clinical practice is described elsewhere.

    Not available online.

     Non-hereditary angioedema treated with tranexamic acid. A 6-month placebo controlled trial with follow-up 4 years later.

    Munch EP, Weeke B. 2/1985 Allergy

    Feb;40(2):92-97

    Ten patients with frequent attacks of non-hereditary angioedema were treated with tranexamic acid or placebo in a double blind manner, each period lasting 3 months. During the tranexamic acid period nine patients became symptom-free, or substantially improved, while one was unaffected (P less than 0.05). In four patients itching was a major accompanying complaint which was relieved in three. Diarrhoea and abdominal discomfort were more pronounced during tranexamic acid treatment (P less than 0.05), but only necessitated dose reduction in one patient. Four years later contact was obtained with eight of the nine responders and six were still taking tranexamic acid regularly, while in two patients the attacks were so infrequent that the drug was not taken regularly.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1985.tb02666.x/abstract (small fee)

    Angioedema

    Farnam J, Grant JA. 1/1985 Dermatol.Clin.

    Jan;3(1):85-95

    Angioedema is characterized by a well-demarcated swelling on the skin, oropharyngolaryngeal tissue, or the gastrointestinal wall. Underlying mechanisms may include IgE-mediated reactions, complement activation, inhibition of the cyclo-oxygenase pathway of arachidonic acid metabolism, direct release of mediators from mast cells, and activation of the kinin-forming system. Foods, drugs, inhalants, insect bites, blood transfusion, collagen vascular disease, infections, physical factors, neoplasms, and hereditary factors can cause angioedema through one or more of these mechanisms. Chronic angioedema lasts more than 6 weeks or recurs during this period. Acute angioedema is a self-limited disorder and resolves spontaneously, or with simple therapy, in several days; the patient rarely requires a complete work-up. Chronic angioedema may necessitate a detailed history, physical examination, and limited clinical or laboratory tests to exclude serious underlying illnesses. The H1 antihistamines are used for the treatment of both acute and chronic angioedema. An H2 antihistamine, a second H1 antihistamine, or rarely even a low dose of corticosteroid may be added to the regimen if H1 antihistamine alone fails to control chronic angioedema. Hereditary angioedema is an autosomal dominant disease that is caused by C1INH deficiency. In patients with this disorder, swelling of the lip, pharynx, and extremities may follow trauma to soft tissue. Other clinical manifestations include abdominal pain, nausea, vomiting, and suffocation because of laryngeal swelling. Diagnosis can be confirmed by the finding of low levels of C4 and C2 and the absence of nonfunction of C1INH. Androgens reverse the biochemical defects.

    Not available online.

    Hereditary angioedema. The swelling disorder.

    Huber MM, Calliari D. 10/1985 American Journal of Nursing

    Oct;85(10):1090-1092.

    Not available online.

    Mechanical trauma and urticaria

    Black AK. 8/1985 American Journal of Industrial Medicine

    8(4-5):297-303

    Urticarial responses in skin may be elicited in different ways, viz, stroking (dermographism), after sustained pressure (delayed pressure urticaria), and after vibration (vibratory angio-oedema). Pressure may localise lesions of chronic idiopathic urticaria. Trauma may exacerbate hereditary angio-oedema. The extent of the morbidity caused by trauma-induced urticaria among workers is unknown.

    Available online at: http://onlinelibrary.wiley.com/doi/10.1002/ajim.4700080408/abstract  (small fee)

    Urticaria

    Synkowski DR 11/1985 Emergency Medicine Clinics of North America

    Urticaria/angioedema is very common and usually not very serious. The main diagnostic task is the history, asking about pharmaceutical agents, foods, focuses of infection, physical agents, and psychogenic factors as well as inhalants, insect bites, internal diseases, immune complex diseases, contactants, and genetic factors. The main therapeutic tool is to eliminate the offending agent. If this cannot be done, therapy should begin with an H1 antihistamine pushed to tolerance or clearing. Life-threatening laryngeal edema and/or anaphylactic shock are extremely rare. Laryngeal edema is usually a component of hereditary angioedema. In such cases, subcutaneous epinephrine is the drug of choice. Laboratory investigation in chronic urticaria should include CBC, erythrocyte sedimentation rate, and a serum multiphasic analysis. A myriad of laboratory tests can be done in chronic urticaria, but some cost-yield effective ones are a test for antinuclear antibodies and x-rays of the sinuses and dentition.

    Nov;3(4):737-745

    Not available online.

    Variability in purified dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies.

    Donaldson VH, Harrison RA, Rosen FS, Bing DH, Kindness G, Canar J, et al. 1/1985 The Journal of Clinical Investigation

    Jan;75(1):124-132

    C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin. Each dysfunctional C1(-)-INH protein showed a unique spectrum of inhibitory activity against these enzymes. Although none of the dysfunctional C1(-)-INH proteins significantly impaired amidolysis by plasmin, all but one inhibited activated Hageman factor. One purified dysfunctional C1(-)-INH (Ta) inhibited purified C1s- to a normal degree. Another C1(-)-INH (Za) had almost seven times as much inhibitory activity as normal C1(-)-INH against activated Hageman factor, but had decreased activity against C1s- and no activity against plasmin. Analyses of mixtures of plasmin and C1(-)-INH proteins in SDS gel electrophoresis revealed variability in the patterns of complex formation and cleavage of dysfunctional proteins after exposure to C1s- and plasmin. Some bound to plasmin and were cleaved, even though none significantly impaired the amidolytic activity of plasmin. Two were cleaved by C1s-, whereas neither normal or other dysfunctional C1(-)-INH were cleaved. Dysfunctional C1(-)-INH proteins from patients with HANE are thus heterogeneous in their inhibitory properties and there must be different structural requirements for the inhibition of the various plasma enzymes that can be regulated by normal C1(-)-INH. The data suggest that in addition to common sites of interactions between these proteases and C1(-)-INH, there are also points of contact that are specific for each protease. Genetic mutations leading to structural changes at some of these sites may have differing effects on the interaction between individual proteases and abnormal C1(-)-INH proteins. These alterations may allow these proteins to serve as probes for structural requirements for inhibitory actions of normal C1(-)-INH.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423417/

    Verstraete M. Clinical application of inhibitors of fibrinolysis

    3/1985 Drugs

    The basic proteinase inhibitor from bovine organs, aprotinin, was first identified in 1930 and its effect on enzyme and other biological systems has since been extensively studied. Aprotinin can only be administered intravenously and has a half-life of about 2 hours. Its administration at the start of cardiopulmonary bypass surgery appears to reduce blood loss and to protect against global myocardial ischaemia. Similarly, a smaller infarct size seems to result from early administration of aprotinin within the first hour after myocardial infarction, though further studies are needed to confirm this effect. A combination of aprotinin with tranexamic acid may be effective in preventing or delaying rebleeding after rupture of an intracerebral aneurysm; the addition of aprotinin seems to decrease the incidence of delayed cerebral vasospasm and ischaemic complications which are sometimes noted when tranexamic acid alone is used. Aprotinin is also effective as adjuvant treatment in traumatic haemorrhagic shock. The recommended loading dose is 15,000 to 20,000 KIU/kg bodyweight administered as a short intravenous infusion, followed by 50,000 KIU/hour by continuous infusion. Side effects of aprotinin are very rare. Epsilon-Aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and tranexamic acid are synthetic antifibrinolytic amino acids. Saturation of the lysine binding sites of plasminogen with these inhibitors displaces plasminogen from the fibrin surface. On a molar basis tranexamic acid is at least 7 times more potent that epsilon-aminocaproic acid and twice as potent as p-aminomethylbenzoic acid. All 3 compounds are readily absorbed from the gastrointestinal tract and excreted in active form in the urine. The plasma half-life of tranexamic acid is about 80 minutes. The main indications for tranexamic acid are the prevention of excessive bleeding after tonsillectomy, prostatic surgery, and cervical conisation, and primary and IUD-induced menorrhagia. It is possible that gastric and intestinal bleeding can also be reduced as well as recurrent epistaxis. Tranexamic acid could also be useful after ocular trauma. The value of fibrinolysis inhibitors in the prevention of bleeding after tooth extraction in patients with haemophilia is well documented, as is the treatment of hereditary angioneurotic oedema. The usual dose of tranexamic acid is 0.5 to 1g (10 to 15 mg/kg bodyweight) given intravenously 2 to 3 times daily, or 1 to 1.5 g orally 3 to 4 times daily. This dose needs to be reduced in patients with renal insufficiency. The main side effects of tranexamic acid are nausea or diarrhoea. [References: 223].

    Mar;29(3):236-261

    Available online at: http://link.springer.com/article/10.2165%2F00003495-198529030-00003 (small fee)

    Alpha-1-antitrypsin-Pittsburgh. A potent inhibitor of human plasma factor XIa, kallikrein, and factor XIIf

    Scott CF, Carrell RW, Glaser CB, Kueppers F, Lewis JH, Colman RW 2/1986 The Journal of Clinical Investigation

    Alpha-1-antitrypsin-Pittsburgh is a human variant that resulted from a point mutation in the plasma protease inhibitor, alpha 1-antitrypsin (358 Met—-Arg). This defect in the alpha 1-antitrypsin molecule causes it to have greatly diminished anti-elastase activity but markedly increased antithrombin activity. In this report, we demonstrate that this variant protein also has greatly increased inhibitory activity towards the arginine-specific enzymes of the contact system of plasma proteolysis (Factor XIa, kallikrein, and Factor XIIf), in contrast to normal alpha 1-antitrypsin, which has modest to no inhibitory activity towards these enzymes. We determined the second-order-inactivation rate constant (k”) of purified, human Factor XIa by purified alpha 1-antitrypsin-Pittsburgh and found it to be 5.1 X 10(5) M-1 s-1 (23 degrees C), which is a 7,700-fold increase over the k” for Factor XIa by its major inhibitor, normal purified alpha 1-antitrypsin (i.e., 6.6 X 10(1) M-1 s-1). Human plasma kallikrein, which is poorly inhibited by alpha 1-antitrypsin (k” = 4.2 M-1 s-1), exhibited a k” for alpha 1-antitrypsin-Pittsburgh of 8.9 X 10(4) M-1 s-1 (a 21,000-fold increase), making it a more efficient inhibitor than either of the naturally occurring major inhibitors of kallikrein (C-1-inhibitor and alpha 2-macroglobulin). Factor XIIf, which is not inhibited by normal alpha 1-antitrypsin, displayed a k” for alpha 1-antitrypsin-Pittsburgh of 2.5 X 10(4) M-1 s-1. This enhanced inhibitory activity is similar to the effect of alpha 1-antitrypsin-Pittsburgh that has been reported for thrombin. In addition to its potential as an anticoagulant, this recently cloned protein may prove to be clinically valuable in the management of septic shock, hereditary angioedema, or other syndromes involving activation of the surface-mediated plasma proteolytic system.

    Feb;77(2):631-634

    Available online at: http://www.jci.org/articles/view/112346

    Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema

    Andriole GL, Brickman C, Lack EE, Sesterhenn IA, Javadpour N, Linehan WM, et al. 1/1986 The Journal of Urology

    Jan;135(1):44-46

    From 1975 through 1983, 69 patients with hereditary angioneurotic edema were treated with danazol, a semisynthetic anabolic steroid. Hematuria developed in 13 of these patients (19 per cent). Careful evaluation of the genitourinary tract showed the presence of a distinct form of hemorrhagic cystitis in 10 patients. Clinically, 9 patients presented with microscopic and 1 with intermittent gross hematuria. Irritative bladder symptoms were reported by 2 patients. Neither the dose nor duration of danazol therapy correlated with the severity of the cystoscopic or pathological findings. Cystoscopically, a rather nonspecific pattern of erythema, submucosal telangiectasia and neovascularity was observed. Histopathologically, bladder biopsy typically showed numerous dilated submucosal vessels with hemorrhage, mucosal ulceration and occasional inflammatory cells. These changes regressed in all but 1 patient when danazol therapy was discontinued. Further studies are needed to elucidate the role of danazol itself or of the danazol-hereditary angioneurotic edema interaction in the pathogenesis of these abnormalities.

    Not available online.

    Immunoreactive precipitation of C1 inhibitor protein from plasma of normal subjects and of patients with hereditary angioedema after isoelectric focusing

    Bergamaschini L, Valle C, Franzinelli M, Cicardi M, Agostoni A. 10/1986 Journal of Clinical Chemistry & Clinical Biochemistry

    Oct;24(10):719-722

    C1-inhibitor is an acid glycoprotein, isoelectric point 3.5-3.6. Plasma of some patients with a variant form of hereditary angioedema contains high levels of functionless C1-inhibitor-albumin complex with an isoelectric point at 4.5-4.6. Therapy with Danazol, which increases C1-inhibitor levels, does not modify the isoelectric focusing pattern of such protein in patients with hereditary angioedema.

    Available online at: http://www.researchgate.net/publication/19379027_Immunoreactive_Precipitation_of_C1_Inhibitor_Protein_from_Plasma_of_Normal_Subjects_and_of_Patients_with_Hereditary_Angioedema_after_Isoelectric_Focusing

    Recombinant alpha 1-antitrypsin Pittsburgh (Met 358—-Arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment.

    Schapira M, Ramus MA, Jallat S, Carvallo D, Courtney M. 2/1986 Journal of Clinical Investigations

    Feb;77(2):635-637

    In normal plasma, the serine protease inhibitor alpha 1-antitrypsin (alpha 1-AT) plays little or no role in the control of plasma kallikrein or activated Factor XII fragment (Factor XIIf), this function being performed by Cl-inhibitor. Recently, an alpha 1-AT variant was described with a Met—-Arg mutation at the reactive center P1 residue (position 358) which altered the specificity of inhibition from the Met- or Val-specific protease neutrophil elastase to thrombin, an Arg-specific protease. We have now examined the inhibition of plasma kallikrein and Factor XIIf, both Arg-specific enzymes, with recombinant alpha 1-AT(Met358—-Arg) produced by an Escherichia coli strain carrying a mutated human alpha 1-AT gene. The engineered protein was a very efficient inhibitor of both enzymes. It was more effective than Cl-inhibitor by a factor of 4.1 for kallikrein and 11.5 for Factor XIIf. These results suggest that recombinant alpha 1-AT(Met358—-Arg) has therapeutic potential for disease states where activation of the plasma kinin-forming system is observed, for example in hereditary angioedema or septic shock.

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423402/

    The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency

    Melamed J, Alper CA, Cicardi M, Rosen FS. 2/1986 Journal of Allergy & Clinical Immunology

    Feb;77(2):322-326

    The metabolism of 125I-labeled C1 inhibitor (C1INH) and C1q was studied in five patients with B cell lymphoproliferative disorders, C1INH deficiency, and angioedema. C1INH catabolism was markedly accelerated in these patients. The fractional catabolic rate (FCR) was 0.053 of the plasma pool per hour compared to that of normal subjects (0.025) or patients with hereditary angioneurotic edema (HANE) (0.035). The catabolism of two dysfunctional proteins Wel and Ta was studied. Protein Wel was catabolized at an accelerated rate (0.041) compared to that in patients with HANE (0.029) or in normal subjects (0.020). In contrast, the FCR of protein Ta was 0.012, which is similar to that in normal patients and in patients with HANE. The extravascular to plasma ratio (E/P) of the normal C1INH in patients was 1.55 compared to 0.60 in normal patients. This is consistent with the rapid extravascular sequestration of the C1INH. The synthesis rate of the C1INH was 0.29 mg/kg/hr in patients that is similar to that in control subjects. The metabolism of C1q was studied in two normal control subjects and three patients. The FCR of C1q was 0.051 in patients compared to 0.023 in control subjects. The E/P was increased in patients (2.8) compared to E/P in control subjects (0.6). The acquisition of C1INH deficiency results from increased consumption of C1INH in vivo.

    Available online at: http://www.jacionline.org/article/S0091-6749%2886%2980111-7/abstract

    The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency

    Zuraw BL, Sugimoto S, Curd JG 12/1986 Journal of Allergy & Clinical Immunology

    The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.

    Dec;78(6):1115-1120

    Available online at: http://www.jacionline.org/article/0091-6749%2886%2990259-9/abstract

    Hereditary angioedema: a decade of management with stanozolol

    Sheffer AL, Fearon DT, Austen KF 12/1987 Journal of Allergy & Clinical Immunology

    Thirty-seven patients with hereditary angioedema, who, without therapy, had attacks of cutaneous angioedema, gastrointestinal colic, and/or upper respiratory symptoms at a frequency and severity sufficient to prompt treatment with an attenuated androgen, have been evaluated for the incidence of side effects and biochemical toxicity during various schedules leading to the minimal effective dose. Stanozolol was administered in a 2 mg daily dose, initially, and after the symptoms and signs were adequately controlled for 2 months at this dose or at 1 mg per day, the drug was administered every other day at 4 mg. Patients who responded adequately to this schedule were administered 2 or 1 mg every other day, and then the interval between doses was gradually increased to 1 week, after which the agent was stopped. Eighteen patients experienced adverse reactions to stanozolol while the minimal effective dose was attained. In each instance the side effect subsided with a reduction in dosage. The most common adverse reactions were biochemical evidence of hepatic dysfunction and, to a lesser extent, hirsutism and menstrual irregularities. Although 21 of 27 patients in an initial study of the minimal effective dose were maintained with daily therapy in 1980, by 1986 this group and 10 additional patients were distributed so that three patients were receiving daily maintenance, 18 were receiving alternate-day maintenance, and 16 patients were receiving no maintenance therapy [corrected]. Thus, stanozolol appears to be a safe and effective agent for management of hereditary angioedema when patients are continually monitored to define the minimal effective dose or the feasibility of stopping the drug.

    Dec;80(6):855-860

    Available online at: http://www.sciencedirect.com/science/article/pii/S0091674987802774 (small fee)

    Abdominal pain in hereditary angioedema: the role of acid hypersecretion

    Collen MJ, Brickman CM, Lewis JH, Deschner WK, Ansher AF, Zurlo JJ, et al. 8/1989 The American Journal of Gastroenterology

    Aug;84(8):873-877

    Hereditary angioedema is a familial disorder characterized by recurrent episodes of soft tissue swelling and abdominal pain. Whereas most patients are successfully treated with androgenic steroids, some have abdominal pain unresponsive to therapy. To determine whether acid-peptic disease could account for the abdominal pain unresponsive to androgen therapy, we performed upper gastrointestinal endoscopy and determined basal acid output in 21 consecutive patients with hereditary angioedema and abdominal pain. Mean basal acid output of this group was 6.0 +/- 5.9 mEq/h, with five patients having gastric acid hypersecretion (defined as a basal acid output of greater than 10.0 mEq/h). The abdominal pain in 18 responded to stanozolol, whereas the pain in three patients did not change. Acid-peptic mucosal disease (esophagitis or duodenal ulcer) was present in these three patients with abdominal pain unresponsive to androgen therapy, all of whom had gastric acid hypersecretion (basal acid outputs of 13.7, 19.1, and 21.5 mEq/h, respectively). These three patients were treated with ranitidine but required increased doses to control their gastric acid hypersecretion, and to promote complete relief of abdominal pain and healing of their esophagitis or ulcer disease. These results indicate that there is a subset of patients with hereditary angioedema whose abdominal pain may be secondary to acid-peptic disease and gastric acid hypersecretion. Such individuals may require increased therapeutic doses of antisecretory medication to promote complete healing of esophagitis or ulcer disease. Basal acid output and upper gastrointestinal endoscopy are important determinants when evaluating abdominal pain in patients with hereditary angioedema that fails to respond to standard therapy.

    Not available online.

    Current status of antifibrinolytic drugs

    Ogston D. 3/1989 Blood Reviews

    Mar;3(1):1-4

    Antifibrinolytic drugs, in particular, epsilon-aminocaproic acid and tranexamic acid, have been used in the management of a wide range of both bleeding and non-haemorrhagic disorders. Recognition of their side-effects and complications, comparison of their efficacy with other forms of therapy and more critical evaluation of their value has reduced the range of their definitive indications to a limited number of relatively uncommon situations; these comprise primary hyperplasminaemia, menorrhagia in women in whom oestrogens are contraindicated or in those with von Willebrand’s disease, severe traumatic hyphaema, dental extraction in haemophiliacs and hereditary angioedema in patients in whom treatment with anabolic steroids is contraindicated. In a few conditions the possible benefit of antifibrinolytic agents, alone or supplementary to other forms of therapy, is unresolved; these include upper gastrointestinal bleeding, recurrent epistaxis and abruptio placentae. [References: 16].

    Available online at: http://www.bloodreviews.com/article/0268-960X%2889%2990019-2/abstract (small fee)

    Danazol

    Donaldson VH. 9/1989 The American Journal of Medicine

    Sep;87(3N):49N-55N

    Danazol is a synthetic attenuated androgen that can interfere with normal interactions between the pituitary-hypothalamic axis and the gonads. These effects are mediated by complex mechanisms, including those in which danazol can compete with natural steroids in binding to androgen receptors or to sex hormone-binding globulin, possibly displacing natural steroids from this protein, and in binding to reactive sites of enzymes required for synthesis of natural steroids, thereby depressing synthesis. Because of danazol’s impairment of the pituitary-hypothalamic interactions with gonads, it is an effective therapeutic agent for treatment of endometriosis and cystic disease of the breast. It is effective in the treatment of hereditary angioneurotic edema, but the mechanism of this therapeutic success is unclear. Danazol has been used, without universal success, in the treatment of other gynecologic and certain hematologic disorders. [References: 92].

    Not available online.

    In vivo function of C1-inhibitor and pathophysiology of edema attack in patients with hereditary angioneurotic edema

    Kodama J, Uchida K, Sakata T, Funakoshi F. 1/1989 Advances in Experimental Medicine & Biology

    ;247B:79-86.

    Not available online.

    The natural history and response to therapy of chronic urticaria and angioedema

    Quaranta JH, Rohr AS, Rachelefsky GS, Siegel SC, Katz RM, Spector SL, et al. 5/1989 Annals of Allergy, Asthma and Immunology

    May;62(5):421-424

    Previous reports have suggested that the etiology of chronic urticaria/angioedema (greater than 6 weeks) can be identified 10% to 30% of the time while few reports have addressed the natural history of chronic urticaria/angioedema. An analysis of all patients referred to the authors’ practice between 1983-1985 with a diagnosis of urticaria/angioedema was performed. Patients with hereditary angioedema were excluded. Eighty-six of the 214 patients had chronic urticaria/angioedema. In the remaining 128 cases of acute urticaria there were four exercise induced, nine contact, six cold induced, six drug induced, 11 food induced, one viral hepatitis associated, 29 with dermographism, and 62 undetermined. An etiology could not be determined in any of the patients with chronic urticaria/angioedema. Laboratory tests, including CBC, chemistry panel, urinalysis, ANA, rheumatoid factor, complement studies, sedimentation rate, and skin tests were all noninformative. Chronic angioedema without urticaria occurred in only nine cases, 31 cases had chronic urticaria alone, and 46 cases had both chronic urticaria and angioedema. Of the patients followed over the 3-year period, 27 resolved while 48 continued to have urticaria/angioedema. Response to medications was variable and will be discussed. Our study suggests that an etiology is determined in much less than 10% of patients with chronic urticaria; fortunately, 32% of our cases resolved over a 3-year period

    Not available online.

    Some historical and methodological developments in early clinical trials at the National Institutes of Health

    Greenhouse SW 8/1990 Statistics in Medicine

    This paper reviews five randomized clinical trials with unusual design or analysis features from institutes other than the National Cancer Institute or the National Heart, Lung and Blood Institute. These are: a Cooperative Study of Retrolental Fibroplasia sponsored by the National Institute of Neurological Diseases and Blindness; the Diabetic Retinopathy Study sponsored by the National Eye Institute; the University Group Diabetes Program sponsored by the National Institute of Arthritis and Metabolic Diseases; a Clinical Trial of the Extracranial to Intracranial Arterial Anastomosis (EC/IC bypass) by the National Institute of Neurological and Communicative Disorders and Stroke; and the Clinical Trial of Hereditary Angioedema by the National Institute of Allergy and Infectious Diseases.

    discussion 903-6; Aug;9(8):893-901

    Not available online.

    The long-term safety of danazol in women with hereditary angioedema

    Zurlo JJ, Frank MM 7/1990 Fertility & Sterility

    Although the short-term safety (less than or equal to 6 months) of danazol has been established in a variety of settings, no information exists as to its long-term safety. We therefore investigated the long-term safety of danazol by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with danazol for a continuous period of 6 months or longer. The mean age of the patients was 35.2 years and the mean duration of therapy was 59.7 months. Virtually all patients experienced one or more adverse reactions. Menstrual abnormalities (79%), weight gain (60%), muscle cramps/myalgias (40%), and transaminase elevations (40%) were the most common adverse reactions. The drug was discontinued due to adverse reactions in 8 patients. No patient has died or suffered any apparent long-term sequelae that were directly attributable to the drug. We conclude that, despite a relatively high incidence of adverse reactions, danazol has proven to be remarkably safe over the long-term in this group of patients.

    Jul;54(1):64-72

    Not available online.

    Alpha 2-macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis

    Kaufman N, Page JD, Pixley RA, Schein R, Schmaier AH, Colman RW 6/1991 Blood

    Activation of the contact system has been documented in severe sepsis and hereditary angioedema, but a sensitive, specific, and quantitative assay for assessing the degree of involvement of this proteolytic enzyme cascade is not yet available. We have developed a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) for the alpha 2-macroglobulin-kallikrein (alpha 2M-Kal) complex using an F(ab’)2 derivative of a monospecific polyclonal antibody against alpha 2 M as the capture antibody and a unique murine monoclonal antibody, 13G11, against the heavy chain of kallikrein as the detector antibody. The assay does not detect complexes in normal plasma but reacts with complexes generated by activating normal plasma with dextran sulfate at 4 degrees C in a range of 5 to 375 nmol/L. A close correlation of the ELISA with an amidolytic assay for alpha 2M-Kal was documented. Patients with sepsis syndrome but negative bacterial blood cultures did not show elevated plasma complexes, whereas a majority of those with positive blood cultures did show modest elevation and a single patient with septic shock showed a very high level of alpha 2M-Kal complex. Similarly, a patient with classic hereditary angioedema (HAE) showed increased concentration of complexes on three separate occasions during attacks but normal levels between attacks. Two other HAE patients did not show elevated levels at quiescent periods. The ELISA for alpha 2M-Kal appears to be sensitive, specific, and quantitative, and it can be used to reflect the degree of contact system activation in human sepsis and in HAE attacks.

    Jun 15;77(12):2660-2667

    http://www.bloodjournal.org/content/77/12/2660.long?sso-checked=true

    Anesthesia for athletes using performance-enhancing drugs

    Joyce JA 4/1991 American Association of Nurse Anesthetists (AANA J)

    Anabolic-androgenic steroids are used in the treatment of numerous medical conditions, including Fanconi’s anemia, hypogonadism, hereditary angioedema, hypopituitarism and impotence. However, because of their potent anabolic properties, athletes began to use them to enhance body strength, size and endurance. Despite warnings from the medical and scientific communities of dangerous side effects such as Wilm’s tumor, hepatocellular carcinoma, stroke and myocardial infarction, some athletes continue to use anabolic steroids. Among the numerous research publications, only one case report was found which related difficulties in anesthesia administration. This paper presents the physiologic changes associated with anabolic steroid ingestion and applies these changes to the administration of anesthesia.

    Apr;59(2):139-144

    Not available online.

    C1-INH defect as an example of deficiency disease

    Madalinski K, Sabbouh K, Chorazykiewicz M, Gregorek H 4/1991 Immunological Investigations: A Journal of Molecular and Cellular Immunology (Immunol.Invest.)

    Primary defect of C1-inhibitor (C1-INH), the regulatory protein of the initial classical pathway of complement, is the cause of hereditary angioedema. Clinical symptoms involve potentially fatal obstruction of the upper respiratory tract, abdominal pains, and subcutaneous edemas. Since the description of functional tests for C1-INH two types of hereditary defect have been known: type I and type II. Sixteen patients with the type I of hereditary angioedema were diagnosed and treated in our hospital. The onset of the disease occurred between 1.5-12 y. of age. Clinical symptoms were observed in skin, gastrointestinal and respiratory tracts. Mean concentration of C1-INH in sera of 16 patients was 3.25 mg/dl, below 8.75 mg/dl that is the critical for well-functioning C1-INH. Inhibitory activity of C1-INH for C1 esterase in plasma was zero in most of the patients, while it was 0.94 +/- 0.20 U/ml in plasma samples of 91 healthy blood donors. Three modalities of treatment are available: substitution with C1-INH concentrate in acute attacks and antifibrinolytic and/or anabolic drugs for prophylaxis. We have obtained good therapeutic results with epsilon-aminocaproic acid (antifibrinolytic), 2g daily during 3 months, with 6 months intervals.

    Apr;20(2):133-141

    Available online at: http://www.tandfonline.com/doi/abs/10.3109/08820139109050781?journalCode=iimm20 (small fee)

    Idiopathic gastric acid hypersecretion: treatment implications for refractory acid/peptic disorders

    Lewis JH /1991 Alimentary Pharmacology and Therapeutics (Aliment.Pharmacol.Ther.)

    Although in most patients with duodenal ulcer disease the ulcer heals after 8 weeks of treatment with standard doses of H2 blockers or other agents, in about 10% the ulcer does not heal. These patients are considered ‘refractory’ to treatment. Reasons often cited for non-healing include poor patient compliance, cigarette smoking, and non-steroidal anti-inflammatory drug (NSAID) use. Gastric acid hypersecretion also appears to be an important factor in non-healing with standard doses of antisecretory agents. We have defined idiopathic gastric acid hypersecretion as a basal acid output of greater than 10 mmol/h in the absence of an elevated fasting serum gastrin level (or a negative secretin test if gastrin level greater than 100 pg/ml) to exclude persons with Zollinger-Ellison syndrome. Among the acid/peptic-related disorders in which idiopathic gastric acid hypersecretion should be considered are refractory duodenal ulcer, refractory gastro-oesophageal reflux disease (especially patients with oesophagitis), postbleeding duodenal ulcer, and certain rare disorders such as hereditary angioedema. Some children with atypical abdominal pain may also be hypersecretors of gastric acid. Once identified, patients with refractory duodenal ulcer or gastro-oesophageal reflux disease are treated with incremental doses of ranitidine titrated against the level of gastric acid secretion that remains during therapy. Ranitidine was selected to avoid the dose-related antiandrogenic effects and potential hepatic cytochrome P450 system-related drug interactions that may occur with cimetidine. In most cases of refractory duodenal ulcer, doubling the standard dose of ranitidine (to 300 mg b.d.) is sufficient to achieve symptomatic relief and mucosal healing. Higher doses appear to be necessary for refractory oesophagitis. To date, no side effects have been associated with high doses of ranitidine (up to 1800 mg/day) for periods of longer than 6 months. Idiopathic gastric acid hypersecretion is an important factor in explaining why not all patients respond to a ‘standard’ ulcer-healing dose of H2 blocker, and it provides a rationale for use of higher-dose therapy as a safe and effective alternative to omeprazole or to combination drug therapy in refractory acid/peptic disease.

    5(Suppl 1):15-24

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.1991.tb00002.x/pdf (small fee)

    Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience

    Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A 4/1991 Journal of Allergy & Clinical Immunology

    Fifty-six patients affected with hereditary angioedema have been followed during long-term prophylaxis with attenuated androgens. The treatment was started in patients who had one or more severe attacks per month. In 24 patients, the therapy lasted for more than 5 years. The minimal effective dose usually did not exceed 2 mg/day of stanozolol or 200 mg/day of danazol. Only in two patients were these doses not sufficient to achieve the complete disappearance of symptoms. Irregular menstruation, but rarely amenorrhea, was the only significant side effect. One patient had to stop the therapy because of laboratory signs of hepatic cell necrosis. In one patient, danazol was administered during the last 8 weeks of pregnancy without side effects for the mother but with transient signs of virilization for the female baby. To find a biochemical marker for the minimal effective dose of androgen derivatives, we measured the plasma levels of C1 C1 INH complexes at different doses of stanozolol in four patients with hereditary angioedema. We found that these complexes, elevated before treatment, promptly reverted to normal values during androgen therapy and remained normal with any reduction of the dose of the drug as long as the patient remained symptom free. Therefore, the measurement of C1 C1 INH complexes appears to reflect the activity of the disease and not the amount of androgen that is administered.

    Apr;87(4):768-773

    Available online at: http://www.jacionline.org/article/0091-6749%2891%2990120-D/abstract

    Oral manifestations and dental management of patients with hereditary angioedema

    Atkinson JC, Frank MM 3/1991 Journal of Oral Pathology & Medicine

    Hereditary angioedema (HAE) is a genetic disorder in which affected individuals develop extensive, spontaneous angioedema of the extremities, gastrointestinal tract, and oropharynx. Dental treatment of unmedicated patients with HAE can trigger life-threatening pharyngeal edema. Previously, it was demonstrated that the administration of fresh frozen plasma (FFP) before surgery prevented angioedema attacks in 6 patients undergoing dental extractions. The present study examines the long term effectiveness of FFP in preventing angioedema from developing in 53 patients with HAE undergoing all types of dental treatment over a ten-year period. Only 3 of 45 patients (6.7%) covered with FFP had a minor angioedema attack after dental therapy in 10 yr. No attacks of moderate or severe swelling were seen. Attacks occurred independently of the disease activity of the patient and the trauma of the dental procedure. The use of fresh frozen plasma is effective in preventing attacks of angioedema in HAE patients undergoing all types of dental procedures.

    Mar;20(3):139-142

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0714.1991.tb00908.x/abstract (small fee)

     

    Angioedema: 5 years’ experience, with a review of the disorder’s presentation and treatment

    Megerian CA, Arnold JE, Berger M 3/1992 Laryngoscope

    Angioedema is a problem that the otolaryngologist-head and neck surgeon is often asked to treat. This report concerns 17 patients admitted for care during a 5-year period. At their initial presentation, 94% of these patients manifested signs and symptoms of angioedema in the head and neck; three of them required urgent tracheotomy or intubation. As treatment of complement-mediated angioedema is distinct, an etiology-specific diagnostic and treatment protocol is presented. Of the patients, 35% had recent initiation of angiotensin-converting enzyme (ACE) inhibitor therapy for hypertension, and 6% demonstrated classic hereditary angioedema. However, the majority of them (59%) had unclear etiologies for their symptoms. Since angioedema is the final result of several possible abnormalities, a thorough knowledge of the differential diagnosis and clinical presentation is vital to patient management. [References: 18].

    Mar;102(3):256-260

    Available online at: http://onlinelibrary.wiley.com/doi/10.1288/00005537-199203000-00005/abstract (small fee)

    Danazol in hereditary angioedema. Ann

    Robinson LC, Hart LL 10/1992 Pharmacother

    Oct;26(10):1251-1252.

    Not available online.

    Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients

    Agostoni A, Cicardi M. 7/1992 Medicine

    71(4):206-215

    Two hundred and twenty-six patients with inherited C1 inhibitor (C1-INH) deficiency, also known as hereditary angioedema (HAE), have been studied. They belonged to 80 unrelated families, and in 11 of them C1-INH was functionally deficient but antigenically normal (type II HAE). Genetic analysis of type 1 families demonstrated restriction fragment length polymorphisms in 11% and abnormal mRNAs in 25%. In type II families, the site of the mutation appeared to determine the rate of catabolism of the dysfunctional C1-INH and its antigenic plasma levels. Clinical symptoms (subcutaneous and mucous swellings) generally first appeared within the second decade of life. The frequency of symptoms was highly variable from patient to patient, but a few patients remained asymptomatic throughout their lives. Prophylactic treatment with attenuated androgens was administered to 59 patients and was totally effective in 57, without significant side effects. Sixty-seven laryngeal and 15 abdominal attacks were treated with C1-INH plasma concentrate, yielding initial regression of symptoms in 30 to 90 minutes. The acquired deficiency of C1-INH, also known as acquired angioedema, was diagnosed in 9 patients. Eight of them had an autoantibody against C1-INH; the only patient without the autoantibody had associated chronic lymphocytic leukemia. Prophylactic treatment with attenuated androgens was effective in this last patient, while those with the autoantibody against C1-INH benefited from prophylaxis with antifibrinolytic agents. Replacement therapy with C1-INH concentrate was necessary only for patients with autoantibodies and required doses 3 or 4 times higher than those used in HAE.

    Available online at: http://journals.lww.com/md-journal/Citation/1992/07000/Hereditary_and_Acquired_C1_Inhibitor_Deficiency_.3.aspx

    Heterozygous alpha 1-antichymotrypsin deficiency may be associated with cold urticaria

    Lindmark B, Wallengren J 10/1992 Allergy

    Proteins of the serpin family (serine protease inhibitor) control key steps in the inflammatory, coagulation and complement systems. C1-inhibitor deficiency predisposes to hereditary angioneurotic oedema, and other serpins control proteolytic enzymes that may cause complement activation or the forming of oedema. We investigated whether deficiency of proteins of the serpin family may predispose to cold urticaria and therefore screened 7 male patients with severe cold urticaria for the presence of deficiency alleles of some of the members of the serpin antiprotease family. There were no findings of C1-inhibitor, alpha 1-antitrypsin, alpha 2-antiplasmin, antithrombin III, tissue plasminogen activator inhibitor or thyroxine binding protein deficiency. The prevalence of heterozygous alpha 1-antichymotrypsin deficiency was significantly higher than expected (prevalence ratio 25.8 (95% confidence interval 6.0-112), p < 0.0001). This finding is in concert with previous studies that have shown lower mean levels of alpha 1-antichymotrypsin among patients with cold urticaria and suggests that heterozygous deficiency of this antiprotease, which controls neutrophil cathepsin G and mast cell chymase may predispose to cold urticaria. The present series is, however, small and the results need confirmation in larger materials.

    Oct;47(5):456-458

    Available online at:  http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1992.tb00663.x/abstract (small fee)

     

    Autoimmune C1 inhibitor deficiency: report of eight patients

    Cicardi M, Bisiani G, Cugno M, Spath P, Agostoni A 8/1993 The American Journal of Medicine

    PURPOSE: In this study, we investigated the clinical and biochemical features and the responses to treatment of eight patients with auto-antibody-mediated C1 inhibitor (C1-INH) deficiency and symptoms of angioedema.

    PATIENTS AND METHODS: In addition to the 8 patients with acquired angioedema (AAE), we also studied 36 subjects with hereditary angioedema (HAE), 15 of them treated with C1-INH plasma concentrate, and 26 patients with different autoantibodies in their plasma (10 with systemic lupus erythematosus, 6 with lupus-like anticoagulant, and 10 with chronic liver disease). Functional C1-INH was measured with the reagent kit of Immuno (Vienna, Austria); C1-INH, C4, and C1q antigen were determined by radial immunodiffusion; and autoantibodies to C1-INH were detected by an enzyme-linked immunosorbent assay method.

    RESULTS: Four patients with AAE had no other diseases, one had breast cancer, one liver hydatidosis, one Waldenstrom’s disease, and one a benign M component. Functional C1-INH levels were below 30% of normal, and C1q plasma levels were low in seven patients but normal in one. Autoantibodies to C1-INH were detectable in all eight AAE patients but in none of the others. Prophylactic treatment with attenuated androgens was successful in one of four patients, and with antifibrinolytic agents (tranexamic acid) in six of seven patients. Laryngeal attacks in five patients were treated with C1-INH plasma concentrate; two patients had marked clinical and biochemical responses. In three, the symptoms resolved only with high doses, and the biochemical parameters did not significantly increase.

    CONCLUSIONS: Our results suggest that patients with autoimmune AAE are clinically and biochemically heterogeneous. They have different responses to treatment that seem to be related to variable C1-INH consumption.

    Aug;95(2):169-175

    Available at: http://www.amjmed.com/article/0002-9343%2893%2990257-P/abstract (small fee)

    Clinical problems in the C1-inhibitor deficient patient

    Agostoni A, Cicardi M, Cugno M, Storti E /1993 Behring Institute Mitteilungen

    The clinical course of C1-INH deficiency is presently well established. There is an inherited form (Hereditary Angioedema) characterized by recurrence of cutaneous and mucous swellings appearing early in life and usually accompanied by substantial family history, and an acquired form (Acquired Angioedema) where identical symptoms start after the fourth decade of life without family history. The acquired form can be associated with other diseases, mainly B cell disorders, and/or with autoantibodies to C1-INH. The biochemical characteristic is the functional deficiency of C1-INH and of C4 and C2. Moreover a marked deficiency of C1 is present in most acquired forms, but never in the inherited ones. C1-INH deficiency can be corrected by attenuated androgens that increase C1-INH levels in a few days and are effective in the prophylaxis of attacks, or by substitutive therapy with C1-INH plasma concentrate that is the life-saving drug in laryngeal edema. Patients with the inherited form have a uniformly good response to both these treatments which are otherwise effective only in a minority of patients with the acquired deficiency. In these subjects C1-INH concentrate needs to be given in higher doses and prevention of attacks is obtained with antifibrinolytic agents (Tranexamic acid).

    Not available online.

    Influence of C1-inhibitor on inflammation, edema and shock

    Dickneite G /1993 Behring Institute Mitteilungen

    C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone. [References: 48].

    Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema

    Davis AE 3rd, Bissler JJ, Cicardi M /1993 Behring Institute Mitteilungen

    Mutations in one C1 INH allele result in the autosomal dominant disease, hereditary angioedema. The plasma antigenic level of C1 INH in this disease may be low, normal, or high, while the functional level is uniformly depressed. Investigation of the mutations in the C1 INH gene reveal several key features about the DNA itself as well as protein structure-function relationships. The largest single group of mutations with a defined mechanism are recombinations associated with Alu repetitive DNA elements. Current data suggest that there may be an increased number of mutations within the region encoding the reactive center which, like some other serpins, contains both primary and secondary structure DNA polymerase pause sites. These sites may enhance the rates of mutation and evolution in the reactive center region. Some of the dysfunctional C1 INH proteins that result from hinge region mutations support models for reactive center loop interaction with beta sheet A during complex formation. The analysis of the dysfunctional mutants, therefore, suggest regions of the molecule that are important for inhibitor function. [References: 45].

    Not available online.

    Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid

    Cugno M, Cicardi M, Agostoni A 5/1994 Journal of Allergy & Clinical Immunology

    C1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS).

    May;93(5):870-876

    http://www.jacionline.org/article/0091-6749%2894%2990380-8/abstract

    Administration of gamma interferon in human subjects decreases plasminogen activation and fibrinolysis without influencing C1 inhibitor

    Gluszko P, Undas A, Amenta S, Szczeklik A, Schmaier AH 2/1994 Journal of Laboratory & Clinical Medicine

    Recombinant gamma interferon (rHuIFN-gamma) has been recognized to increase mRNA and protein levels of C1 inhibitor (C1 INH) in various human cells. Further, when administered to patients with colon cancer, it increased plasma C1 INH levels. A prospective trial was initiated to determine whether rHuIFN-gamma could elevate plasma C1 INH levels in six normal volunteers and two patients with type I angioedema. After 1 month of observation of plasma C1 INH levels, rHuIFN-gamma was administered subcutaneously at 25 micrograms/M2 daily for 4 consecutive days. All healthy volunteers and patients experienced local erythema, headache, myalgias, and chills during the administration of rHuIFN-gamma. C1 INH, prekallikrein, high-molecular-weight kininogen, and factor XII levels in plasma were not influenced by the rHuIFN-gamma administration. One patient with hereditary angioedema (HAE) had an attack of angioedema 3 days after completion of rHuIFN-gamma therapy. During the attack, circulating cleaved high-molecular-weight kininogen, kallikrein-alpha 2-macroglobulin complexes, and an altered 50 kd form of kallikrein were detected in the patient’s plasma. Additional studies showed that rHuIFN-gamma treatment resulted in decreased total fibrinolytic activity. It was found that immediately after rHuIFN-gamma treatment, tissue plasminogen activator activity and antigen levels were not significantly decreased in volunteers. Plasminogen activator inhibitor levels rose significantly, but this activity was not due to plasminogen activator inhibitor-1 antigen, whose value significantly fell. These data suggest that rHuIFN-gamma may stimulate the expression of another plasminogen activator inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS).

    Feb;123(2):232-240

    Not available online.

    Improved detection of proteolytically cleaved high molecular weight kininogen by immunoblotting using an antiserum against its reduced 47 kDa light chain

    Buhler R, Hovinga JK, Aebi-Huber I, Furlan M, Lammle B 5/1995 Blood Coagulation & Fibrinolysis

    Several ligand blotting or immunoblotting assays for the detection of single-chain and proteolytically cleaved two-chain high molecular weight kininogen (HK) in whole plasma have been described. Since they may suffer from poor sensitivity for the light chain species of cleaved HK on reduced blots, an antiserum against the reduced and alkylated 47 kDa light chain of HK was raised in rabbits allowing improved immunodetection of HK species on blots of reduced electropherograms. This immunoblotting method is highly specific and sensitive, permitting detection of 0.2 ng single-chain HK or the light chains of 2 ng proteolytically cleaved HK in whole plasma. Thus, this immunoblotting technique is at least 50-100 times more sensitive than ligand blotting with radiolabelled factor XI overlay. A similar cleavage pattern was observed following in vitro activation of normal human plasma by dextran sulphate and after plasma kallikrein-induced proteolysis of purified HK. However, bands of different molecular weights were generated after HK had been cleaved by purified leukocyte elastase. During acute attack in a patient with hereditary angioedema, high levels of in vivo cleaved HK were noticed, whereas concentration of cleaved HK in plasma samples and synovial fluids from patients suffering from various inflammatory conditions were not substantially higher than those in normal plasma. During in vitro cold activation of plasma samples of pregnant women concomitant HK cleavage and plasma kallikrein generation were observed.

    May;6(3):223-232

    Available online at: http://journals.lww.com/bloodcoagulation/Abstract/1995/05000/Improved_detection_of_proteolytically_cleaved_high.5.aspx (small fee)

    Reduction in transmission of hepatitis C after the introduction of a heat-treatment step in the production of C1-inhibitor concentrate

    Cicardi M, Mannucci PM, Castelli R, Rumi MG, Agostoni A 3/1995 Transfusion

    BACKGROUND: The transmission of viral infections via protein concentrates made from a large pool of plasma depends on the selection of donors, fractionation process, and virucidal methods. To date, no data are available on the infectivity risk of plasma concentrates of the inhibitor of the first component of complement (C1-INH).

    STUDY DESIGN AND METHODS: The prevalence of blood-borne viral infections and levels of transaminases were evaluated in patients treated with a large-pool plasma concentrate of the inhibitor of C1-INH before and after the introduction of virucidal methods. The study included 85 patients with hereditary angioedema and 4 with acquired angioedema. The patients were divided into three groups: 1) 48 untreated patients; 2) 22 patients treated with non-virus-inactivated C1-INH concentrates; and 3) 19 patients treated with virus-inactivated concentrates. Serum samples obtained at various times after the infusion of concentrate were assayed for alanine amino-transferase and tested for hepatitis B surface antigen and antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency virus (anti-HIV); anti-HCV-negative subjects exposed to the concentrate were also tested for HCV RNA.

    RESULTS: Prevalences of HCV infection and elevated alanine aminotransferase are significantly lower in patients treated with virus-inactivated concentrates than in those exposed to non-virus-inactivated concentrates. No patients were anti-HIV positive.

    CONCLUSION: This study suggests that C1-INH concentrates transmitted HCV, but that the virucidal methods adopted are effective in reducing the infectivity.

    Mar;35(3):209-212

    Available online at: http://onlinelibrary.wiley.com/doi/10.1046/j.1537-2995.1995.35395184276.x/pdf (small fee)

    Stanozolol as a novel therapeutic agent in dermatology

    Helfman T, Falanga V 8/1995 The Journal of the American Academy of Dermatology (JAAD)

    Anabolic steroids are synthetic derivatives of testosterone that were developed in the 1950s in an attempt to dissociate the anabolic and androgenic effects of testosterone. The anabolic steroid stanozolol has been particularly helpful because it has one of the largest anabolic/androgenic ratios. In addition, stanozolol has substantial fibrinolytic properties. We discuss the safety profile and the use of stanozolol for a variety of clinical applications. Stanozolol is approved for use in the treatment of hereditary angioedema, but numerous reports have detailed the effectiveness of this agent in the treatment of urticaria, Raynaud’s phenomenon, and, more recently, cryofibrinogenemia and lipodermatosclerosis. Side effects are mostly dose related and are preventable with appropriate follow-up. [References: 32].

    Aug;33(2 Pt 1):254-258

    Available online at: http://www.sciencedirect.com/science/article/pii/0190962295902449 (small fee)

     

    The value of C1 esterase inhibitor in patients with aspirin-sensitive urticaria

    Grzelewska-Rzymowska I, Szmidt M, Rozniecki J 9/1995 Journal of Investigational Allergology & Clinical Immunology

    The aim of the study was to evaluate the concentration and activity of C1 esterase inhibitor (C1 INH) in patients with aspirin-sensitive urticaria. C1 INH deficiency is the basis of hereditary angioneurotic edema. The study was performed on 32 subjects with aspirin-sensitive urticaria. The value of C1 INH in examined patients was the same as in the control group. There seems to be no coexistence of aspirin-sensitive urticaria and C1 esterase inhibitor deficiency.

    Sep-Oct;5(5):272-275

    Not available online.

    Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate

    Waytes AT, Rosen FS, Frank MM 6/1996 The New England Journal of Medicine (N.Engl.J.Med)

    BACKGROUND: Hereditary angioedema results from a congenital deficiency of functional C1 inhibitor and is characterized by episodic bouts of edema, which may be life-threatening when they involve the larynx. We evaluated the effectiveness of a C1 inhibitor concentrate in the prevention and treatment of attacks of hereditary angioedema. The concentrate was vapor-heated to inactivate hepatitis and human immunodeficiency viruses.

    METHODS: We conducted two double-blind, placebo-controlled studies. The first was a crossover study consisting of two 17-day trials in which prophylactic infusions of either C1 inhibitor (25 plasma units per kilogram of body weight) or placebo were given intravenously every third day to six patients with hereditary angioedema. The second study was conducted in patients with acute attacks of hereditary angioedema and assessed the length of time to a clinical response after infusions of either 25 plasma units of C1 inhibitor per kilogram (55 infusions in 11 patients) or placebo (49 infusions in 11 patients).

    RESULTS: The infusions of C1 inhibitor concentrate resulted in close to normal functional levels of C1 inhibitor and C4. As compared with placebo, prophylactic infusions of C1 inhibitor resulted in significantly lower daily symptom scores for the severity of edema of the extremities (P<0.01), larynx (P<0.05), abdomen (P<0.05), and genitourinary tract (P<0.05). Likewise, during the treatment study the time from the start of an infusion to the beginning of improvement in symptoms was shorter for the C1 inhibitor infusions than the placebo infusions (55 vs. 563 minutes, P<0.001). There was no evidence of toxicity.

    CONCLUSIONS: Infusions of a vapor-heated C1 inhibitor concentrate are a safe and effective means of both preventing attacks of hereditary angioedema and treating acute attacks.

    . . . 1996 Jun 20;334(25):1630-1634

    Available online at: http://www.nejm.org/doi/full/10.1056/NEJM199606203342503#t=article

     

    Complement abnormalities with lower extremities discomfort in Vietnamese immigrants

    Luong KV, Nguyen LT 7/1997 Allergy & Asthma Proceedings

    The objective was to measure complement C’l esterase inhibitor (CIINH) in a group of Vietnamese outpatients with lower extremities discomfort of undetermined etiology. All 25 female patients were followed between 1992 and 1995. Their age ranged from 24 to 82 years old (mean age, 46.68 +/- 13.77). They presented with unexplained lower extremities discomfort. They were found to have low levels of CIINH (mean, 11.36 +/- 1.44 mg/dL versus control subjects, 15.64 +/- 2.22 mg/dL). Twenty-one patients were treated with oral Danazol 200 mg daily for 1-2 months. The improvement of the symptoms in our patients coincided with increased CIINH level in all of our patients (pretreatment, 11.33 +/- 1.46 mg/dL versus posttreatment, 16.82 +/- 2.98 mg/dL with p < 0.001) and the return to normal functional activity of CIINH associated with and without Danazol treatment. These patients may represent a form of androgen-responsive limited to the lower extremity’s discomfort associated with low levels of CIINH, normal levels of Clq and normal ratio of C4d/C4 that differentiated them from angioedema (hereditary or acquired form), having no known precipitating factors or a family history of hereditary angioedema.

    Jul-Aug;18(4):239-244

    Available online at: http://www.ingentaconnect.com/content/ocean/aap/1997/00000018/00000004/art00005 (small fee)

    Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients

    Cicardi M, Castelli R, Zingale LC, Agostoni A 2/1997 Journal of Allergy & Clinical Immunology

    Feb;99(2):194-196.

    Available online at: http://www.jacionline.org/article/S0091-6749%2897%2970095-2/abstract

    A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema

    Kunschak M, Engl W, Maritsch F, Rosen FS, Eder G, Zerlauth G, et al 6/1998 Transfusion

    BACKGROUND: No effective treatment exists in the United States for acute attacks of hereditary angioedema (HAE). STUDY DESIGN AND METHODS: To evaluate the efficacy and safety of C1 inhibitor concentrate in treating HAE, a large primary care and referral center hospital conducted a randomized, placebo-controlled, double-blind trial with

    STUDY DESIGN AND METHODS: To evaluate the efficacy and safety of C1 inhibitor concentrate in treating HAE, a large primary care and referral center hospital conducted a randomized, placebo-controlled, double-blind trial with intent-to-treat analysis. Of the 36 patients enrolled in the study, 23 received treatment, and 22 completed the trial. C1 inhibitor concentrate or albumin (placebo) infusions were administered in a blind fashion to HAE patients who came to the hospital for treatment no later than 5 hours after an attack began. RESULTS: Relief was almost twice as fast in persons receiving C1 inhibitor concentrate than in the controls: 7.62 hours (mean; SD 7.08) versus 15.35 hours (mean; SD 8.31), respectively. The difference for time-to-relief was highly significant (p = 0.007, Mann-Whitney U test). The median time-to-relief was 6.17 hours (interquartile range 0.33-15.35) in the treatment group and 15.35 hours (interquartile range 14.00-22.83) in the control group. Resolution of symptoms was one-third faster in the C1 inhibitor concentrate group than in the placebo group: 23.98 hours (mean; SD 14.81) and 34.58 hours (mean; SD 13.56), respectively (p = 0.09, Mann-Whitney U test). Recovery of functional C1 inhibitor was 119.65 percent (mean; SD 50.80), and half-life was 37.87 hours (mean; SD 19.75). Recovery of antigenic C1 inhibitor was 147.75 percent (mean; SD 97.68), and half-life was 24.01 hours (mean; SD 9.70). There were no viral infections or serious adverse effects from the drug after 70 attacks in the treatment group and 96 attacks in the control group. CONCLUSIONS: C1 inhibitor concentrate is a safe, effective treatment for acute attacks of HAE.

    RESULTS: Relief was almost twice as fast in persons receiving C1 inhibitor concentrate than in the controls: 7.62 hours (mean; SD 7.08) versus 15.35 hours (mean; SD 8.31), respectively. The difference for time-to-relief was highly significant (p = 0.007, Mann-Whitney U test). The median time-to-relief was 6.17 hours (interquartile range 0.33-15.35) in the treatment group and 15.35 hours (interquartile range 14.00-22.83) in the control group. Resolution of symptoms was one-third faster in the C1 inhibitor concentrate group than in the placebo group: 23.98 hours (mean; SD 14.81) and 34.58 hours (mean; SD 13.56), respectively (p = 0.09, Mann-Whitney U test). Recovery of functional C1 inhibitor was 119.65 percent (mean; SD 50.80), and half-life was 37.87 hours (mean; SD 19.75). Recovery of antigenic C1 inhibitor was 147.75 percent (mean; SD 97.68), and half-life was 24.01 hours (mean; SD 9.70). There were no viral infections or serious adverse effects from the drug after 70 attacks in the treatment group and 96 attacks in the control group.

    CONCLUSIONS: C1 inhibitor concentrate is a safe, effective treatment for acute attacks of HAE.

     

    Jun;38(6):540-549

    Available online at: http://onlinelibrary.wiley.com/doi/10.1046/j.1537-2995.1998.38698326333.x/abstract (small fee)

    Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants

    Wolozin B, Maheshwari S, Jones C, Dukoff R, Wallace W, Racchi M, et al 11/1998 Molecular Psychiatry (Mol.Psychiatry)

    The beta-amyloid (A beta) peptide is present both in serum and in platelets, however it is unclear whether A beta plays a role in platelet function. We have now investigated the effects of soluble A beta on platelet function and have found that low levels (0.1-1 nM) of soluble A beta augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A beta to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A beta ratios. The structure activity requirements for A beta activity showed intriguing constraints. Only full length A beta has significant activity. Truncated A beta peptides, such as A beta(1-16) or A beta(25-35), or reverse A beta(40-1) all show little or no activity. We also examined the activity of mutant A beta peptides, corresponding with the APP(692A-G) and APP(693E-Q) (at A beta21 and A beta22, respectively) which are found in familial Alzheimer’s disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A beta interacts with platelets in a highly specific manner and may play a role in regulating platelet function.

    Nov;3(6):500-507

    Available online at: http://www.nature.com/mp/journal/v3/n6/abs/4000451a.html

    C1-esterase inhibitor transfusions in patients with hereditary angioedema

    Visentin DE, Yang WH, Karsh J 6/1998 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema results from the deficiency of C1-esterase inhibitor (C1-INH), and C1-INH replacement would represent definitive treatment for angioedema attacks. In Canada, C1-INH is available only on a compassionate basis at select medical facilities. Our objective is to assess the efficacy of C1-INH transfusions during angioedema attacks at a single Canadian institution.

    METHODS: A retrospective chart review of transfusion data between January 1, 1995 and June 30, 1996 was performed. Phone interviews with patients elicited their opinions of the treatment. Data collected included the number and duration of angioedema attacks, dose of transfused C1-INH, and side effects of treatment.

    RESULTS: Of a cohort of 13 patients with hereditary angioedema, seven received transfusions with C1-INH. Attacks totaled 87, and more than 100,000 units of the product were transfused. The mean time for abatement of an attack after initiation of transfusion was 50 +/- 8 minutes (1 SD). There were no reports of adverse effects. Although patients were satisfied with the treatment, they raised concerns regarding long-term safety and availability.

    CONCLUSIONS: C1-INH transfusion is a satisfactory means of treating angioedema attacks.

    Jun;80(6):457-461

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2963067-0/abstract (small fee)

    Molecular genetics of C1 inhibitor

    Tosi M 8/1998 Immunobiology

    More than 100 different C1 inhibitor gene mutations have been described in hereditary angioedema (HAE) patients. Sixty-nine mutations have been reported in patients with the quantitative C1 inhibitor defect (type 1 HAE) in two recent large-scale studies. These changes were found distributed over all exons and exon/intron boundaries. The molecular defects can be divided as follows: Alu-repeat-mediated deletions or duplications (accounting for 21% of all cases), missense mutations (> 36%), frameshifts (14%), Stop codon mutations (10%), promoter variants (4%), splice site mutations (7-10%), deletions of a few amino acids (less than 3%). Several recent studies indicate that up to 25% of these changes are found in patients without a family history of angioedema and represent de novo mutations. Pathogenic amino acid substitutions were found distributed over the entire length of the coding sequence, except for the 100 amino-acid-long glycosylated amino-terminal extension, whose sequence tolerates extensive variation, as indicated by comparisons across species. Functional studies have been carried out only on a fraction of these amino acid substitutions and indicate that defects affecting intracellular transport are often at the basis of type 1 hereditary angioedema. An interesting promoter variant (a C to T transition at position -103) was found in an exceptional family with recessive transmission of the disease. Regulatory elements in the promoter region and in intron 1 were revealed by their sequence conservation in mouse and man and by functional studies. C1 inhibitor “minigene” constructs directing correct mRNA and protein synthesis in transgenic mice have provided valuable information on hormonal control and cell-type specificity of gene expression. [References: 23].

    Aug;199(2):358-365

    Available online at: http://www.sciencedirect.com/science/article/pii/S0171298598800405 (small fee)

    Angioedema due to angiotensin-converting enzyme inhibitors

    Agostoni A, Cicardi M, Cugno M, Zingale LC, Gioffre D, Nussberger J 10/1999 Immunopharmacology

    Angiotensin-converting enzyme (ACE) inhibitor associated angioedema was detected in 39 subjects (17%) of 231 consecutive patients examined in the last 5 years at our out-patient clinic for symptoms of angioedema without urticaria. In these patients, angioedema was most commonly localized to the face. The duration of ACE-inhibitor treatment at the onset of angioedema ranged from 1 day to 8 years with a median of 6 months. The time elapsed between onset of angioedema and withdrawal of ACE-inhibitor ranged from 1 day to 10 years with a median of 10 months. Delayed diagnosis is explained by the unusual characteristics of this adverse reaction: angioedema may start years after beginning the treatment and then it recurs irregularly. In fact, ACE-inhibitors seem to facilitate angioedema in predisposed subjects, rather than causing it with an allergic or idiosyncratic mechanism. Thus, while Cl-inhibitor levels are usually normal in subjects developing ACE-inhibitor-dependent angioedema, we found that ACE-inhibitors caused angioedema in Cl-inhibitor-deficient patients. Because the main inactivator of bradykinin is kininase II, which is identical with ACE, it is believed that bradykinin mediates ACE-inhibitor-dependent angioedema. We had the possibility to examine the plasma bradykinin levels in one ACE-inhibitor-treated patient during an angioedema attack and we found very high levels, but we did not find an increase of break-down products of high-molecular-weight-kininogen as observed during acute attacks in hereditary angioedema. Bradykinin fell to normal levels during remission after withdrawal of the drug. These observations indicate that in ACE-inhibitor-induced angioedema, contrary to hereditary angioedema, the reduction of bradykinin catabolic rate plays a predominant role.

    Oct 15;44(1-2):21-25

    Available online at: http://www.sciencedirect.com/science/article/pii/S0162310999001071 (small fee)

    C1 inhibitor in anti-inflammatory therapy: from animal experiment to clinical application

    Kirschfink M, Nurnberger W 3/1999 Molecular Immunology (Mol.Immunol.)

    Potentially life-threatening consequences due to severe inflammatory tissue destruction are often closely associated with an excessive activation of the complement system. Various clinical disorders, including capillary leak syndrome, septic shock, multiple organ failure and hyperacute graft rejection are at least in part driven by an overactivated complement system. Therapeutic support of complement regulation appears to be a logical approach to reduce undesirable inflammatory reactions. C1 inhibitor, a multifunctional regulator of all major kinin-generating protein cascade systems, is frequently observed to be reduced in patients suffering from severe inflammation, due to ligand-induced inactivation of the regulatory protein. After C1 inhibitor has for many years been proven beneficial in acute treatment of hereditary angioedema, a growing number of reports now suggests that C1 inhibitor provides an effective means to protect against complement-mediated inflammatory tissue damage. These studies not only include pathophysiologically relevant animal models but also first attempts to prove the benefits of C1 inhibitor as a novel therapeutic approach in clinical trials. [References: 85].

    1999 Mar-Apr;36(4-5):225-232

    Available online at: http://www.sciencedirect.com/science/article/pii/S0161589099000486 (small fee)

    The efficacy of short-term danazol prophylaxis in hereditary angioedema patients undergoing maxillofacial and dental procedures

    Farkas H, Gyeney L, Gidofalvy E, Fust G, Varga L 4/1999 Journal of Oral & Maxillofacial Surgery

    PURPOSE: This study evaluated the efficacy of short-term danazol prophylaxis in hereditary angioedema patients undergoing maxillofacial or dental procedures.

    PATIENTS AND METHODS: Twelve patients with a history of edema after dental procedures were administered danazol (600 mg/d) 4 days preoperatively and 4 days postoperatively. The serum levels of complement components were determined preoperatively and postoperatively as well as at 6, 12 and 24 hours in six patients.

    RESULTS: None of the 12 patients developed angioneurotic edema. The serum levels of the complement components were decreased immediately after surgery and returned to normal within 24 hours.

    CONCLUSION: The short-term prophylactic use of danazol in patients with hereditary angioedema undergoing oral surgery is an effective preventive measure.

    Apr;57(4):404-408

    Available at: http://www.joms.org/article/S0278-2391%2899%2990280-X/abstract (small fee)

    C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema

    Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE 3/2000 Pharmacological Reviews (Pharmacol.Rev.)

    C1-esterase inhibitor (C1-Inh) therapy was introduced in clinical medicine about 25 years ago as a replacement therapy for patients with hereditary angioedema caused by a deficiency of C1-Inh. There is now accumulating evidence, obtained from studies in animals and observations in patients, that administration of C1-Inh may have a beneficial effect as well in other clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, acute myocardial infarction, or other diseases. Activation of the complement system, the contact activation system, and the coagulation system has been observed in these diseases. A typical feature of the contact and complement system is that on activation they give rise to vasoactive peptides such as bradykinin or the anaphylatoxins, which in part explains the proinflammatory effects of either system. C1-Inh, belonging to the superfamily of serine proteinase inhibitors (serpins), is a major inhibitor of the classical complement pathway, the contact activation system, and the intrinsic pathway of coagulation, respectively. It is, therefore, endowed with anti-inflammatory properties. However, inactivation of C1-Inh occurs locally in inflamed tissues by proteolytic enzymes (e.g., elastase) released from activated neutrophils or bacteria thereby leading to increased local activation of the various host defense systems. Here we will give an overview on the biochemistry and biology of C1-Inh. We will discuss studies addressing therapeutic administration of C1-Inh in experimental and clinical conditions. Finally, we will provide an explanation for the therapeutic benefit of C1-Inh in so many different diseases. [References: 270].

    Mar;52(1):91-112

    Available online at: http://pharmrev.aspetjournals.org/content/52/1/91.long

    Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema

    Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, et al /2000 Journal of Allergy & Clinical Immunology

    C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Societe d’Angioedeme Hereditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future. [References: 77].

    Available online at: http://www.jacionline.org/article/S0091-6749%2804%2901746-4/fulltext

    Hereditary angioneurotic edema: review of the literature

    Ebo DG, Stevens WJ 1/2000 Acta Clinica Belgica (Acta Clinica Belgica (Acta Clin.Belg.))

    Congenital C1-inhibitor deficiency, or hereditary angioneurotic edema (HAE), is a rare autosomal dominant disease due to alterations in the C1 inhibitor gene that results in a deficiency of antigenic and/or functional C1-INH. Affected patients are heterozygous, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor. The disease is characterised by recurrent, circumscribed, non-pitting, and non-pruritic subepithelial swellings of sudden onset, which fade during the course of 48-72 hours, but can persist up to 1 week. Lesions can be solitary or multiple and primarily involve the extremities, larynx, face, and bowel wall. Bradykinin is believed to be the main, but certainly not the sole, mediator responsible for the bouts of edema in HAE. The diagnosis is suggested by family history, the lack of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colics, and episodes of laryngeal edema. Diminished C4 concentrations during symptomatic periods are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-INH antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. Prophylactic administration of either attenuated androgens or protease inhibitors has proved useful in reducing frequency or severity of attacks. Infusions of a vapour-heated C1-INH concentrate are safe and effective means of both preventing and treating attacks. Nevertheless, this treatment is expensive and this extract is not readily available. It is emphasised that administration of angiotensin converting enzyme inhibitors is contraindicated in patients suffering from protease inhibitor deficiency states. [References: 58].

    Jan-Feb;55(1):22-29

    Available online at: http://www.researchgate.net/publication/12532280_Hereditary_angioneurotic_edema_Review_of_the_literature

    Life-threatening laryngeal oedema in a pregnant woman with hereditary angioedema

    McGlinchey PG, Golchin K, McCluskey DR 5/2000 Ulster Med.J.

    May;69(1):54-57

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2449162/

    Therapeutic inhibition of the complement system-Y2K update

    Asghar SS, Pasch MC /2000 Frontiers in Bioscience

    Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barre syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases. [References: 151].

    Available online at: https://www.bioscience.org/2000/v5/e/asghar/fulltext.htm

    A major advance in emergency treatment of hereditary angioneurotic oedema

    C1 esterase inhibitor: new preparation 6/2001 Prescrire International

    (1) The reference prophylaxis of attacks of hereditary angioneurotic oedema is oral danazol, an androgenic steroid, which takes a few days to act. There was previously no curative treatment authorised in France. (2) C1 esterase inhibitor is now licensed in France as replacement therapy for patients with hereditary angioneurotic oedema due to a quantitative or qualitative deficiency in this protein. (3) The clinical evaluation file partly answers the practical questions that arise in this setting, but it does not include trials versus danazol. (4) In 36 patients with acute attacks of angioneurotic oedema, a double-blind trial showed that symptom relief was achieved in less than half an hour in 69% of attacks treated with C1 esterase inhibitor, compared to only 2% of attacks treated with placebo. (5) In the prophylactic setting, a crossover trial involving six patients refractory to conventional androgen therapy showed that injections of C1 esterase inhibitor every three days were more effective than a placebo in reducing the risk of attacks. (6) No major adverse effects have been attributed so far to C1 esterase inhibitor, but the fact that the drug is derived from human blood means that treatment carries a theoretical risk of infection by conventional infectious agents (especially nude viruses) and prions. (7) In practice, for life-threatening attacks of angioneurotic oedema, C1 esterase inhibitor is rapidly effective in two-thirds of patients and is now the reference treatment. In the absence of comparative trials, danazol remains the first-line prophylaxis when patients are scheduled for surgery a few days later, but C1 esterase inhibitor is useful when danazol is ineffective. C1 esterase inhibitor is the only available prophylaxis for patients undergoing emergency surgery (within a few hours).

    Jun;10(53):67-70

    Not available online.

    A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids

    Shahidi NT 9/2001 Clinical Therapeutics (Clin.Ther.)

    BACKGROUND: Since its discovery in 1935, numerous derivatives of testosterone have been synthesized, with the goals of prolonging its biological activity in vivo, producing orally active androgens, and developing products, commonly referred to as anabolic-androgenic steroids (AAS), that are more anabolic and less androgenic than the parent molecule.

    OBJECTIVE: This article reviews the structure, biotransformation, and mechanism of action of testosterone and some of the most commonly used AAS. Clinical applications of the AAS are discussed, and guidelines and therapeutic maneuvers for minimizing their side effects are outlined.

    METHODS: Literature for inclusion in this review was identified using the libraries of the University of Wisconsin Medical School and School of Pharmacy, the author’s files, and searches of MEDLINE, Science Citation Index, Biological Abstracts, and Chemical Abstracts.

    RESULTS: The myotrophic action of testosterone and its derivatives and their stimulatory effects on the brain have led to widespread use of AAS by athletes and “recreational” drug users. Consequently, all AAS were classified as class III controlled substances in 1991. Nonetheless, AAS have shown benefit in a variety of human disorders, including HIV-related muscle wasting and other catabolic conditions such as chronic obstructive pulmonary disease, severe burn injuries, and alcoholic hepatitis. Because of their diverse biological actions, AAS have been used to treat a variety of other conditions, including bone marrow failure syndromes, constitutional growth retardation in children, and hereditary angioedema. AAS therapy is associated with various side effects that are generally dose related; therefore, illicit use of megadoses of AAS for the purpose of bodybuilding and enhancement of athletic performance can lead to serious and irreversible organ damage. The most common side effects of AAS are some degree of masculinization in women and children, behavioral changes (eg, aggression), hepatotoxicity, and alteration of blood lipid levels and coagulation factors.

    CONCLUSIONS: To minimize or avoid serious toxicities with AAS therapy, close medical supervision and periodic monitoring are important, with dose adjustment as appropriate to achieve the minimum effective dose. Given the biological effects and potential adverse effects of AAS, administration of these agents should be avoided in pregnant women, women with breast cancer or hypercalcemia, men with carcinoma of the prostate or breast, and patients with nephrotic syndromes or significant liver dysfunction. [References: 239].

    Sep;23(9):1355-1390

    Available online at: http://www.clinicaltherapeutics.com/article/S0149-2918%2801%2980114-4/abstract (small fee)

    C1-inhibitor: an anti-inflammatory reagent with therapeutic potential

    Kirschfink M, Mollnes TE 7/2001 Expert Opinion on Pharmacotherapy (Expert Opin.Pharmacother.)

    Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis. [References: 138].

    Jul;2(7):1073-1083

    Available online at: http://www.tandfonline.com/doi/abs/10.1517/14656566.2.7.1073 (small fee)

    Dental experience and self-perceived dental care needs of patients with angioedema

    Lodi G, Sardella A, Bez C, Demarosi F, Cicardi M, Carrassi A /2001 Special Care in Dentistry

    The purpose of this study was to investigate the self-perceived dental care needs and dental experiences of patients with angioedema. At the 1998 annual meeting of the Voluntary Association for the Fight, Study and Treatment of Hereditary Angioedema (“Associazione volontaria per la lotta, lo studio e la terapia dell’angioedema ereditario”), a self-administered questionnaire was distributed to participants affected by hereditary or acquired angioedema. Fifty-seven persons completed the questionnaire (37 females, 20 males; mean age, 39 +/- 17 yrs; range, 5-76). The vast majority (91%) had the hereditary form of the disease. One-third of the respondents had some problems in obtaining oral treatment, with one person having been refused care. About half of the group had experienced an acute attack following dental treatment. Preventive measures needed improvement in about two-thirds of respondents. More than half (58%) of the group perceived a need for dental care. We conclude that persons with angioedema may experience difficulty in obtaining dental treatment, a common cause of acute attacks.

    21(1):27-31

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1754-4505.2001.tb00220.x/abstract (small fee)

    Hereditary angioedema: a broad review for clinicians

    Nzeako UC, Frigas E, Tremaine WJ 11/2001 Archives of Internal Medicine (Arch.Intern.Med.)

    Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain. [References: 100].

    Nov 12;161(20):2417-2429

    Available online at: http://archinte.jamanetwork.com/article.aspx?articleid=649449

    Rapid detection by fluorescent multiplex PCR of exon deletions and duplications in the C1 inhibitor gene of hereditary angioedema patients

    Duponchel C, Di Rocco C, Cicardi M, Tosi M /2001 Hum.Mutat

    Hereditary angioedema (HAE) is due to a variety of defects in the C1 inhibitor gene (C1NH gene), including approximately 20% of partial deletions/duplications whose boundaries are usually within Alu repeats. To ensure complete molecular characterization of C1 inhibitor deficiencies a fluorescent multiplex assay was constructed to amplify simultaneously five exons of C1NH and an exon of the BRCA1 gene. PCR protocols were optimized for these amplicons (size range between 300 and 700 bp). Forward and reverse chimeric primers that carry strand-specific 5′ tags of 16 nucleotides were used to ensure similar levels of PCR products for each amplicon in the multiplex. Data were analyzed by superposing fluorescent profiles of test and control DNA and by visually comparing the normalized peak levels of corresponding amplicons, rather than by calculating the ratios of peak areas. Tests on a collection of known defects, including five different Alu-mediated deletions and a partial duplication have validated this approach. In a study of 19 sporadic cases of HAE, of which four had failed to reveal mutations upon screening all exons by fluorescent chemical cleavage, three de novo deletions were diagnosed by using this multiplex PCR approach: a deletion of exon 4, a deletion of exons 5 and 6, and an apparently complete gene deletion. Besides being suitable for the initial DNA screening of the C1NH gene in HAE patients prior to screening for point mutations, this method can be easily adapted to complex genes for the screening of rearrangements.Copyright 2001 Wiley-Liss, Inc.

    17(1):61-70

    Available online at: http://onlinelibrary.wiley.com/doi/10.1002/1098-1004%282001%2917:1%3C61::AID-HUMU7%3E3.0.CO;2-9/abstract;jsessionid=C1383B899400799A193ACFE43E278D79.f02t01 (small fee)

    Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study

    Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M 1/2001 Stroke

    Jan;32(1):17-21

    Available online at: http://stroke.ahajournals.org/content/32/1/17.long

    Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema

    Bork K, Barnstedt SE 3/2001 Archives of Internal Medicine (Arch.Intern.Med.)

    BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease (Mendelian Inheritance in Man 106100) caused by an inherited deficiency of C1 inhibitor (C1-INH) function. The clinical symptoms include skin swelling, abdominal pain, and life-threatening episodes of upper airway obstruction. We evaluated the efficacy of C1-INH concentrate for treating sudden airway compromise. METHODS: A series of 95 patients with HAE and a functional deficiency of C1-INH belonging to 59 families underwent screening for laryngeal edema. Double-blind treatment of randomized patients was not justifiable because of the life-threatening nature of this condition. Efficacy was evaluated by determining the interval from injection of C1-INH concentrate to the beginning of resolution of symptoms. The mean duration of episodes of laryngeal edema was compared in treated and untreated patients. Clinical information was obtained from emergency department physicians, the hospitals involved, reports of the general practitioners, and patients and their relatives. RESULTS: Forty-two patients had 517 episodes of laryngeal edema. Eighteen patients received 500- or 1000-U injections of C1-INH concentrate in 193 episodes. The C1-INH concentrate was effective in all laryngeal edemas. The interval from injection to interruption in progress of symptoms ranged from 10 minutes to 4 hours (mean +/- SD, 42.2 +/- 19.9 minutes). The mean +/- SD duration of laryngeal edema was 15.3 +/- 9.3 hours in patients who received C1-INH concentrate and 100.8 +/- 26.2 hours in those who did not. CONCLUSIONS: Injected C1-INH concentrate is highly and rapidly effective in the treatment of laryngeal edema of HAE. Relief and resolution of symptoms begins 30 to 60 minutes after injection, and duration of the upper airway obstruction is substantially reduced.

    Mar 12;161(5):714-718

    Available online at:  http://archinte.jamanetwork.com/article.aspx?articleid=647595

    A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency

    Gompels MM, Lock RJ, Morgan JE, Osborne J, Brown A, Virgo PF 2/2002 J.Clin.Pathol.

    AIM: To determine the diagnostic efficiency of assays routinely used in the investigation of hereditary angio-oedema. METHODS: Over a four year period, 1144 samples were received for analysis from 907 patients suspected of C1 inhibitor deficiency. Analyses were performed for C4 and C1 inhibitor (functional and immunochemical). Notes were reviewed retrospectively on patients with low serological indicators to determine diagnosis. RESULTS: These are the first data to indicate the sensitivity, specificity, and predictive values of the assays most frequently used to screen for C1 inhibitor deficiency. A combination of low C4 and low C1 inhibitor function has 98% specificity for C1 inhibitor deficiency in this population and a 96% negative predictive value, and is thus a very effective screen. All patients with untreated C1 inhibitor deficiency had a low C4 value. CONCLUSIONS: All patients considered for a diagnosis of C1 inhibitor deficiency should have serum examined to measure both C4 and functional C1 inhibitor. If either is normal at presentation this essentially excludes a diagnosis of C1 inhibitor deficiency. These tests can be performed sequentially. If C4 is normal it is not necessary to proceed to C1 inhibitor analysis. If C1 inhibitor function and C4 are both low then a repeat sample should be obtained to confirm the findings.

    Feb;55(2):145-147

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769585/

    C1 inhibitor infusion modifies platelet activity in hereditary angioedema patients

    Coppola L, Guastafierro S, Verrazzo G, Coppola A, De Lucia D, Tirelli A 7/2002 Archives of Pathology & Laboratory Medicine (Arch.Pathol.Lab.Med.)

    CONTEXT: C1 inhibitor (C1-INH) is an alpha2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The alpha-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE).

    OBJECTIVE: To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE. DESIGN: Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate.

    PATIENTS: In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria.

    MEASUREMENTS: Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5 microM; collagen, 5 microg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay).

    RESULTS: After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate- and collagen-induced platelet aggregation versus preinfusion values (maximum after 1-2 days; P <.001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively.

    CONCLUSIONS: These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.

    Jul;126(7):842-845

    Available online at: http://www.archivesofpathology.org/doi/full/10.1043/0003-9985%282002%29126%3C0842%3ACIIMPA%3E2.0.CO%3B2

    Clinical management of hereditary angio-oedema in children

    Farkas H, Harmat G, Fust G, Varga L, Visy B 6/2002 Pediatric Allergy & Immunology

    Hereditary angio-oedema (HAE) results from the deficiency of C1-esterase inhibitor (C1-INH). The clinical picture of this autosomal dominant disorder is characterized by recurrent attacks of subcutaneous oedema and/or potentially life-threatening swelling of the submucosa. This review discusses the authors’ decade-long experience obtained in the treatment and follow-up of pediatric patients with HAE. Twenty-six children with HAE were reviewed. Pedigree analysis was performed in all cases to identify afflicted relatives. C1-INH concentrate was reserved for the emergency treatment of acute oedematous attacks, whereas tranexamic acid and danazol were administered for short- or long-term prophylaxis. Follow-up care included laboratory tests and abdominal ultrasound, which was repeated at regular intervals. Twenty-one children had Type I HAE and five suffered from Type II HAE. Clinical manifestations of the disease first occured in children when 2.5-12 years of age. Oedema formation primarily afflicted subcutaneous tissues. Mechanical trauma was identified as a precipitating factor in 20 patients. Pedigree analysis revealed 24 patients with relatives who suffered from HAE. Long-term prophylaxis with tranexamic acid or danazol was initiated in 11 patients; two children required short-term prophylaxis. No drug-related adverse effects were observed, except for one case of delayed menarche. Therapy improved serum complement parameters significantly and substantially reduced the frequency and severity of clinical episodes. Adequate prophylaxis and follow-up care can spare pediatric patients from oedematous attacks caused by HAE. Undesirable adverse effects can be avoided and the patient’s quality of life enhanced considerably by administering the lowest effective drug dose. [References: 30].

    Jun;13(3):153-161

    Available online at: http://onlinelibrary.wiley.com/doi/10.1034/j.1399-3038.2002.01014.x/full (small fee)

    Current management of hereditary angio-oedema (C’1 esterase inhibitor deficiency)

    Fay A, Abinun M 4/2002 J.Clin.Pathol.

    Hereditary angio-oedema is characterised by recurrent swellings in any part of the body and also by recurrent attacks of severe abdominal pain. The disease is inherited in an autosomal dominant manner but up to 25% of cases can occur as a spontaneous mutation. Attacks of swelling can be precipitated by trauma, certain drugs, and emotional stress. Treatment usually involves a combination of prophylaxis, using androgens or antifibrolytic drugs, and replacement with C’1 esterase inhibitor concentrate for acute attacks and before surgery or other traumatic procedures. [References: 106].

    Apr;55(4):266-270

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769636/

    Does heparin prophylaxis prevent exacerbations of hereditary angioedema?

    Weiler JM, Quinn SA, Woodworth GG, Brown DD, Layton TA, Maves KK 6/2002 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by episodes of angioedema of the skin, mucous membranes, and gastrointestinal tract resulting from a defect in the gene that produces C1 esterase inhibitor. Although in vitro laboratory data and past reports suggested that heparin might be efficacious in preventing HAE attacks, no controlled study has been reported to examine heparin’s efficacy in this regard.

    OBJECTIVES: We sought to determine the safety and efficacy of inhaled and subcutaneous heparin versus that of placebo in the prevention of HAE attacks.

    METHODS: We performed a double-blind, double-dummy, saline placebo-controlled, randomized, 3-way crossover study with 11 visits.

    RESULTS: The study was designed to enroll 24 patients. Twenty-two patients were randomized and received the study drug. Patients did not have a significant decrease in average flare intensity after they received injected or inhaled heparin compared with that seen after placebo, the primary endpoint. However, when patients received injected heparin, they had a statistically significant decrease in average flare intensity compared with that seen with inhaled heparin after a normalizing transformation was applied. When the means are back transformed, this translates into median flare intensities of 9.2, 8.0, and 5.1 in the patients treated with inhaled heparin, placebo, and injected heparin, respectively. There were no significant differences when individual symptoms were examined, when total numbers of flares over a 6-week observation period were examined, or when global evaluations by the patients and investigators were evaluated. Adverse event severity was fairly uniform across treatments, with the majority of events classified as moderate and the remainder split between mild and severe. Injected heparin treatment was associated with higher rates of relatedness than other treatments, which was partially explained by 17 adverse events specifically related to the injection process itself (tenderness, bruising, redness, pain, and itching at the injection site). The injection treatment was also associated with a larger overall number of reported adverse events (70 vs 48 in the placebo treatment). Tenderness and bruising at the injection site were entirely confined to the injected heparin treatment.
    CONCLUSIONS: Injected and inhaled heparin failed to attenuate average flare intensity, the primary endpoint, compared with placebo. Interestingly, after patients injected heparin, they had a significant decrease in average flare intensity compared with that seen after inhalation of heparin. There were no differences among groups in other efficacy parameters. Taken together, these data indicate that commercial heparin was ineffective in preventing exacerbations of HAE.

    Jun;109(6):995-1000

    Available online at: http://www.jacionline.org/article/S0091-6749%2802%2900014-3/fulltext

    Prolonged cerebral transit time in CADASIL: a transcranial ultrasound study

    Liebetrau M, Herzog J, Kloss CU, Hamann GF, Dichgans M 2/2002 Stroke

    BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmophilic material in the vicinity of degenerating vascular smooth muscle cells. In this study, we measured the arteriovenous cerebral transit time (CTT) to identify changes related to the microangiopathy in CADASIL.

    METHODS: CTT is the time that a contrast agent needs to pass from a cerebral artery to its corresponding vein. CTT was measured in 17 CADASIL individuals (mean age, 50.2+/-12.3 years) and an equal number of age- and sex-matched control subjects (mean age, 48.9+/-13.0 years) with transcranial color-coded duplex sonography. The intensity curves were recorded in the P2 segment of the posterior cerebral artery and the vein of Galen after injection of the ultrasound contrast agent Levovist.

    RESULTS: CTT was significantly prolonged in individuals with CADASIL (4.4+/-1.9 seconds) compared with control subjects (1.3+/-0.5 seconds, P<0.0001). This difference was also significant when only nondisabled CADASIL individuals (Rankin score=0, n=9) were analyzed (P<0.0001). There was a nonsignificant trend for a correlation between Rankin score and CTT (r=0.39, P=0.11).

    CONCLUSIONS: The prolonged CTT likely reflects microvascular changes in CADASIL. Measurements of the CTT may be used clinically to disclose small-vessel disease. Studies comparing CADASIL subjects with other patient populations seem warranted to determine possible differences in CTT between different types of small-vessel disease.

    Feb;33(2):509-512

    Available online at: stroke.ahajournals.org/content/33/2/509.full.pdf

    Angioedema and oral contraception

    Bouillet L, Ponard D, Drouet C, Jullien D, Massot C /2003 Dermatology

    BACKGROUND: Oral contraceptives can precipitate attacks of hereditary angioedema (ANE) or induce acquired forms.

    OBJECTIVE: We studied 5 patients who had an ANE which had begun under oral contraception and disappeared after stopping the pill.

    METHODS: We explored the clinical and biological characteristics of these patients.

    RESULTS: The symptoms developed during the first year or later after starting contraception; the patients reported relapsing swelling of the lips, hands, larynx and abdomen. All women had normal serum C4 and C1 inhibitor (C1Inh) antigen levels, but a lowered C1Inh activity, with a marked protein cleavage on the immunoblot. The suppression of the pill was associated with the regression of the edema and normalization of C1Inh function.

    CONCLUSION: The mechanism of these ANE is unknown. The could be due to a modulation of C1Inh expression upon androgens or an imbalance between coagulation proteins favoring C1Inh cleavage by its target proteases.Copyright 2003 S. Karger AG, Basel.

    206(2):106-109

    Available online at: https://www.karger.com/Article/Abstract/68456 (small fee)

    Diagnosis and management of hereditary angioedema: an American approach

    Zuraw BL 12/2003 Immunology & Allergy Clinics of North America

    Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of angioedema, and caused by a deficiency of the plasma protein C1 inhibitor. HAE attacks carry a substantial risk of morbidity or even mortality, making it imperative that the correct diagnosis be established and an appropriate management plan be in place. This report reviews the current diagnostic and therapeutic approaches available in the United States. Areas in which the diagnostic or therapeutic tools are deficient are discussed, and the prospects for improved therapeutic modalities highlighted.

    Dec;29(3):239-245

    Available online at: http://www.trasci.com/article/S1473-0502%2803%2900174-5/fulltext (small fee)

    DX-88 and HAE: a developmental perspective

    Williams A, Baird LG 12/2003 Transfusion & Apheresis Science

    An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.

    Dec;29(3):255-258

    Available online at: http://www.sciencedirect.com/science/article/pii/S1473050203001708 (small fee)

    Extracellular proteases and their inhibitors in genetic diseases of the central nervous system

    Molinari F, Meskanaite V, Munnich A, Sonderegger P, Colleaux L 10/2003 Hum.Mol.Genet.

    Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field. [References: 38].

    Oct 15;12(Spec 2):R195-200

    Available online at: http://hmg.oxfordjournals.org/content/12/suppl_2/R195.long

    How do we treat patients with hereditary angioedema

    Cicardi M, Zingale L 12/2003 Transfusion & Apheresis Science

    Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.

    Dec;29(3):221-227

    Available online at: http://www.trasci.com/article/S1473-0502%2803%2900164-2/fulltext (small fee)

    Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol

    Pappalardo E, Zingale LC, Cicardi M 5/2003 Immunol.Lett.

    The attenuated androgen Danazol can partially reverse the biochemical defect and prevent angioedema in patients with inherited C1-inhibitor (C1-INH) deficiency (hereditary angioedema, HAE). Though its clinical effectiveness is independent from significant increase of C1-INH plasma levels, its mechanism of action remains unknown. Since angioedema is a local phenomenon, it could be controlled by restoring tissue levels of C1-INH. We measured the expression of C1-INH mRNA in peripheral blood mononuclear cells (PBMCs) of 13 patients with HAE type 1 (seven untreated and asymptomatic, and six on Danazol at the minimal effective dose) and of eight normal controls. mRNA levels were quantitated by computerized optical densitometry of reverse transcriptase-PCR products, normalized for the amount of glyceraldehyde-3-phosphate-dehydrogenase and expressed as percent of normal pooled RNAs. Each determination represented the mean of three separate experiments. Measurement of C1-INH mRNA in two patients before and after 1 month of Danazol 400 mg per day demonstrated a post-treatment increase of 15 and 21%, respectively. When HAE patients and controls were analyzed as groups, C1-INH mRNA levels of patients untreated and asymptomatic (median 73%, range 65-78) were significantly lower (P=0.001) compared to controls (median 101%, range 87-121) and to patients on Danazol (median 91%, range 82-96); the difference among the last two groups was not statistically significant. Our data demonstrate that minimal effective doses of Danazol increase the expression of C1-INH mRNA in PBMC of HAE patients even in the absence of a significant increase of C1-INH plasma levels.

    May 1;86(3):271-276

    Available online at: http://www.sciencedirect.com/science/article/pii/S0165247803000294 (small fee)

    Management of hereditary angioedema: a Canadian approach.

    Bowen T, Hebert J, Ritchie B, Burnham J, MacSween M, Warrington R, Yang W, Issekutz A, Karitsiotis N, McCombie N, Giulivi T. 12/2003 Transfusion and Apheresis Science

    C1 esterase inhibitor (C1-INH) deficiency is a rare disorder that lacks consensus for diagnosis therapy and management. Recognizing that Canada is behind the European approach to this disorder, we have formed the Canadian Hereditary Angioedema Society (CHAES)/Société d’angioédème héréditaire du Canada (SAHC) to foster knowledge of this disorder in Canada and to advance care of patients with this disorder in Canada. We here present a review of treatment of this disorder in Canada including prevention of angioedema events and use of replacement therapy and present an algorithm for diagnosis therapy and management of C1-INH deficiency in Canada for discussion at our International Conference on Hereditary Angioedema to be held in Toronto, Canada, October 24th to 26th, 2003.

    Available online at: http://www.ncbi.nlm.nih.gov/pubmed/14572811?dopt=Abstract

    Protease inhibitors in the treatment of hereditary angioedema

    Ritchie BC 12/2003 Transfusion & Apheresis Science

    Deficiency of C1 Inhibitor leads to unopposed activation of complement, with localized, unpredictable, and sometimes life-threatening attacks of angioedema. Treatment with plasma-derived C1 Inhibitor rapidly aborts attacks, and may be lifesaving, but is expensive, requires use of a pooled blood product, may need to be repeated and may not be effective in autoantibody mediated angioedema. The antifibrinolytic agents aprotinin, tranexamic acid, and epsilon-aminocaproic acid are useful for prophylaxis and treatment of angioedema, likely by inhibiting plasmin. Specific drugs to replace the deficient C1 Inh have not been reported. The kallikrein inhibitor DX-88 (Dyax) has received orphan drug status in Europe and is undergoing clinical trial in Europe and the USA. [References: 98].

    Dec;29(3):259-267

    Available online at: http://www.trasci.com/article/S1473-0502%2803%2900169-1/fulltext (small fee)

    Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy

    Bork K, Fischer B, Dewald G 3/2003 The American Journal of Medicine (Am.J.Med.)

    PURPOSE: Recurrent angioedema, characterized by skin swelling, colicky attacks of abdominal pain, and life-threatening laryngeal edema, can be either hereditary or acquired. According to anecdotal reports, it may be associated with use of oral contraceptives and hormone replacement therapy. We investigated potential interactions between these medications and various types of recurrent angioedema in a large cohort of women.

    METHODS: Women with recurrent angioedema (n = 516) underwent a thorough medical evaluation. They were then classified by type of angioedema, using standard criteria.

    RESULTS: Of the 516 women, 228 (44%) had used oral contraceptives or hormone replacement therapy, including 103 (45%) with urticaria-related angioedema, 50 (22%) with idiopathic angioedema, 39 (17%) with hereditary angioedema type III, 32 (14%) with hereditary angioedema type I, and 4 (2%) with angioedema induced by angiotensin-converting enzyme inhibitors. Oral contraceptives or hormone replacement therapy led to angioedema attacks in 46 women (20%), including 20 (63%) of the women with hereditary angioedema type I, 24 (62%) of those with hereditary angioedema type III, and 2 (4%) of those with idiopathic angioedema. These 46 women included 26 in whom symptoms occurred for the first time after use of these medications and 20 in whom pre-existing recurrent angioedema worsened considerably.

    CONCLUSION: Oral contraceptives or hormone replacement therapy can either induce or exacerbate symptoms of hereditary angioedema type I or type III, or idiopathic angioedema. However, many women with these diseases tolerate these medications without having any effects on their angioedema.

    Mar;114(4):294-298

    Available online at: http://www.amjmed.com/article/S0002-9343%2802%2901526-7/pdf (small fee)

    Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. jean.de.serres@aventis.com.

    De Serres J, Groner A, Lindner J /2003 Transfusion & Apheresis Science

    Available online at: http://www.sciencedirect.com/science/article/pii/S147305020300171X (full text)

     

    Sudden upper airway obstruction in patients with hereditary angioedema

    Bork K, Ressel N 12/2003 Transfusion & Apheresis Science

    Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

    Dec;29(3):235-238

    Available online at:  http://www.trasci.com/article/S1473-0502%2803%2900172-1/fulltext (small fee)

    Biological effects of C1 inhibitor

    Davis AE,3rd 9/2004 Drug News & Perspectives

    C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium. [References: 113].

    Sep;17(7):439-446

    Available online at: https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=3&p_RefId=496 (small fee)

    Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema.

    Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, Varga L, Martinez-Saguer I, Aygören-Pürsün E, Binkley K, Zuraw B, Davis A 3rd, Hebert J, Ritchie B, Burnham J, Castaldo A, Menendez A, Nagy I, Harmat G, Bucher C, Lacuesta G, Issekutz A, Warrington R, Yang W, Dean J, Kanani A, Stark D, McCusker C, Wagner E, Rivard GE, Leith E, Tsai E, MacSween M, Lyanga J, Serushago B, Leznoff A, Waserman S, de Serres J. 09/2004 J Allergy Clin Immunol.

    C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Société d’Angioédème Héréditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.

    Available online at: http://www.ncbi.nlm.nih.gov/pubmed/15356569

    Erythema marginatum and hereditary angioedema

    Starr JC, Brasher GW, Rao A, Posey D 10/2004 South.Med.J.

    OBJECTIVE: To search for anaphylatoxin activity in plasma during episodes of erythema marginatum, and to evaluate the histology of erythema marginatum by electron microscopy and immunohistologic techniques. METHODS: Plasma samples were studied for C5a activity by granulocyte aggregation, and C3 conversion by immunoelectrophoresis. A skin biopsy of erythema

    METHODS: Plasma samples were studied for C5a activity by granulocyte aggregation, and C3 conversion by immunoelectrophoresis. A skin biopsy of erythema marginatum was done, and the tissue stained with a rabbit antibody to bradykinin. RESULTS: No plasma anaphylatoxin was found. Dense deposits of bradykinin were discovered in stromal tissue and lining endothelial cells. CONCLUSIONS: Bradykinin may be important in the causality of the erythema

    RESULTS: No plasma anaphylatoxin was found. Dense deposits of bradykinin were discovered in stromal tissue and lining endothelial cells. CONCLUSIONS: Bradykinin may be important in the causality of the erythema

    CONCLUSIONS: Bradykinin may be important in the causality of the erythema marginatum associated with hereditary angioedema.

    Oct;97(10):948-950

    Available online at: http://sma.org/southern-medical-journal/article/erythema-marginatum-and-hereditary-angioedema/ (small fee)

    Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond

    Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al 9/2004 Journal of Allergy & Clinical Immunology

    Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

    Sep;114(3 Suppl):S51-131

    Available online at: http://pharmrev.aspetjournals.org/content/50/1/59.long

    Hereditary angioedema: the rewards of studying a rare disease

    Frank MM 7/2004 Journal of Allergy & Clinical Immunology

    Jul;4(4):251-253

    Available online at: http://link.springer.com/article/10.1007%2Fs11882-004-0064-7#page-1 (small fee)

    Icatibant: HOE 140, JE 049, JE049

    /2004 Drugs in R & D

    Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin beta2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now Sanofi-Aventis). Jerini is seeking a partner for development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis, angioedema and burns. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. Positive results from an icatibant formulation comparative study, in patients with acute attacks of hereditary angioedema, were announced in August 2004; IV and SC formulations showed no difference in efficacy and safety. It was announced in September 2004 by Jerini that a pivotal study, known as For Angioedema Subcutaneous Treatment (FAST) 1, had been initiated in the US and Canada. The protocol of a European study, to be known as FAST 2, is to be submitted to the authorities in September 2004. Jerini expects to launch the product in 2006. The US FDA granted icatibant, for the treatment of hereditary angioedema, fast-track designation in July 2004. In January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema. In November 2003, Jerini announced that effective December 2003, icatibant had orphan drug status in the US for the same indication. [References: 26].

    5(6):343-348

    Available online http://link.springer.com/article/10.2165%2F00126839-200405060-00006 (small fee)

    Sex hormones in hereditary angioneurotic oedema

    Visy B, Fust G, Varga L, Szendei G, Takacs E, Karadi I, et al 4/2004 Clin.Endocrinol.(Oxf)

    OBJECTIVE: The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy or during the use of oral contraceptives can precipitate oedematous attacks in hereditary angioneurotic oedema (HANO). Attacks usually disappear after the onset of menopause. This study was undertaken to establish any relationship between the serum levels of sex hormones and the incidence of HANO attacks.

    PATIENTS AND MEASUREMENTS: Serum levels of LH, FSH, progesterone, oestradiol, testosterone, PRL and SHBG were measured in 78 patients [mean age 30.3 years (range 4-70 years)] with HANO. A questionnaire was used to explore the medical history of adult patients to characterize the evolution and the characteristics of attacks.

    RESULTS: The number of attacks was significantly higher [odds ratio (OR) 6.36 (1.31-30.81); P = 0.022] in females with high progesterone levels (> or = 4 nmol/l), irrespective of age, menstrual cycle and danazol dose. The OR was even higher [13.4 (2.2-81.4); P = 0.005] when only subcutaneous attacks were considered. Multiple logistic regression analysis demonstrated a significantly lower attack frequency during 1-year follow-up in patients with a higher (40 nmol/l) SHBG level (OR 0.25 (0.07-0.90); P = 0.034). This difference existed independently of age and danazol dose.

    CONCLUSION: In view of these results, the monitoring of progesterone and SHBG levels can prove useful in the prediction of attacks in hereditary angioneurotic oedema.

    Apr;60(4):508-515

    Available online at: http://onlinelibrary.wiley.com/wol1/doi/10.1111/j.1365-2265.2004.02009.x/full (small fee)

    A direct role for C1 inhibitor in regulation of leukocyte adhesion

    Cai S, Dole VS, Bergmeier W, Scafidi J, Feng H, Wagner DD, et al 5/2005 Journal of Immunology

    Plasma C1 inhibitor (C1INH) is a natural inhibitor of complement and contact system proteases. Heterozygosity for C1INH deficiency results in hereditary angioedema, which is mediated by bradykinin. Treatment with plasma C1INH is effective not only in patients with hereditary angioedema, but also in a variety of other disease models, in which such therapy is accompanied by diminished neutrophil infiltration. The underlying mechanism has been explained primarily as a result of the inhibition of the complement and contact systems. We have shown that C1INH expresses the sialyl-Lewis(x) tetrasaccharide on its N-linked glycan, via which it binds to E- and P-selectins and interferes with leukocyte-endothelial adhesion in vitro. Here we show that both native C1INH and reactive center cleaved C1INH significantly inhibit selectin-mediated leukocyte adhesion in several in vitro and in vivo models, whereas N-deglycosylated C1INH loses such activities. The data support the hypothesis that C1INH plays a direct role in leukocyte-endothelial cell adhesion, that the activity is mediated by carbohydrate, and that it is independent of protease inhibitory activity. Direct involvement of C1INH in modulation of selectin-mediated cell adhesion may be an important mechanism in the physiologic suppression of inflammation, and may partially explain its utility in therapy of inflammatory diseases.

    May 15;174(10):6462-6466

    Available online at: http://www.jimmunol.org/content/174/10/6462.full

    A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema

    van Doorn MB, Burggraaf J, van Dam T, Eerenberg A, Levi M, Hack CE, et al 10/2005 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a congenital disorder with recurrent attacks of localized swelling of submucosal tissue, subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor (C1 esterase inhibitor [C1INH]).

    OBJECTIVE: We sought to evaluate the effects of recombinant human C1INH (rhC1INH) isolated from the milk of transgenic rabbits in 12 asymptomatic patients with HAE.

    METHODS: rhC1INH was intravenously administered at doses of 6.25 to 100 U/kg on 2 occasions.

    RESULTS: rhC1INH appeared safe and was well tolerated. The course of functional C1INH in plasma showed a full initial recovery (dose-normalized maximum concentration of about 0.02 U/mL/U/kg) and a dose-dependent clearance of rhC1INH. After infusion of rhC1INH at 100 U/kg, a clearance of approximately 13 mL/min, a half-life of approximately 3 hours, and a volume of distribution of approximately 3 L were observed. Infusion at this dose led to functional C1INH levels in plasma of at least twice the normal level for about 2 hours and greater than 0.4 U/mL for about 9 hours. rhC1INH displayed dose-dependent biologic activity by increasing the C4 level, which was about 2-fold at 12 hours after rhC1INH at 100 U/kg, and decreasing levels of cleaved C4.

    CONCLUSION: The observed safety profile and biologic activity of rhC1INH warrants further clinical studies to assess its efficacy in treating HAE attacks.

    Oct;116(4):876-883

    Available online at: http://www.jacionline.org/article/S0091-6749%2805%2901318-7/fulltext

    Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema

    Szeplaki G, Varga L, Valentin S, Kleiber M, Karadi I, Romics L, et al 4/2005 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare disorder caused by the deficiency of the C1-inhibitor gene (C1INH) . Patients experience recurrent bouts of edema, which can occur in almost any region of the body. As regards the treatment of the disease, danazol (an attenuated androgen) is used, among other agents, for long-term prophylaxis.

    OBJECTIVE: The aim of this study was to investigate the possible adverse effects of danazol on serum lipid profile, as well as to ascertain whether danazol treatment is associated with an increased risk of atherosclerosis.

    METHODS: Serum concentrations of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, apolipoprotein A-I, apolipoprotein B-100, and lipoprotein(a) were compared between danazol-treated patients with HAE and 2 control groups (ie, patients who did not receive long-term danazol prophylaxis and untreated healthy subjects).

    RESULTS: Serum concentrations of HDL ( P = .0002 and P < .0001) and apolipoprotein A-I ( P = .0015 and P < .0001) were significantly lower, whereas LDL ( P = .0129 and P = .0127) and apolipoprotein B-100 ( P = .0456 and P = .0013) were higher in the danazol-treated patients compared with the 2 control groups, respectively. No significant difference was found in total cholesterol, triglyceride, or lipoprotein(a) levels. Patients who received danazol had an 11.6 (95% CI, 2.7-49.7) times higher risk for abnormally low HDL levels and a 4.4 (95% CI, 1.2-16.0) times lower risk for high LDL concentrations.

    CONCLUSIONS: Our findings indicate that the long-term use of danazol is associated with an increased risk for early atherosclerosis in patients with HAE. Consequently, monitoring of HDL and LDL levels at regular intervals is recommended during follow-up.

    Apr;115(4):864-869

    Available online at: http://www.jacionline.org/article/S0091-6749%2805%2900028-X/fulltext

    Angioedema

    Kaplan AP, Greaves MW 9/2005 Journal of the American Academy of Dermatologya (Journal of the American Academy of Dermatologya (J.Am.Acad.Dermatol.)

    UNLABELLED: Although first described more than 130 years ago, the pathophysiology, origin, and management of the several types of angioedema are poorly understood by most dermatologists. Although clinically similar, angioedema can be caused by either mast cell degranulation or activation of kinin formation. In the former category, allergic and nonsteroidal anti-inflammatory drug-induced angioedema are frequently accompanied by urticaria. Idiopathic chronic angioedema is also usually accompanied by urticaria, but can occur without hives. In either case, an autoimmune process leading to dermal mast cell degranulation occurs in some patients. In these patients, histamine-releasing IgG anti-FcepsilonR1 autoantibodies are believed to be the cause of the disease, removal or suppression by immunomodulation being followed by remission. Angiotensin-converting enzyme inhibitor-induced angioedema is unaccompanied by hives, and is caused by the inhibition of enzymatic degradation of tissue bradykinin. Hereditary angioedema, caused by unchecked tissue bradykinin formation, is recognized biochemically by a low plasma C’4 and low quantitative or functional C’1 inhibitor. Progress has now been made in understanding the molecular genetic basis of the two isoforms of this dominantly inherited disease. Recently, a third type of hereditary angioedema has been defined by several groups. Occurring exclusively in women, it is not associated with detectable abnormalities of the complement system. Angioedema caused by a C’1 esterase inhibitor deficiency can also be acquired in several clinical settings, including lymphoma and autoimmune connective tissue disease. It can also occur as a consequence of specific anti-C’1 esterase autoantibodies in some patients. We have reviewed the clinical features, diagnosis, and management of these different subtypes of angioedema. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the classification, causes, and differential diagnosis of angioedema, the molecular basis of hereditary and non-hereditary forms of angioedema, and be able to formulate a pathophysiology-based treatment strategy for each of the subtypes of angioedema. [References: 115].

    quiz 389-92; Sep;53(3):373-388

    Available online at: http://www.jaad.org/article/S0190-9622%2804%2902515-0/fulltext (small fee)

    Basic and clinical immunology

    Chinen J, Shearer WT 8/2005 Journal of Allergy & Clinical Immunology

    The authors selected articles published in the literature from January 2004 through December 2004 that were relevant to the areas of basic and clinical immunology. Several articles explored the development of TH1 or TH2 response and the role of the monocyte-T cell interaction. Others were articles describing the action of drugs commonly used in asthma to inhibit cytokine responses and the anti-inflammatory role of nonimmune pulmonary cells present in the lung. Several reports show how dendritic cells are being developed as vehicles for DNA vaccines aimed at stimulating cellular responses, an advance of great importance for HIV researchers working on vaccines, who are concerned about the different ways HIV evades the immune response. Other publications described Toll-like receptors in diverse cells, including mast cells and CD4+ T cells, for the recognition of viruses and bacteria. In the area of clinical immunology, an updated classification for primary immunodeficiencies with more than 100 identified genes responsible for these diseases and the report on the second clinical trial of gene therapy for X-linked severe combined immunodeficiency syndrome were published. Significant advances included the clinical prognosis in common variable immunodeficiency for patients presenting with lung pathology, the safety of live vaccines in partial DiGeorge syndrome, the report of patients with complete DiGeorge syndrome with the presence of peripheral blood T cells, the clinical spectrum of patients with NF-kappaB essential modifier (NEMO) gene deficiency, the publication of a consensus algorithm for the management of hereditary angioedema, and the report of immune restoration syndrome in pediatric HIV infection. [References: 54].

    Aug;116(2):411-418

    Available online at: http://www.jacionline.org/article/S0091-6749%2805%2901305-9/fulltext

    C1 inhibitor deficiency: consensus document

    M. M. Gompels, R. J. Lock1, M. Abinun2, C. A. Bethune, G. Davies, C. Grattan, A. C. Fay, H. J. Longhurst, L. Morrison1, A. Price, M. Price andD. Watters 02/2005 Clinical & Experimental Immunology

    We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification.

    The electronic version of this article is the complete one and can be found online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2249.2005.02726.x/full

    C1 inhibitor deficiency: consensus document

    Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al 3/2005 Clinical & Experimental Immunology

    We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification. [References: 138].

    Mar;139(3):379-394

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2249.2005.02726.x/full

    Current and future therapy for hereditary angioedema

    Zuraw BL 1/2005 Clinical Immunology

    Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. Attacks of angioedema in HAE patients typically last 3 or more days, begin during childhood, and continue to occur throughout life. Tragically, patients with HAE continue to die as a direct consequence of the disease. Minimizing the morbidity and mortality associated with HAE requires both effective treatment of acute attacks as well as strategies to prevent HAE attacks. While there is currently no effective therapy available in the United States for the treatment of acute attacks of HAE, several molecules have demonstrated impressive efficacy in this setting, and it is likely that one or more of these new drugs will become available in the United States soon. This article will review both the current and the future therapeutic options for the treatment of HAE. [References: 63].

    Jan;114(1):10-16

    Available online at: http://www.sciencedirect.com/science/article/pii/S1521661604002414 (small fee)

    Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence?

    Longhurst HJ 5/2005 Int.J.Clin.Pract.

    Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase-inhibitor (C1-INH) and is characterised by skin swelling, abdominal pain and episodes of upper respiratory tract obstruction. Oedema of the larynx can result in rapid asphyxiation and requires emergency treatment. Three treatment options for emergency treatment of HAE are reviewed: fresh frozen plasma, solvent/detergent-treated plasma and C1-INH concentrate. It is concluded that while all three treatment options are theoretically effective in the emergency treatment of HAE, C1-INH is the treatment of choice. [References: 31].

    May;59(5):594-599

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2005.00352.x/full

    Hereditary angioedema

    Frank MM 12/2005 Immunology & Allergy Clinics of North America

    PURPOSE OF REVIEW: Major advances have been made in understanding the clinical signs and symptoms, the pathophysiology and the treatment of hereditary angioedema. This disease that often begins in childhood is caused by partial absence of the plasma protein C1-inhibitor. At the present time five pharmaceutical companies are planning or conducting clinical trials of a variety of agents to treat acute attacks of this illness. Here we review our current understanding of this illness and the current approaches to treatment.

    RECENT FINDINGS: This disease is often missed in childhood or confused with other illness. The clinical signs and symptoms are reviewed. The importance of the kinin generating pathway and bradykinin in causing edema has become central to our understanding of pathophysiology. The many new approaches to therapy all appear promising.

    SUMMARY: Currently we have effective chronic therapy for this disease, although available drugs have real or potential difficulties in use in children. In the future it is likely that effective therapy for acute attacks of disease will become available in the US. It is important to recognize the clinical manifestations of this potentially fatal illness and to understand the therapeutic options. [References: 31].

    Dec;17(6):686-689

    Available online at: http://journals.lww.com/co-pediatrics/Abstract/2005/12000/Hereditary_angioedema.3.aspx (small fee)

    Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema

    Bork K, Meng G, Staubach P, Hardt J 11/2005 Transfusion

    BACKGROUND: Abdominal edema attacks in patients with hereditary angioedema are often extremely painful, associated with vomiting and diarrhea, and have a high potential for causing recurrent disability of the patient. STUDY DESIGN AND METHODS: Intraindividual comparison of retrospective data in 75 hereditary angioedema patients comprising 4,834 abdominal attacks treated with C1 inhibitor concentrate versus 17,444 untreated abdominal attacks. RESULTS: The mean duration of abdominal attacks was 92.0 hours (SD, 40.8 hr) when untreated compared to 39.9 hours (SD, 30.0 hr) when treated. Patients reported a mean maximal pain score of 8.6 (SD, 1.7; range, 1-10) for untreated attacks compared to 4.5 (SD, 2.9) when treated. Vomiting occurred in 83.3 percent of untreated attacks and in 6.0 percent of treated attacks, respectively. Diarrhea was reported in 41.8 percent of untreated attacks and in 11.0 percent of treated attacks, whereas cardiovascular collapse due to hypovolemia was observed in 3.5 percent of untreated attacks versus 0.1 percent in treated attacks. Mean time to relief of symptoms was 53.5 minutes when treated early compared to 114 minutes when treatment was delayed. No drug-related adverse or serious adverse events were observed as far as the injections were performed correctly. CONCLUSION: C1 inhibitor concentrate is highly effective and safe in treating abdominal attacks in patients suffering from hereditary angioedema.

    Nov;45(11):1774-1784

    Available online at:  http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2005.00602.x/full (small fee)

    Ecallantide (Dyax/Genzyme)

    Lehmann A 3/2006 Expert Opinion on Biological Therapy

    Ecallantide is one of a series of small-protein kallikrein inhibitors, identified through Dyax Corp’s phage display technology, that is being developed by Dyax and Genzyme as a potential subcutaneous treatment for hereditary angioedema (HAE). Dyax is also independently developing ecallantide for the reduction of peri-operative blood loss during cardiopulmonary bypass surgery. The company had expected to begin phase II clinical studies in coronary bypass graft patients in the first half of 2005; however, by October 2005, these trials had been delayed until partnership negotiations for the program were completed. A pivotal, phase III clinical trial of ecallantide in HAE began in December 2005.

    Mar;7(3):282-290

    Not available online.

    Evaluation and management of angioedema of the head and neck

    Bas M, Hoffmann TK, Kojda G 7/2006 Current Opinion in Otolaryngology & Head & Neck Surgery

    PURPOSE OF REVIEW: Sudden occurrence of subcutaneous or submucosal swelling, the so-called angioedema, is an established and potentially life-threatening condition. Several forms of angioedema show a great variety of tissue localizations and different underlying mechanisms such as genetic mutations, allergic reactions and nonallergic reactions exist. Unfortunately, angioedema is often unrecognized and/or incorrectly treated. To change this situation, a better understanding of angioedema and possible therapeutic approaches appears necessary.

    RECENT FINDINGS: Recent investigations have shed new light on the pathomechanism of nonallergic drug-induced angioedema and new therapeutic options targeting the kallikrein-kinin system have become available for patients in clinical trials. Furthermore, extensive clinical evaluations of commonly used inhibitors of the renin-angiotensin system have provided reliable data on the incidence of angioedema induced by these drugs. Accordingly, several thousand patients worldwide experience severe fatal attacks although timely medical care would have saved their lives.

    SUMMARY: Current data suggest that the nonapetide bradykinin plays a crucial role in the pathogenesis of most forms of nonallergic angioedema, while histamine acts as the main biogenic mediator in allergic angioedema. Thus, correct diagnosis is crucial for effective treatment. Standard antiallergic drugs such as glucocorticoids and antihistamines are most probably ineffective in nonallergic angioedema forms. [References: 48].

    Jun;14(3):170-175

    Available online at: http://journals.lww.com/co-otolaryngology/pages/articleviewer.aspx?year=2006&issue=06000&article=00013&type=abstract (small fee)

    Hereditary angioedema

    Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M 10/2006 Journal of Drugs in Dermatology: JDD

    Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a C1-inhibitor deficiency. It is characterized by potentially life-threatening recurrent episodes of angioedema of the skin and mucosa. Several recent studies have further elucidated the immunology of HAE implicating bradykinin, the key mediator of the contact system. This article reviews the pathophysiology, subtypes, and clinical features of HAE. Therapeutic approaches for various clinical situations (emergency and prophylactic regimens) are also discussed. [References: 48].

    Oct;5(9):848-852

    Available online at: http://jddonline.com/articles/dermatology/S1545961606P0848X/1 (small fee)

    Hereditary angioedema: causes, manifestations and treatment

    Longhurst HJ, Bork K 12/2006 Br.J.Hosp.Med.

    Dec;67(12):654-657

    Available online at: http://www.magonlinelibrary.com/doi/abs/10.12968/hmed.2006.67.12.22439 (small fee)

    Hereditary angioedema: the clinical syndrome and its management in the United States

    Frank MM 11/2006 Annals of Allergy, Asthma, & Immunology

    There have been important breakthroughs in the understanding and treatment of hereditary angioedema (HAE). An associated abnormality of the serum protein C1 inhibitor led to purified protein use to end attacks. Consideration of the endocrine functions led to rediscovery of impeded androgen use in disease prophylaxis. Considerations of pathophysiology led to introduction of epsilon aminocaproic and tranexemic acids in prophylaxis and to a resurgence in trials of new therapeutic agents. We have gone from a situation where it was not uncommon for patients to have a severe attack sometime in their lives that led to airway compromise and possible death to a situation where death from disease is highly unusual. Thus HAE is in many ways a success story of modern medicine. [References: 50].

    Nov;26(4):653-668

    Available online at: http://www.immunology.theclinics.com/article/S0889-8561%2806%2900082-8/fulltext (small fee)

    Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant

    Bas M, Bier H, Greve J, Kojda G, Hoffmann TK 12/2006 Allergy

    Dec;61(12):1490-1492

    Available online at: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1398-9995.2006.01197.x/

    Novel therapies for hereditary angioedema

    Zuraw BL 11/2006 N.Engl.J.Med.

    Advances in our understanding of the molecular mechanisms underlying hereditary angioedema (HAE) have led to the development of new treatment modalities. Five new drugs for the treatment of HAE are currently undergoing clinical testing in the United States. These novel therapeutics can be divided into two groups: drugs that replace C1 inhibitor (C1INH) functional activity and drugs that abrogate the bradykinin-mediated increase in vascular permeability associated with HAE attacks. The first group includes two plasma-derived C1INH concentrates as well as a recombinant transgenic human C1INH protein, and the second group includes an engineered plasma kallikrein inhibitor as well as a B2 bradykinin receptor antagonist. This article reviews the rationale, development, and potential use of these novel therapeutics. [References: 64].

    Nov;26(4):691-708

    Available online at: http://www.immunology.theclinics.com/article/S0889-8561%2806%2900084-1/fulltext (small fee)

    Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency

    Bork K, Staubach P, Eckardt AJ, Hardt J 3/2006 The American Journal of Gastroenterologyy (Am.J.Gastroenterol.)

    OBJECTIVES: Recurrent abdominal attacks belong to the cardinal and most distressing symptoms of hereditary angioedema (HAE) due to C1 inhibitor deficiency. They are characterized by crampy pain, but may include vomiting, diarrhea, and other features. Detailed clinical data about the symptoms and course of abdominal attacks have not been reported. METHODS: We retrospectively observed a total of 33,671 abdominal attacks in 153 patients with HAE including a prospectively examined subgroup of 23 patients. Symptoms, course, frequency of

    METHODS: We retrospectively observed a total of 33,671 abdominal attacks in 153 patients with HAE including a prospectively examined subgroup of 23 patients. Symptoms, course, frequency of attacks, and complications were analyzed. RESULTS: The relation of mild, moderate, and severe attacks was 1:1.4:5.6 in the prospective part of the study. Extra-abdominal symptoms preceded the abdominal symptoms. The mean maximal pain score was 8.4 (range 1-10). Vomiting occurred in 73% (24,696) and diarrhea in 41% (13,682) of the attacks. Circulatory collapse accompanied 4.4% (1,468) of the attacks, with

    RESULTS: The relation of mild, moderate, and severe attacks was 1:1.4:5.6 in the prospective part of the study. Extra-abdominal symptoms preceded the abdominal symptoms. The mean maximal pain score was 8.4 (range 1-10). Vomiting occurred in 73% (24,696) and diarrhea in 41% (13,682) of the attacks. Circulatory collapse accompanied 4.4% (1,468) of the attacks, with loss of consciousness (LOC) occurring in 2.2% (739). Nine patients could clearly distinguish two types of abdominal attacks: vomiting and diarrhea. Rare complications included tetany, hemorrhagic stools, and intussusception of the colon. In 28% (43) of the patients, recurrent abdominal attacks had started before the characteristic swelling of the skin had ever occurred. A model is proposed to classify the severity of the attacks and to describe the clinical course. CONCLUSIONS: Abdominal attacks in HAE constitute a more disabling and complex syndrome than previously assumed. Our results add to the understanding of symptoms and course of HAE and may aid in the early recognition of an impending attack and improve clinical management.

    CONCLUSIONS: Abdominal attacks in HAE constitute a more disabling and complex syndrome than previously assumed. Our results add to the understanding of symptoms and course of HAE and may aid in the early recognition of an impending attack and improve clinical management.

    Mar;101(3):619-627

    Available online at: http://www.researchgate.net/publication/7310645_Symptoms_Course_and_Complications_of_Abdominal_Attacks_in_Hereditary_Angioedema_Due_to_C1_Inhibitor_Deficiency

    The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema

    Levy JH, O'Donnell PS 9/2006 Expert Opin.Investig.Drugs

    Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE. [References: 95].

    Sep;15(9):1077-1090

    Available online at: http://www.tandfonline.com/doi/full/10.1517/13543784.15.9.1077 (small fee)

    Anti-cholesterol antibody levels in hereditary angioedema

    Varga L, Biro A, Szeplaki G, Toth L, Horvath A, Fust G, et al 11/2007 Journal of Cellular & Molecular Medicine

    Hereditary angioedema (HAE) is a rare disorder caused by the deficiency of the C1-inhibitor gene (C1INH) and characterized by recurrent bouts of angioedema. Autoimmune disorders frequently occur in HAE. Previously we found, that danazol has an adverse effect on serum lipid profile: reduced high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL) cholesterol levels are associated with long-term prophylactic use, whereas total cholesterol levels are unchanged. Our aim was to study the anti-cholesterol antibody (ACHA) production in HAE patients and compare it with those of healthy blood donors, and to investigate the possible associations between ACHA levels and serum lipid profile alterations caused by danazol. Anti-cholesterol IgG levels were measured by ELISA and their correlation with serum concentrations of total cholesterol, HDL, LDL, triglycerides was determined in HAE patients receiving/not receiving danazol. Serum ACHA levels were significantly higher in HAE patients, compared to healthy blood donors (P<0.0001). Longterm danazol prophylaxis had no effect on serum ACHA levels in HAE patients. However, we found a significant, negative correlation between ACHA levels and serum total cholesterol (r=-0.4033, P=0.0200), LDL (r=-0.4565, P=0.0076) and triglyceride (r=-0.4230, P=0.0121) levels only in danazol-treated patients, but not in HAE patients who did not receive long-term prophylaxis. Patients with HAE have higher baseline ACHA levels compared to healthy subjects, and this might reflect polyclonal B-cell activation. The latter would be a potential explanation for the lack of an increased incidence of infectious diseases in HAE patients, but might lead to increased autoimmunity.

    Nov-Dec;11(6):1377-1383

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1582-4934.2007.00124.x/full

    C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option

    Longhurst HJ, Carr S, Khair K 1/2007 Clinical & Experimental Immunology

    Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life-threatening. These attacks are treated with C1-inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far. [References: 56].

    Jan;147(1):11-17

    Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804208/

    C1-inhibitor deficiencies (hereditary angioedema): where are we with therapies?

    Lock RJ, Gompels MM 7/2007 Current Allergy & Asthma Reports

    Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema. [References: 52].

    Jul;7(4):264-269

    Available online at: http://link.springer.com/article/10.1007/s11882-007-0039-6 (small fee)

    Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor

    Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T 8/2007 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene mutation. Patients with HAE experience intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein activation generates bradykinin, the likely mediator of the swelling and pain characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits kallikrein. This is the first placebo-controlled assessment in human beings of a therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that the contact cascade is the putative pathway responsible for HAE pathology.

    OBJECTIVE: To determine the safety and efficacy of ecallantide in patients with HAE. METHODS: This double-blind, placebo-controlled, ascending-dose study assessed efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m(2) intravenously) in individuals experiencing acute HAE attacks (N = 49). Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort.

    RESULTS: Ecallantide treatment ameliorated the symptoms of HAE attacks: 72.5% (29/40) of patients treated with ecallantide versus 25.0% (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (P = .0169). Ecallantide was well tolerated at all doses.

    CONCLUSION: Ecallantide, a potent, specific inhibitor of plasma kallikrein, significantly improved HAE symptoms over placebo. The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE. Further clinical trials are underway.

    CLINICAL IMPLICATIONS: Ecallantide is a promising new therapy for HAE attacks.

    Aug;120(2):416-422

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2900864-0/fulltext

    Fresh frozen plasma for the treatment of hereditary angioedema

    Prematta M, Gibbs JG, Pratt EL, Stoughton TR, Craig TJ 4/2007 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Fresh frozen plasma (FFP) has been used as a treatment option for patients with hereditary angioedema (HAE) because it contains Cl esterase inhibitor, and alternate therapies are not yet available in the United States. However, because FFP also contains other substrates, it has been hypothesized to have the potential to worsen or precipitate an acute attack of HAE.

    OBJECTIVE: To research patient records and the medical literature to determine whether FFP can exacerbate symptoms or precipitate an attack of HAE.

    METHODS: The following keywords were searched in PubMed and OVID: hereditary angioedema, angioedema and fresh frozen plasma, angioedema and FFP, and hereditary angioneurotic edema. English-language articles were searched from 1966 to the present. Also, after institutional review board approval, the medical records of patients with HAE at our institution who have received FFP since 1990 were reviewed to determine if there was evidence that FFP exacerbated the symptoms of HAE.

    RESULTS: The English-language literature review and our patient medical record review failed to identify instances when FFP exacerbated symptoms of HAE or precipitated an attack. Several reports and our experience suggest that FFP is an effective prophylactic agent before surgery and for treatment of acute HAE attacks without evidence of exacerbation or initiation of symptoms.

    CONCLUSIONS: FFP seems to be safe and effective in preventing exacerbations of HAE before surgery and for acute exacerbations of HAE without evidence of it initiating an attack or worsening a preexisting attack. [References: 26].

    Apr;98(4):383-388

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960886-1/fulltext (small fee)

    Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema

    Visy B, Fust G, Bygum A, Bork K, Longhurst H, Bucher C, et al 6/2007 Helicobacter

    BACKGROUND: Helicobacter pylori infection is considered among the causative factors of urticaria and angioedema. Having conducted a study on 65 patients, Hungarian authors reported in 2001 that successful eradication of H. pylori is followed by a significant reduction in the number of attacks in patients with hereditary angioedema (HAE). The present study aimed to reinvestigate the relationship between H. pylori infection and the attack rate in the framework of an international collaborative study.

    MATERIALS AND METHODS: Within the framework of the PREHAEAT project launched by the European Union, further 152 patients were studied in seven collaborating centers, and participants of the earlier study were followed up in order to detect any relationship between H. pylori infection and the occurrence of attacks in patients suffered from HAE.

    RESULTS: The proportion of patients experiencing frequent (> or = 5 per year) abdominal attacks was higher (p = .002) among the H. pylori-infected participants of the international study who underwent eradication as compared to the rest of patients. Successful eradication of H. pylori significantly (p = .0006) reduced the number of attacks in these patients as well. Nine subjects of the previous Hungarian study who underwent eradication therapy for dyspepsia were followed up for an additional 4 years. In these patients, attack frequency remained consistently low.

    CONCLUSIONS: As shown by experience from the Hungarian and the international trial, the number of frequent, edematous abdominal attacks may decrease substantially following the eradication of H. pylori from HAE patients infected with this pathogen. Therefore, screening of patients with HAE for H. pylori infection seems warranted. Eradication of H. pylori may lead to a marked reduction in disease severity.

    Jun;12(3):251-257

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1523-5378.2007.00501.x/full (small fee)

    Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian

    Bowen T, Cicardi M, Bork K, Zuraw B, Frank M, Ritchie B, et al /2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema

    BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004.

    OBJECTIVE: To ensure that this consensus remains current.

    METHODS: In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted.

    RESULTS: This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings.

    CONCLUSIONS: There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients. [References: 68].

    Annals of Allergy, Asthma, & Immunology

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960584-4/fulltext (small fee)

    Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema

    Marco Cicardi, Konrad Bork, Bruce Zuraw, Mike Frank, Bruce Ritchie, Henriette Farkas, Lilian Varga, Lorenza C. Zingale, Karen Binkley, Eric Wagner, Peggy Adomaitis, Kristylea Brosz, Jeanne Burnham, Richard Warrington, Chrystyna Kalicinsky, Sean Mace, Christine McCusker, Robert Schellenberg, Lucia Celeste, Jacques Hebert, Karen Valentine, Man-Chiu Poon, Bazir Serushago, Doris Neurath, William Yang, Gina Lacuesta, Andrew Issekutz, Azza Hamed, Palinder Kamra, John Dean, Amin Kanani, Donald Stark, Georges-Etienne Rivard, Eric Leith, Ellie Tsai, Susan Waserman, Paul K. Keith, David Page, Silvia Marchesin, Hilary J. Longhurst, Wolfhart Kreuz, Eva Rusicke 12/2007 Annals of Allergy, Asthma & Immunology

    Background
    We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004.

    Objective
    To ensure that this consensus remains current.

    Methods
    In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted.

    Results
    This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings.

    Conclusions
    There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients.

     

    Available online at: http://dx.doi.org/10.1016/S1081-1206(10)60584-4

    Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy

    Farkas H, Jakab L, Temesszentandrasi G, Visy B, Harmat G, Fust G, et al 20/2007 Journal of Allergy & Clinical Immunology

    BACKGROUND: C1-inhibitor (C1-INH) is a serine protease inhibitor regulating the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. Hereditary angioedema (HAE) is caused by an inherited deficiency of C1-INH characterized by sudden, recurrent edematous swellings of the subcutaneous or submucosal tissues. The optional therapy for the acute management of HAE is administration of human C1-INH (hC1-INH) concentrate. However, hC1-INH is not available in many countries, in which case fresh frozen plasma is an alternative.

    OBJECTIVE: To summarize our experience with hC1-INH concentrate in patients with HAE.

    METHODS: Clinical and laboratory information on the effectiveness and safety of hC1-INH administered to relieve 468 acute edematous attacks in 61 patients with HAE was analyzed.

    RESULTS: Severe abdominal or subcutaneous attacks and laryngeal edema were consistently relieved by the administration of 500 U hC1-INH concentrate. Symptoms improved within 15 to 60 minutes of administration. Progression of the attacks was never observed, and there were no recurrent attacks within 72 hours. hC1-INH concentrate requirements did not change after repeated use. hC1-INH concentrate proved effective in the management of 94 attacks in 22 children and 6 attacks in 4 pregnant women. Adverse reactions, viral infections, and antibody formation against the purified protein did not occur.

    CONCLUSION: The administration of hC1-INH concentrate in HAE is highly effective and safe for the treatment of acute attacks and short-term prophylaxis and in pediatric patients and pregnant women.

    CLINICAL IMPLICATIONS: Human C1-INH concentrate is effective and safe for the treatment of acute HAE attacks as well as for short-term prophylaxis.

    Oct;120(4):941-947

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2901246-8/fulltext

    Hereditary angioedema: Safety of long-term stanozolol therapy

    Sloane DE, Lee CW, Sheffer AL 9/2007 Journal of Allergy & Clinical Immunology

    BACKGROUND: Attenuated androgens control attacks of hereditary angioedema. Short-term studies of such patients treated at our institution with attenuated androgens demonstrated no adverse effects. However, the side-effect frequencies in patients receiving long-term treatment are relatively less well characterized.

    OBJECTIVE: To assess the frequencies of various side effects of the attenuated androgen stanozolol in a population of patients with hereditary angioedema treated for 20 to 40 years.

    METHODS: Data on side effects in patients who continued stanozolol therapy since 1987 were obtained by means of questionnaire. Patients were evaluated by physical examination; biochemical assays of hepatic function, serum lipids, and prostate specific antigen; and liver ultrasound.

    RESULTS: The minimal initial effective dosage of stanozolol was 0.5 to 2.0 mg daily, although most patients achieved symptomatic control and decreased the dose and frequency as the frequency of attacks decreased. Treatment-related symptoms developed in 10 of 21 patients. No interruption in stanozolol therapy was required because symptoms subsided with a reduction in the stanozolol dosage. Adverse side effects included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays revealed no persistent abnormalities. Liver ultrasounds in 8 patients revealed 3 abnormalities deemed unrelated to therapy. Five patients had a reduced high-density lipoprotein, and 2 patients had elevated triglycerides.

    CONCLUSION: Stanozolol is a safe and effective drug for the long-term management of hereditary angioedema.

    CLINICAL IMPLICATIONS: Stanozolol may be used in the long-term treatment of patients with hereditary angioedema provided such patients are closely supervised with routine clinical, biochemical, and radiologic assessments.

    Sep;120(3):654-658

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2901265-1/fulltext

    Laboratory testing for C1 inhibitor deficiency: a comparison of two approaches to C1 inhibitor function

    Gompels MM, Lock RJ 1/2007 Ann.Clin.Biochem.

    BACKGROUND: C1 inhibitor deficiency may be hereditary or acquired. It is characterized by absent or poorly functioning C1 inhibitor. The disorder is rare, with prevalence estimated at 1/50,000. The very low incidence of the condition makes the sensitivity and specificity of assays used particularly important. Two different methods are commercially available to measure C1 inhibitor function. There are few data comparing these assays. METHODS: Two assays of C1 inhibitor function (C1 inhibitor-C1s complex formation or inhibition of C1 esterase cleavage of artificial substrate [colorimetric]) were compared in 71 patients (28 hereditary angioedema, 2 acquired angioedema and 41 controls). RESULTS: Qualitatively, the two assays showed good correspondence (92%). Six of 71 results were discordant. Correlation in quantitative terms was moderate (R = 0.81). CONCLUSIONS: Both assays show high sensitivity for hereditary/acquired angioedema. The colorimetric assay is more prone to false-positive results. However, clinical interpretation is not adversely affected.

    Jan;44(Pt 1):75-78

    Available online at: http://acb.sagepub.com/content/44/1/75.long (small fee)

    Lack of dehydroepiandrosterone in type I and II hereditary angioedema and role of danazol in steroid hormone conversion

    Thon V, Harle P, Scholmerich J, Kuklinek P, Lokaj J, Straub RH 11/2007 Allergy

    BACKGROUND: Hereditary angioedema (HAE) is successfully treated with danazol, a therapeutic steroid compound. To investigate hormones of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis in patients with HAE with and without danazol.

    METHODS: We included 16 patients with type I HAE, nine patients with type II HAE, and 16 healthy subjects. Serum levels of adrenocorticotropic hormone (ACTH), cortisol, androstenedione, dehydroepiandrosterone (DHEA), free testosterone, and 17beta-oestradiol were measured.

    RESULTS: Serum levels of ACTH were markedly decreased in patients with type II HAE compared to the other groups (P < 0.001). Serum cortisol was similar between groups but danazol treatment decreased cortisol levels, particularly in women (P = 0.019). Serum levels of DHEA were significantly decreased in all patients with type I and II HAE compared to controls (P < 0.05), which was only partly dependent on prior danazol therapy as patients without danazol had also decreased serum levels of DHEA (P < 0.05). Furthermore, free testosterone serum levels were markedly increased in patients under danazol (P < 0.005) and the ratio of 17beta-oestradiol/free testosterone was significantly decreased in these patients (P < 0.005).

    CONCLUSIONS: This study demonstrated decreased DHEA in patients with type I and II HAE independent of danazol therapy, which was particularly evident in women. It also demonstrates that danazol induced a marked up-regulation of free testosterone in relation to precursors and downstream 17beta-oestradiol. In HAE, there seems to be a primary lack of the adrenal androgen DHEA.

    Nov;62(11):1320-1325

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2007.01477.x/full

    Management of hereditary angioedema in pediatric patients

    Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T 9/2007 Pediatrics

    Hereditary angioneurotic edema is a rare disorder caused by the congenital deficiency of C1 inhibitor. Recurring angioedematous paroxysms that most commonly involve the subcutis (eg, extremities, face, trunk, and genitals) or the submucosa (eg, intestines and larynx) are the hallmarks of hereditary angioneurotic edema. Edema formation is related to reduction or dysfunction of C1 inhibitor, and conventional therapy with antihistamines and corticosteroids is ineffective. Manifestations occur during the initial 2 decades of life, but even today there is a long delay between the onset of initial symptoms and the diagnosis of hereditary angioneurotic edema. Although a variety of reviews have been published during the last 3 decades on the general management of hereditary angioneurotic edema, little has been published regarding management of pediatric hereditary angioneurotic edema. Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood. [References: 81].

    Sep;120(3):e713-22

    Available online at: http://pediatrics.aappublications.org/content/120/3/e713.full (small fee)

    Recombinant human C1-inhibitor in the treatment of acute angioedema attacks

    Choi G, Soeters MR, Farkas H, Varga L, Obtulowicz K, Bilo B, et al 6/2007 Transfusion

    BACKGROUND: Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effects of rHuC1INH in the treatment of acute angioedema attacks in patients with a hereditary C1-inhibitor deficiency.

    STUDY DESIGN AND METHODS: Patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH (at a dose of 100 U/kg) within 8 hours after onset of an acute attack. Time to initiation of relief and time to minimal symptoms were reported by both the patient and the treating physician.

    RESULTS: Thirteen severe angioedema attacks in 9 patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH. There was rapid improvement of clinical conditions for all attacks, with approximately 80 percent of treated patients experiencing symptom relief within 2 hours and minimal symptoms within 12 hours. There were no drug-related adverse events or immunogenic reactions to C1-inhibitor or rabbit proteins.

    CONCLUSION: The transgenically produced rHuC1INH was successfully used in the treatment of acute angioedema attacks in patients with hereditary C1-inhibitor deficiency.

    Jun;47(6):1028-1032

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2007.01239.x/full (small fee)

    The deficiency of C1 inhibitor and its treatment

    Cicardi M, Zingale LC /2007 Immunobiology

    In this article, we review the traditional therapies of hereditary angioedema (HAE) that have been used for several years. Some of these therapies were proposed before the definition of the underlying defect and the understanding of the pathogenesis of the disease. We also describe new compounds under investigation at present as potential therapies for HAE. Two of these new therapies (a plasma-kallikrein inhibitor and a bradykinin B(2)-receptor antagonist) have been developed based on the understanding that the pathogenesis of symptoms was mainly due to kallikrein activation and bradykinin release. [References: 72].

    212(4-5):325-331

    Available online at: http://www.sciencedirect.com/science/article/pii/S0171298507000496 (small fee)

    The use of plasma-derived C1 inhibitor in the treatment of hereditary angioedema

    Cicardi M, Zingale LC, Zanichelli A, Deliliers DL, Caccia S 12/2007 Expert Opinion on Pharmacotherapy (Expert Opin.Pharmacother.)

    C1-inhibitor (C1-INH) deficiency is the genetic defect underlying hereditary angioedema (HAE). Subjects with HAE suffer from recurrent angioedema that may result in death when it affects the larynx, severe abdominal pain when it affects the gastrointestinal mucosa and disfiguration when it affects the skin. The use of plasma-derived C1-INH concentrates to revert angioedema in HAE patients started in the 1970s. Since that time, three different preparations arrived onto the market, two of them are still present. Controlled studies and a large clinical experience indicate that C1-INH concentrate should be considered the treatment of choice for disabling angioedema attacks at any site. Efficacy has also been shown in preventing angioedema induced by invasive medical manoeuvres. Limited experience with repeated weekly infusions indicates that C1-INH can be used for long-term prophylaxis in selected patients. The safety profile is excellent and there are no reports of transmission of viral infections with the preparations available at present. C1-INH is licensed only in a limited number of countries. Clinical trials are ongoing at present to expand registration. [References: 84].

    Dec;8(18):3173-3181

    Available online at: http://www.tandfonline.com/doi/full/10.1517/14656566.8.18.3173 (small fee)

    Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant)

    Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W 6/2007 Journal of Allergy & Clinical Immunology

    BACKGROUND: In hereditary angioedema, bradykinin is assumed to be the most important mediator of edema formation. OBJECTIVE: To assess whether the selective bradykinin receptor-2 antagonist Icatibant is effective in acute edema attacks of hereditary angioedema. METHODS: In this uncontrolled pilot study, 15 patients with 20 attacks were treated with Icatibant. The attacks were analyzed by using a standardized and validated visual analog scale measurement and compared with historical data of untreated attacks. Plasma bradykinin concentration was measured before and 4 hours after intravenous Icatibant treatment. RESULTS: Symptom intensity decreased within 4 hours after administration of Icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hours in the intravenous groups and 0.58 and 0.45 hours in the subcutaneous groups, respectively. The median difference in the 10-cm visual analog scale 4 hours after start of treatment was 4.11 cm (95% CI, 1.72-6.07). Compared with untreated attacks, Icatibant treatment reduced the mean (SD) time to onset of symptom relief by 97% from 42 +/- 14 to 1.16 +/- 0.95 hours (all groups combined). Median bradykinin concentration was 7-fold above the norm during acute attacks at 48.5 pmol/L and decreased to 18.0 pmol/L 4 hours after Icatibant infusion or injection. CONCLUSION: Icatibant was effective in treating acute attacks of hereditary angioedema. CLINICAL IMPLICATIONS: This is the first report demonstrating the clinical usefulness of antagonizing bradykinin binding to bradykinin receptor-2 in hereditary angioedema.

    Jun;119(6):1497-1503

    Available online at:  http://www.jacionline.org/article/S0091-6749%2807%2900379-X/fulltext

    Treatment of hereditary angioneurotic oedema (HANE) with tibolone

    Ott HW, Mattle V, Hadziomerovic D, Licht P, Doinghaus K, Rubbert A, et al 2/2007 Clin.Endocrinol.(Oxf)

    OBJECTIVE: Eight women, aged 25-58 years, with hereditary angioneurotic oedema (HANE) were treated with tibolone, a synthetic steroid exhibiting oestrogenic, androgenic and progestational activity. DESIGN: Pilot study. RESULTS: Tibolone at a dose of 2.5-7.5 mg/day significantly reduced the number and severity of attacks and the number of ampoules of C1-esterase inhibitor (C1-INH) needed for symptomatic therapy. The efficacy of tibolone was comparable to that of danazol, while the androgenic side-effects were considerably reduced. CONCLUSIONS: Tibolone may represent an alternative to danazol administration for the prophylaxis of HANE in women.

    Feb;66(2):180-184

    Available online at: http://onlinelibrary.wiley.com/wol1/doi/10.1111/j.1365-2265.2006.02704.x/full (small fee)

    Urticaria and urticaria related skin condition/disease in children

    Novembre E, Cianferoni A, Mori F, Calogero C, Bernardini R, Di Grande L, et al 10/2007 European Annals of Allergy & Clinical Immunology

    Oct;39(8):253-258

    Not available online.

    8 Hereditary angioedema

    Frank MM /2008 Current Allergy & Asthma Reports

    Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death. [References: 18].

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2901463-7/fulltext

    Appraisal of danazol prophylaxis for hereditary angioedema

    Craig TJ 5/2008 Allergy & Asthma Proceedings

    Hereditary angioedema (HAE) is an autosomal dominant disease characterized by painful, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation can be disfiguring, debilitating, quite painful, and, in the case of laryngeal attacks, life-threatening. Attacks are frequently the source of unnecessary exploratory abdominal procedures, extended hospital stays affecting a patient’s ability to retain employment, and severe compromise of the patient’s quality of life. HAE is estimated to affect 10,000 people in the US and is caused by deficient or dysfunctional C1-inhibitor, a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in plasma. The treatment and management of HAE have been hampered by the dearth of safe and effective therapies. In the United States, there are currently no approved therapies for the treatment of acute HAE attacks. Although prophylactic HAE therapies do exist, they are often viewed as suboptimal due to moderate degrees of efficacy and the existence of adverse effects associated with therapy. Danazol, an attenuated androgen, is the most commonly prescribed prophylaxis treatment for HAE in the United States. Although it has demonstrated moderate efficacy in the prevention of HAE attacks, danazol’s side-effect profile can be problematic because there is a correlation between frequency and severity of adverse events and dosage and duration of therapy. [References: 44].

    May-Jun;29(3):225-231

    Available online at: http://www.ingentaconnect.com/content/ocean/aap/2008/00000029/00000003/art00001 (small fee)

    Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients

    Bork K, Bygum A, Hardt J 2/2008 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency is clinically characterized by relapsing skin swellings, abdominal pain attacks, and life-threatening upper airway obstruction. Treatment with androgens prevents attacks for those with this condition.

    OBJECTIVE: To examine the benefits and risks of long-term treatment with danazol.

    METHODS: Data were generated retrospectively from 118 German and Danish patients who had HAE due to C1 inhibitor deficiency and were treated with danazol from 2 months to 30 years. The frequency and severity of acute attacks were registered before and during danazol treatment, and adverse effects to the treatment were noted. Data were collected by using standardized questionnaires.

    RESULTS: In all, 111 of 118 patients responded to danazol. During treatment, 54 of the 118 patients (45.8%) became symptom free or had 1 attack or less per year. In the other patients, hereditary angioedema ran a mild course. The frequency of acute attacks during danazol treatment was reduced to 16.2%, and the attacks were considerably milder than before treatment. Laryngeal edema was reduced to 4.8%. Adverse effects (weight gain, virilization, menstrual irregularities, headache, depression, and/or liver adenomas) occurred in 93 of the 118 patients and led to discontinuation of danazol therapy in 30 patients.

    CONCLUSIONS: Danazol is highly beneficial in patients with frequent and severe attacks of HAE. Because the risk of adverse effects is high, close monitoring of patients is mandatory. However, many patients accept the adverse effects of prophylactic treatment to avoid the distressing and sometimes life-threatening attacks of this condition.

    Feb;100(2):153-161

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960424-3/fulltext (small fee)

    C1 inhibitor: just a serine protease inhibitor? New and old considerations on therapeutic applications of C1 inhibitor

    Wouters D, Wagenaar-Bos I, van Ham M, Zeerleder S 8/2008 Expert Opinion on Biological Therapy

    C1 inhibitor is a potent anti-inflammatory protein as it is the major inhibitor of proteases of the contact and the complement systems. C1-inhibitor administration is an effective therapy in the treatment of patients with hereditary angioedema (HAE) who are genetically deficient in C1 inhibitor. Owing to its ability to modulate the contact and complement systems and the convincing safety profile, plasma-derived C1 inhibitor is an attractive therapeutic protein to treat inflammatory diseases other than HAE. In the present review we give an overview of the biology of C1 inhibitor and its use in HAE. Furthermore, we discuss C1 inhibitor as an experimental therapy in diseases such as sepsis and myocardial infarction. [References: 176].

    Aug;8(8):1225-1240

    Available online at: http://www.tandfonline.com/doi/full/10.1517/14712598.8.8.1225 (small fee)

    Clinical practice-Hereditary angioedema

    Zuraw BL /2008 Transfusion & Apheresis Science

    Available online at: http://www.nejm.org/doi/full/10.1056/NEJMcp0803977 (small fee)

    Current and emerging management options for hereditary angioedema in the US

    Epstein TG, Bernstein JA /2008 Drugs

    Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of swelling that may involve multiple anatomical locations. In the majority of patients, it is caused by a functional or quantitative defect in the C1 inhibitor (C1-INH), which is an important regulator of the complement, fibrinolytic, kallikrein-kinin and coagulation systems. Standard treatments used for other types of angioedema are ineffective for HAE. Traditional therapies for HAE, including fresh frozen plasma, epsilon-aminocaproic acid and danazol, may be well tolerated and effective in some patients; however, there are limitations both in their safety and efficacy. Several novel therapies have completed phase III trials in the US, including: (i) plasma-derived C1-INH replacement therapies (Berinert P and Cinryze); (ii) a recombinant C1-INH replacement therapy (conestat alfa; Rhucin); (iii) a kallikrein inhibitor (ecallantide [DX-88]); and (iv) a bradykinin-2-receptor antagonist (icatibant). Both Berinert P and Cinryze are reported to have excellent efficacy and safety data from phase III trials. Currently, only Cinryze has been approved for prophylactic use in the US. US FDA approval for other novel agents to treat HAE and for the use of Cinryze in the treatment of acute attacks is pending. [References: 79].

    68(18):2561-2573

    Available online at: http://link.springer.com/article/10.2165/0003495-200868180-00003 (small fee)

    Disease expression in women with hereditary angioedema

    Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A, et al 11/2008 American Journal of Obstetrics & Gynecology

    OBJECTIVE: Fluctuations in sex hormones can trigger angioedema attacks in women with hereditary angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women.

    STUDY DESIGN: Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire.

    RESULTS: Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients.

    CONCLUSION: The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

    Nov;199(5):484.e1-484.e4

    Available online at: http://www.ajog.org/article/S0002-9378%2808%2900430-4/fulltext

    Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery

    Lehmann A 8/2008 Current Opinion in Investigational Drugs

    BACKGROUND: Plasma kallikrein plays a major role in the contact (kallikrein-kinin) cascade producing bradykinin. Bradykinin is a vasodilator, which increases vascular permeability, activates inflammation and produces pain. Plasma kallikrein is also crosslinked to the coagulation system and the complement cascade. OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. Ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor. It was identified through phage display technology. METHODS: The search terms ‘ecallantide’, ‘DX-88’ and ‘hereditary angioedema’ were entered into Pubmed/Medline, ClinicalTrials and Google. RESULTS/CONCLUSION: At present, the drug is being studied for two major indications. First, the results for the treatment of hereditary angioedema are promising. Second, a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008.

    Aug;8(8):1187-1199

    Available online at: http://www.tandfonline.com/doi/full/10.1517/14712598.8.8.1187 (small fee)

    Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema

    Birjmohun RS, Kees Hovingh G, Stroes ES, Hofstra JJ, Dallinga-Thie GM, Meijers JC, et al 12/2008 Clinical Therapeutics (Clin.Ther.)

    BACKGROUND: Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients with hereditary angioedema (HAE) due to complement-1 esterase inhibitor deficiency. However, danazol has been reported to decrease high-density lipoprotein cholesterol (HDL-C) levels and to adversely affect coagulation parameters, which are considered to be proatherothrombotic.

    OBJECTIVE: The short- and long-term effects of danazol were evaluated on proatherogenic intermediate end points in healthy volunteers and patients with HAE.

    METHODS: Short-term effects were evaluated in healthy men randomly assigned to 200 mg/d of danazol or placebo for 4 weeks in a crossover trial with no washout period. Long-term effects of danazol on lipoproteins, coagulation, and carotid intima-media thickness (CIMT) were evaluated in a cross-sectional study in which patients with HAE treated with danazol, a mean dose of 170 mg/d for >or=2 years, were compared with healthy controls matched for age, sex, and body mass index (BMI). Drug tolerability was assessed by questionnaires and adherence was measured by pill count when drug bottles were returned after every study visit.

    RESULTS: Patients in the short-term study were 15 men with a mean (SD) age of 32.6 (6.9) years and BMI of 24.3 (4.1) kg/m(2). In the long-term study, patients with HAE were 10 women and 7 men with a mean (SD) age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m(2); the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m(2). Short-term danazol treatment was associated with a decrease from baseline in apolipoprotein A-I of 21% and in HDL-C of 23%. Flow-mediated dilation and coagulation parameters were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect HDL-C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L), HDL-related transfer proteins such as paraoxonase-1 activity (92 [62] vs 80 [40] U/mM), cholesteryl-ester transfer protein mass (1.5 [0.4] vs 2.2 [0.6] microg/mL), lecithin cholesterol acyltransferase activity (21.2 [4.5] vs 32.1 [7.2] nmol CE . mL(-1) . h(-1)), plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU), and apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P = NS). However, HAE patients using danazol had increased coagulation activation when compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P = 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] microg/L, P = 0.01). CONCLUSIONS: Short-term danazol treatment in healthy volunteers was associated with a reduction in HDL-C levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with HAE treated for >2 years with danazol had increased activation of coagulation, but there were no significant differences in HDL-C or CIMT compared with matched healthy controls.

    Dec;30(12):2314-2323

    Available online at:  http://www.clinicaltherapeutics.com/article/S0149-2918%2808%2900456-6/pdf (small fee)

    Hereditary angiodema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new?

    Zuraw BL 1/2008 Annals of Allergy, Asthma, & Immunology

    OBJECTIVE: To provide a context to understand the opportunity for novel therapeutic modalities to transform the treatment of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving current treatment of HAE in the United States.

    STUDY SELECTION: Studies were selected based on their relevance to the treatment of HAE.

    RESULTS: The current HAE treatment strategy is far from satisfactory, and its limitations create an unmet clinical need. Current prophylactic treatment exposes patients with HAE to significant risk of adverse effects, and the efficacy of prophylactic treatment, although generally good, is far from perfect.

    CONCLUSIONS: No specific treatment is currently available in the United States for acute HAE attacks that will reliably work, resulting in a significant unmet clinical need. The emergence of several promising drugs for the treatment of HAE attacks is, thus, an extraordinarily important development in the management of these patients.

    Jan;100(1 Suppl 2):S13-8

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960581-9/fulltext (small fee)

    Hereditary angiodema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema

    Frank MM 1/2008 Curr.Opin.Pediatr.

    OBJECTIVE: To provide a comprehensive overview on clinical trial design and results of emerging therapies for the treatment of hereditary angioedema (HAE).

    DATA SOURCES: MEDLINE or PubMed literature searches were conducted to identify double-blind, placebo-controlled trials investigating C1 esterase replacement, kallikrein inhibitor, and bradykinin receptor 2 antagonist therapies.

    STUDY SELECTION: Ongoing trials or those just recently completed from all companies developing a product for the treatment of HAE are discussed.

    RESULTS: All of these agents are believed to be effective when tested in patients in phase 1 or phase 2 trials. The studies have many features in common, including being placebo-controlled and blinded; having a preliminary screening visit at which the diagnosis is confirmed; having either low circulating C1 inhibitor protein levels or low levels of functional C1 inhibitor, low C4 levels, and normal C1q levels; enrolling individuals who are relatively early in attacks (4-6 hours from the onset); and stipulating that patients continue taking the medications that they have been taking in the long term. The type of attack acceptable for each treatment protocol varies from study to study. Some allow peripheral edema attacks, some facial attacks, and in some studies, the Food and Drug Administration has allowed purified serum C1 inhibitor to be used as a rescue medication if the patient remains in difficulty after the study drug has been used and found to be ineffective.

    CONCLUSION: The outlook for new, effective short-term therapy appears to be excellent. In the near future, a whole new therapeutic armamentarium to care for patients with HAE should be available in the United States. [References: 17].

    Jan;100(1 Suppl 2):S23-9

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960583-2/fulltext (small fee)

    Hereditary angioedema: a current state-of-the-art review, II: historical perspective of non-histamine-induced angioedema

    Bernstein IL 1/2008 Annals of Allergy, Asthma, & Immunology

    OBJECTIVE: To review the evolution of our understanding of hereditary angioedema (HAE) from the first historical reference to the present day.

    DATA SOURCES: MEDLINE and PubMed were searched using the following keywords: history of HAE, C1 inhibitor, complements system, genetics of HAE, mechanisms of HAE, and treatment of HAE.

    STUDY SELECTION: Information was selected that outlines the advances made in complementology, the first report of HAE, and subsequent studies that elucidated the underlying mechanisms of this disease, leading to current therapy of this orphan disease.

    RESULTS: Generational research efforts in HAE have focused on the following: (1) several new clinical presentations, (2) acquired forms of non-histamine-induced angioedema, (3) the genetic basis for the inherited forms, (4) the effects of C1 inhibitor on contact phases of coagulation-fibrinolytic pathways, and (5) various therapies for short- and long-term control of the disease.

    CONCLUSION: The progress made in understanding the pathogenesis and treatment of HAE is an excellent example of the “”bench to the bedside”” paradigm involving the collaboration between clinicians and researchers. [References: 65]. ”

    Jan;100(1 Suppl 2):S2-6

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960579-0/fulltext (small fee)

    Hereditary angioedema: a current state-of-the-art review, IX: the US Hereditary Angioedema Association: a message from the president

    Castaldo AJ 1/2008 Annals of Allergy, Asthma, & Immunology

    Jan;100(1 Suppl 2):S47-8

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960586-8/fulltext (small fee)

    Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema

    Banerji A, Sloane DE, Sheffer AL 1/2008 Annals of Allergy, Asthma, & Immunology

    OBJECTIVE: To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. STUDY SELECTION: Studies were selected based on their relevance to the use of androgens for the treatment of HAE. RESULTS: Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. CONCLUSIONS: Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising. [References: 33].

    Jan;100(1 Suppl 2):S19-22

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960582-0/fulltext (small fee)

    Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies

    Bernstein JA 1/2008 Annals of Allergy, Asthma, & Immunology

    OBJECTIVE: To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States.

    DATA SOURCES: Summary statements were obtained from each pharmaceutical company regarding their agent.

    STUDY SELECTION: Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials.

    RESULTS: Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points.

    CONCLUSIONS: The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease. [References: 38]. ”

    Jan;100(1 Suppl 2):S41-6

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960585-6/fulltext (small fee)

    Hereditary angioedema: new hopes for an orphan disease

    Reshef A, Leibovich I, Goren A 12/2008 Israel Medical Association Journal: Imaj

    Hereditary angioedema is a rare genetic disorder, manifested by recurrent edema leading to disfigurement, organ dysfunction and life-threatening respiratory impairment that may become fatal. The hallmark of HAE is C1 esterase inhibitor deficiency, but recent evidence points at bradykinin as the main mediator that causes hyperpermeability of small vasculature, leading to accumulation of edema fluid. Current therapeutic options for HAE are limited, and consist of drugs, replacement therapy, and supportive treatment. In view of many disadvantages of the current therapeutic modalities, new approaches to the treatment of HAE are now being offered. This review summarizes our experience with a new line of medications developed for the treatment of acute exacerbations and prophylaxis of HAE–icatibant: bradykinin receptor antagonist, ecallantide: kallikrein inhibitor, and two C1 INH preparations: Berinert-P, human plasma-derived concentrate, and Rhucin: novel recombinant C1-INH produced in transgenic rabbits. Preliminary results of these studies are encouraging and may bring new hope to the patients with this distressing condition. The exact number of HAE patients in Israel is unknown and because patients are treated individually and comprehensive laboratory assessment is partial, many cases might be missed or not treated according to accepted guidelines. We offer a new specialty center for HAE patients, addressing the medical and psychosocial needs of patients and their families. [References: 40].

    Dec;10(12):850-855

    Available online at: http://www.ima.org.il/IMAJ/ViewArticle.aspx?year=2008&month=12&page=850

    Long-term danazol prophylaxis does not lead to increased carotid intima-media thickness in hereditary angioedema patients

    Szegedi R, Szeplaki G, Varga L, Prohaszka Z, Szeplaki Z, Karadi I, et al 5/2008 Atherosclerosis

    BACKGROUND: Hereditary angioedema (HAE) is characterized by episodic edematous attacks due to the deficiency of the C1-inhibitor (C1-INH). Recently, we have described that the long-term use of danazol affects lipid metabolism, resulting in decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL) cholesterol levels, which might lead to accelerated, early atherosclerosis. Our aim in the present study was to investigate the impact of danazol treatment on the risk of atherosclerosis in HAE patients.

    METHODS: The prevalence of vascular disease, as well as carotid intima-media thickness (IMT)–an objective marker of atherosclerosis–was determined in 32 HAE patients undergoing danazol prophylaxis, and compared to 25 HAE patients without danazol treatment, as well as to 20 healthy controls. Distinct atherosclerosis risk profiles were determined in addition.

    RESULTS: HAE patients with danazol prophylaxis had higher body mass index (p=0.0055 and 0.0020), creatinine (p=0.0001 and 0.0130), alanine aminotransferase (p=0.0298 and 0.0457), LDL (p=0.0060 and <0.0001) and decreased HDL (p<0.0001 and <0.0001) levels compared to both control groups. The prevalence of vascular diseases did not differ in the two patient groups. No significant differences were observed in mean (0.43 (0.37-0.50)mm vs. 0.40 (0.35-0.49)mm, p=0.5465) carotid IMT values, when comparing patients with or without long-term danazol prophylaxis.

    CONCLUSIONS: Thickening of IMT due to danazol use was not observed in HAE patients. We hypothesize that the functional deficiency of C1-INH might confer protection against atherosclerosis in these patients.

    May;198(1):184-191

    Available online at: http://www.atherosclerosis-journal.com/article/S0021-9150%2807%2900565-5/fulltext (small fee)

    Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P

    Drouet C, Desormeaux A, Robillard J, Ponard D, Bouillet L, Martin L, et al 2/2008 Journal of Allergy & Clinical Immunology

    BACKGROUND: Aminopeptidase P (APP) plays an important role in the catabolism of kinins in human plasma, mostly for des-Arg(9)-bradykinin. Impaired degradation of this active bradykinin metabolite was found to be associated with a decreased APP activity in hypertensive patients who experienced angioedema while being treated with angiotensin I-converting enzyme inhibitors. The pathophysiology of hereditary angioedema is presently attributed only to a quantitative/qualitative C1 inhibitor (CI-INH) defect with increased bradykinin release.

    OBJECTIVES: In the context of androgen prophylaxis, increased CI-INH function cannot fully explain protection from angioedema attacks alone because of the limited reversion of the CI-INH defects. Therefore we hypothesized that androgen prophylaxis could enhance plasma APP activity.

    METHODS: Patients with hereditary angioedema were investigated for plasma metallopeptidase activities responsible for kinin catabolism (APP, angiotensin I-converting enzyme, and carboxypeptidase N) and for CI-INH function in treated and untreated patients. RESULTS: APP activity was asymmetrically distributed in untreated patients (n = 147): the mean value was significantly lower than the value in a reference healthy and unmedicated population (n = 116; P < or = .001). Prophylaxis with androgen induced a significant increase in APP activity (P < or = .001), whereas it did not affect the other metallopeptidase activities. In both patient groups, APP activity showed a significant inverse relationship to disease severity (P < or = .001).

    CONCLUSION: In addition to the effect on circulating CI-INH levels, the increase in APP levels brought on by androgens could contribute to a more effective control of the kinin accumulation considered to be responsible for the symptoms of angioedema.

    Feb;121(2):429-433

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2902218-X/fulltext

    New promise and hope for treating hereditary angioedema

    Zuraw BL, Christiansen SC 5/2008 Expert Opin.Investig.Drugs

    BACKGROUND: While there is no approved effective therapy for the treatment of acute attacks of hereditary angioedema in the USA, four different drugs are completing or have recently completed Phase III clinical trials.
    OBJECTIVE: To review the clinical status and future prospects of the new therapies under development for the treatment of hereditary angioedema.
    METHODS: A review was carried out of the literature and presentations at meetings on the efficacy and safety of plasma-derived C1 inhibitor, recombinant human C1 inhibitor, the kallikrein inhibitor DX-88, and the B2 bradykinin receptor antagonist HOE-140.
    RESULTS/CONCLUSION: Each of these drugs has been shown to be effective and safe for the treatment of hereditary angioedema; however, subtle differences in their mechanisms of action and delivery may influence how physicians and patients utilize the different drugs. The availability of effective therapy is expected to reshape the management of hereditary angioedema. [References: 57].

    May;17(5):697-706

    Available online at: http://www.tandfonline.com/doi/full/10.1517/13543784.17.5.697 (small fee)

    New therapies for hereditary angioedema: disease outlook changes dramatically

    Frank MM, Jiang H 1/2008 Journal of Allergy & Clinical Immunology

    Hereditary angioedema (HAE) is an autosomal dominant disease associated with episodic attacks of nonpitting edema that may affect any external or mucosal body surface. Attacks most often affect the extremities, causing local swelling, the GI tract, leading to severe abdominal pain, and the mouth and throat, at times causing asphyxiation. Most patients with HAE have low levels of the plasma serine protease inhibitor C1 inhibitor. The edema in these patients is caused by unregulated generation of bradykinin. Effective chronic therapy of patients with impeded androgens or plasmin inhibitors has been available for decades, but in the United States, we do not have therapy for acute attacks. Five companies have completed or are in the process of conducting phase 3 clinical trials, double-blind, placebo-controlled studies of products designed to terminate acute attacks or to be used in prophylaxis. Two companies, Lev Pharmaceuticals and CSL Behring, have preparations of C1 inhibitor purified from plasma that have been used in Europe for decades (trade names Cinryze and Berinert P, respectively). One company, Pharming, has developed a recombinant C1 inhibitor preparation. One company, Dyax, is testing a kallikrein inhibitor (ecallantide), and one company, Jerini, is completing testing of a bradykinin type 2 receptor antagonist (Icatibant). Although little has been published thus far, all of these products may prove effective. It is likely that HAE treatment will change dramatically within the next few years.

    Jan;121(1):272-280

    Available online at: http://www.jacionline.org/article/S0091-6749%2807%2902267-1/fulltext

    Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults

    Cedzynski M, Madalinski K, Gregorek H, Swierzko AS, Nowicka E, Obtulowicz K, et al 1/2008 Archivum Immunologiae et Therapia Experimentalis (Arch.Immunol.Ther.Exp.(Warsz.))

    INTRODUCTION: Hereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-binding lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections to the severity and frequency of clinical symptoms of HAE. MATERIALS AND METHODS: The study was performed in 65 patients with HAE and 113 healthy persons. The parameters measured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV, and HCV infection. Scores for the frequency and severity of HAE symptoms were determined. RESULTS: HAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with activity of 10-52% (p=0.016). No significant differences were found in the median levels of MBL concentration and MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequency of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients. CONCLUSIONS: These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).

    Jan-Feb;56(1):69-75

    Available online at: http://link.springer.com/article/10.1007/s00005-008-0004-7/fulltext.html

    Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia

    Longhurst H 3/2008 Current Opinion in Investigational Drugs

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. [References: 110].

    Mar;9(3):310-323

    Not available online.

    The spectrum and treatment of angioedema

    Temino VM, Peebles RS Jr 4/2008 Am.J.Med.

    Angioedema manifests as episodes of localized swelling in the dermis and submucosa. The key to successful management is detection and avoidance of triggers, early recognition of attacks, and aggressive airway management when warranted. Review of a patient’s medication list may identify drugs that include angiotensin-converting enzyme inhibitor or angiotensin receptor blockers as the cause. Initial treatment in a patient presenting with most forms of angioedema includes antihistamines and glucocorticoids if required. Epinephrine should be administered if there is concern for laryngeal edema. Patients who have a known history of hereditary angioedema should receive C1 esterase inhibitor concentrate or fresh-frozen plasma. [References: 12].

    Apr;121(4):282-286

    Available online at: http://www.amjmed.com/article/S0002-9343%2807%2901091-1/fulltext (small fee)

    Therapeutic potential of icatibant (HOE-140, JE-049)

    Cruden NL, Newby DE 9/2008 Expert Opinion on Pharmacotherapy (Expert Opin.Pharmacother.)

    There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental. [References: 57].

    Sep;9(13):2383-2390

    Available online at: http://www.tandfonline.com/doi/full/10.1517/14656566.9.13.2383 (small fee)

    Treatment of hereditary angioedema: current perspectives

    Krassilnikova SI, Nikiforov YS, Craig TJ 11/2008 Recent Patents on Inflammation & Allergy Drug Discovery

    Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed. [References: 56].

    Nov;2(3):166-174

    Available online at: http://www.eurekaselect.com/92892/article (small fee)

    Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angio-oedema

    Bork K, Staubach P, Hardt J 6/2008 Allergy

    BACKGROUND: Skin swellings are the most frequent symptoms in hereditary angio-oedema (HAE) arising out of C1-inhibitor (C1-INH) deficiency. They may be painful and impact daily activities of patients. Detailed clinical data concerning the treatment of skin swellings by C1-INH concentrate have not been reported yet.

    METHODS: From 1976 through 2007, a total of 2104 skin-swelling attacks in 47 patients with HAE were treated with the C1-INH concentrate. Time to relief and duration of the swellings were documented during personal interviews using standardized questionnaires. The results were compared with 9046 untreated skin swellings in the same patients.

    RESULTS: The first clinical sign of efficacy was a slowdown of progress of symptoms accompanied by a decreased feeling of tension and pain in the swollen area. The mean time to the first relief of symptoms was 1.1 +/- 1.4 h in treated skin swellings and 50.4 +/- 33 h in untreated skin swellings. Improvement of facial skin swellings took longer than swellings of the extremities, genitals or trunk. The duration of treated skin swellings was 1.7 day in treated and 3.2 day in untreated ones. In treated swellings, there was long-lasting control and no rebound within the 48 h following the drug administration and no laryngeal oedema following facial oedema were observed. No severe side-effects occurred.

    CONCLUSIONS: The C1-INH concentrate has proven to be highly effective and safe for treating skin swellings in patients with HAE arising out of C1-INH deficiency.

    Jun;63(6):751-757

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2007.01577.x/full

    Urticaria and urticaria related skin condition/disease in children

    Novembre E, Cianferoni A, Mori F, Barni S, Calogero C, Bernardini R, et al 5/2008 European Annals of Allergy & Clinical Immunology

    Urticaria is a rash, that typically involves skin and mucosa, and is characterized by lesions known as hives or wheals. In some cases there is an involvement of deep dermis and subcutaneous tissue that causes a skin/mucosa manifestation called angioedema. Urticaria and angioedema are very often associated: urticaria-angioedema syndrome. The acute episodic form is the most prevalent in the pediatric population, and it is often a recurrent phenomenon (recurrent urticaria). Acute episodic urticaria it is usually triggered by viruses, allergic reactions to foods and drugs, contact with chemicals and irritants, or physical stimuli. In many instances it is not possible to identify a specific cause (idiopathic urticaria). Chronic urticaria is a condition that can be very disambling when severe. In children is caused by physical factors in 5-10% of cases. Other trigger factors are infections, foods, additives, aeroallergens and drugs. The causative factor for chronic urticaria is identified in about 20% of cases. About one-third of children with chronic urticaria have circulating functional autoantibodies against the high affinity IgE receptor or against IgE. (chronic urticaria with autoantibodies or “autoimmune” urticaria). It is not known why such antibodies are produced, or if the presence of these antibodies alter the course of the disease or influence the response to treatment. Urticaria and angioedema can be symptoms of systemic diseases (collagenopathies, endocrinopathies, tumors, hemolytic diseases, celiachia) or can be congenital (cold induced familiar urticaria, hereditary angioedema). The diagnosis is based on patient personal history and it is very important to spend time documenting this in detail. Different urticaria clinical features must guide the diagnostic work-up and there is no need to use the same blood tests for all cases of urticaria. The urticaria treatment includes identification of the triggering agent and its removal, reduction of aspecific factors that may contribute to the urticaria or can increase the itch, and use of anti-H1 antihistamines (and/or steroids for short periods if antihistamines are not effective). In some instances an anti-H2 antihistamine can be added to the anti-H1 antihistamines, even if the benefits of such practice are not clear. The antileucotriens can be beneficial in a small subgroup of patients with chronic urticaria. In case of chronic urticaria resistant to all the aforementioned treatments, cyclosporine and tacrolimus have been used with good success. When urticaria is associated to anaphylaxis, i.m epinephrine needs to be used, together with antihistamines and steroids (in addition to fluids and bronchodilatators if required). [References: 31].

    May;40(1):5-13

    Available online at: http://www.eurannallergyimm.com/cont/journals-articles/112/volume-urticaria-related-skin-conditiondisease-children-294allasp1.pdf

    Allergy & Asthma Proceedings

    Szema AM, Paz G, Merriam L, Stellaccio F, Jen J 5/2009 Allergy & Asthma Proceedings

    Hereditary angioedema (HAE), deficiency of C1 esterase inhibitor, poses a risk of airway compromise during trauma, including surgery, due to activation of the complement cascade. Classical surgical management includes emergent/slash tracheostomy and cricothyrotomy, associated with high complication rates. We provide here an evidence-based review of available medical literature to construct guidelines for managing patients with HAE pre- and intra-operatively. We also describe our experience with a patient for whom we cared using these guidelines. Our objective was to explain new preventive measures to prevent airway compromise in HAE and their level of evidence for averting potential therapeutic misadventure. We analyzed PUBMED literature regarding airway management and etiology of angioedema and its prevention, followed by application of guidelines based on these data in a patient with HAE undergoing inguinal hernia repair. An analysis of contemporary literature yielded key points: (1) using a Cook Exchange catheter to facilitate re-intubation, (2) measuring cuff leak pressure to verify whether airway pressure had increased during surgery, (3) visualizing the airway directly using a fiberoptic laryngoscope connected to a digital flat-screen monitor for real-time assessment, (4) following conventional dictum to double stanozolol dosages 2 weeks before admission, (5) administering fresh frozen plasma pre- and intraoperatively, and (6) preparing recombinant C1 esterase inhibitor for instantaneous intraoperative use; and using FDA-approved human-derived C1-esterase inhibitor prophylactically. Biotechnology in the form of novel but currently available and in-practice medical devices, as well as new therapeutic agents, have expanded the armamentarium for safely managing patients with HAE pre- and intraoperatively. [References: 9].

    May-Jun;30(3):338-342

    Available online at: http://www.ingentaconnect.com/content/ocean/aap/2009/00000030/00000003/art00016

    C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis

    Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, Rusicke E, Heller C, Klingebiel T 9/2009 Transfusion

    BACKGROUND: Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL) associated with a pasteurized plasma-derived C1-inhibitor (pC1-INH) concentrate for individual replacement therapy (IRT) in patients with severe HAE suffering from frequent attacks who were intolerant or not responding to danazol. STUDY DESIGN AND METHODS: Twenty-two patients with severe HAE and danazol incompatibility or insufficient efficacy of danazol were recruited. Intraindividual comparisons of efficacy, safety, and QoL with pC1-INH concentrate IRT versus danazol treatment were made using retrospective and prospective patient data. Pharmacokinetic data were collected for 15 of the 22 patients. RESULTS: In patients receiving pC1-INH regularly, the median number of attacks per year decreased significantly compared to danazol prophylaxis (p < 0.001), and the 24 laryngeal edema episodes per year ceased. Superior efficacy of pC1-INH was found for all QoL variables (e.g., general condition, social activities). No transmission of human immunodeficiency virus or hepatitis A, B, or C was observed. CONCLUSION: In patients with severe HAE who experience severe side effects and/or lack of efficacy of danazol prophylaxis, very early substitution with pC1-INH can completely abolish the incidence of potentially fatal laryngeal edema and can reduce the incidence of acute attacks.

    Sep;49(9):1987-1995

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2009.02230.x/full (small fee)

    Clinical review of hereditary angioedema: diagnosis and management

    Weis M 11/2009 Postgrad.Med.

    Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase inhibitor and is characterized by sudden attacks of edema associated with discomfort and pain. The disease places patients at risk for disability and death if left untreated. Symptom severity and frequency can be extremely variable even among affected members of the same family. Attacks are not associated with inflammation or allergy, with most occurring secondary to trauma or stress. Swelling can affect any part of the body or multiple sites at once. Commonly affected areas include the extremities, genitalia, trunk, gastrointestinal tract, face, and larynx. Swelling typically worsens over 24 to 36 hours and resolves within 48 hours in less severe cases. Attacks result in 15,000 to 30,000 emergency department visits each year. Many of these emergency cases will undergo unnecessary surgeries or medical procedures due to misdiagnosis. The hallmarks of HAE–recurrent episodes of swelling without urticaria, a family history of HAE, first attack in childhood, and worsening at puberty–can be identified by a thorough family history, and the diagnosis can be confirmed by laboratory studies. Nevertheless, diagnosis may be delayed by 2 decades. We review available therapies and clinical characteristics that will both help clinicians diagnose HAE and distinguish among emergencies and nonemergency cases. [References: 27].

    Nov;121(6):113-120

    Available online at: http://www.tandfonline.com/doi/abs/10.3810/pgm.2009.11.2071 (small fee)

    Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks

    Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtulowicz K, et al 10/2009 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder.

    OBJECTIVE: To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema.

    METHODS: This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours.

    RESULTS: Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus.

    CONCLUSION: C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

    Oct;124(4):801-808

    Available online at: http://www.jacionline.org/article/S0091-6749%2809%2901085-9/fulltext

    Hereditary angioedema and pregnancy

    Chinniah N, Katelaris CH 2/2009 Australian and New Zealand Journal of Obstetrics and Gynaecology (Aust.N.Z.J.Obstet.Gynaecol.)

    BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease caused by a quantitative or functional defect in C1-esterase inhibitor (C1-INH). Patients with this deficiency present with episodes of angioedema which can be life-threatening. Studies examining HAE and pregnancy are scarce with little known about the interrelationship between the two.

    OBJECTIVE: To examine the effect, and evaluate the clinical manifestations of HAE in pregnancy using retrospective interviews of affected women.

    METHODS: Women with HAE who have undergone one of more pregnancies were identified throughout Australia using the national Australasian Society of Clinical Immunology and Allergy immunodeficiency database. Following informed consent, identified women were interviewed regarding their HAE status during pregnancy and the perinatal period using a questionnaire.

    RESULTS: Seven women with a total of 16 pregnancies were identified. During the first trimester of pregnancy, more than ten attacks of angioedema were experienced in six of 16 pregnancies. During the second trimester only in three of 16 pregnancies did women experience greater than ten attacks. During the post-partum period, four of seven women experienced increased frequency and severity of attacks as compared to the pre-pregnancy state. For two of four patients, this impacted on their breast-feeding routine.

    CONCLUSION: Our study showed that women with HAE have greatly reduced or absent attacks in the last two trimesters of pregnancy, although, during the post-partum period, the majority of women experienced increased frequency and severity of attacks.

    Feb;49(1):2-5

    Available online at: http://onlinelibrary.wiley.com/doi/10.1111/j.1479-828X.2008.00945.x/full (small fee)

    Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy

    Bork K, Wulff K, Hardt J, Witzke G, Staubach P 7/2009 Journal of Allergy & Clinical Immunology

    BACKGROUND: Hereditary angioedema caused by mutations in the factor XII gene is a recently described disease entity that occurs mainly in women. It differs from hereditary angioedema caused by C1 inhibitor deficiency.

    OBJECTIVE: To assess the clinical symptoms, factors triggering acute attacks, and treatments of this disease.

    METHODS: Thirty-five female patients with hereditary angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came from 13 unrelated families were studied. The observation period was 8.4 years on average (range, 2-26 years).

    RESULTS: Patients had on average 12.7 +/- 7.9 angioedema attacks per year. Recurrent facial swellings occurred in all patients; skin swellings other than facial, abdominal pain attacks, tongue swellings, and laryngeal edema occurred less frequently. Some factors that triggered angioedema attacks were trauma, physical pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptive use (8 women), pregnancy (7 women), hormone replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1 receptor blocker (1 woman). Effective treatments included C1 inhibitor concentrate for angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman). No difference between mutation p.Thr309Arg and p.Thr309Lys was found.

    CONCLUSIONS: Facial swelling is a cardinal symptom of this condition. Estrogens may have a great influence, but this influence is highly variable. Various treatment options are available.

    Jul;124(1):129-134

    Available online at: http://www.jacionline.org/article/S0091-6749%2809%2900548-X/fulltext?refuid=S1081-1206%2810%2960369-9&refissn=1081-1206&mobileUi=0

    Hereditary angioedema with normal c1 inhibition

    Bork K 7/2009 Current Allergy & Asthma Reports

    Until recently, it was assumed that hereditary angioedema was a disease resulting exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with this condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families, mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.

    Jul;9(4):280-285

    Available online at:  http://www.amjmed.com/article/S0002-9343%2807%2900802-9/abstract (small fee)

    Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate

    Bork K, Hardt J 8/2009 Am.J.Med.

    OBJECTIVE: C1 inhibitor concentrate is regarded as effective and safe in treating acute attacks of hereditary angioedema caused by C1 inhibitor deficiency. This study investigated the course of disease in 3 women treated frequently with C1 inhibitor concentrate.

    METHODS: Three women are described who received C1 inhibitor concentrate for the treatment of acute attacks of hereditary angioedema and experienced an increase in the frequency of attacks during that treatment period. In a control group of 24 patients aged more than 60 years with hereditary angioedema, the natural course of disease was determined.

    RESULTS: The 3 women (ages 50, 69, and 72 years) had received C1 inhibitor concentrate for 27, 18, and 22 years, respectively, for acute abdominal and skin attacks. Before this treatment, all attacks were severe. The treatment was always effective: The attacks were mild, and the duration of the attacks was shortened. During the treatment period, the number of attacks increased slowly but continuously, starting at the onset of treatment and paralleling the course of treatment. At the end of the observation period, the number of attacks increased by 4-fold, 12-fold, and 5-fold in the 3 women, respectively. No factors known to increase the frequency of attacks in hereditary angioedema were found in these patients. The control group did not show a similar increase in attacks during a comparable period of time.

    CONCLUSION: A possible explanation for the increase in the frequency of attacks may lie in the large number of injections of C1 inhibitor concentrate.

    Aug;122(8):780-783

    Available online at:  http://www.amjmed.com/article/S0002-9343%2809%2900406-9/pdf (small fee)

    Human C1-esterase inhibitor concentrate (Berinert)

    Keating GM /2009 Biodrugs

    Human C1-esterase inhibitor concentrate (C1-INH concentrate) is derived from human plasma and is indicated for the treatment of acute episodes of hereditary angioedema. Intravenous C1-INH concentrate provided rapid symptom relief in patients with acute abdominal or facial episodes associated with type I or II hereditary angioedema, according to the results of the randomized, double-blind, multicenter, placebo-controlled IMPACT-1 trial. The median time to the onset of symptom relief was significantly shorter with C1-INH concentrate 20 U/kg than with placebo (0.5 vs 1.5 hours). A subsequent noncomparative extension trial (IMPACT-2) showed the ongoing efficacy of ‘on-demand’ treatment with C1-INH concentrate; overall, the onset of symptom relief occurred in a median 30 minutes. Several additional studies demonstrated the efficacy of intravenous C1-INH concentrate in patients with laryngeal edema, skin swellings, or abdominal episodes associated with type I or II hereditary angioedema. Self-administered home therapy with intravenous C1-INH concentrate significantly improved health-related quality of life in patients with hereditary angioedema. Dermatology Life Quality Index and Short Form 36-item Health Survey scores were significantly improved from baseline by self-administered home therapy with C1-INH concentrate. Intravenous C1-INH concentrate was well tolerated in patients with hereditary angioedema, with no confirmed cases of viral transmission. [References: 28].

    23(6):399-406

    Available online at: http://link.springer.com/article/10.2165%2F11201100-000000000-00000 (small fee)

    Icatibant for hereditary angioedema

    Gras J 12/2009 Drugs of Today

    Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening disease, characterized by recurrent self-limiting bouts of edema mainly involving the extremities, genitalia, face, intestines and airways. The prevalence of HAE in the general population has been estimated to be in the range of 1:10,000 to 1:150,000. Currently, acute attacks of HAE are treated mainly symptomatically, with poor outcomes. Recently, it has been demonstrated that bradykinin (BK) is responsible for most of the symptoms of HAE. Icatibant (Firazyr, HOE 140, JE049) is a potent, specific and selective B2 BK receptor antagonist that has recently been approved by the EMEA for the treatment of HAE. In phase III clinical trials, 30 mg of subcutaneous icatibant demonstrated rapid and stable relief from symptoms in cutaneous, abdominal or laryngeal HAE attacks. Local site reactions after subcutaneous injection of icatibant were observed, however, these reactions were mild to moderate in severity and resolved spontaneously and quickly. Icatibant is a new, safe and effective treatment for acute attacks of HAE.Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved. [References: 69].

    Dec;45(12):855-864

    Available online at: https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1424267 (small fee)

    New drugs 09, part 2

    Hussar DA 6/2009 Nursing

    In this article, you’ll learn about six new drugs, including: • clevidipine, an I.V. antihypertensive for use when oral medication isn’t feasible • romiplostim and eltrombopag olamine, new agents for chronic immune thrombocytopenic purpura • C1 inhibitor (human) for hereditary angioedema. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug’s safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs

    quiz 40; Jun;39(6):33-39

    Available online at: http://journals.lww.com/psnjournalonline/pages/articleviewer.aspx?year=2009&issue=10000&article=00014&type=abstract (small fee)

    Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency

    Bossi F, Fischetti F, Regoli D, Durigutto P, Frossi B, Gobeil F Jr, et al 12/2009 Journal of Allergy & Clinical Immunology

    BACKGROUND: Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications.

    OBJECTIVE: Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency.

    METHODS: The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy.

    RESULTS: We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A.

    CONCLUSION: Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.

    Dec;124(6):1303-10.e4

    Available online at: http://europepmc.org/articles/PMC2798851;jsessionid=6al6ZU49LschTHx0ZtAX.0

    Psychometric validation of two patient-reported outcome measures to assess symptom severity and changes in symptoms in hereditary angioedema

    Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A 9/2009 Quality of Life Research

    PURPOSE: Hereditary angioedema (HAE) is a rare disorder characterized by highly variable, acute attacks of swelling at various anatomical locations. Clinical measures do not adequately assess the diversity of symptoms characteristic of an attack. Two disease-specific, patient-reported outcome measures were developed to comprehensively capture symptom severity and change: the Treatment Outcome Score (TOS) and the Mean Symptom Complex Severity (MSCS) score.

    METHODS: This study comprised a secondary analysis of pooled data from a randomized controlled trial to evaluate the psychometric properties, including reliability and validity, and minimally important difference (MID) of the TOS and MSCS score.

    RESULTS: HAE patients (n = 73) had a mean age of 33 years, and 60% were female. Test-retest evaluation demonstrated moderate to substantial agreement (ICCs = 0.53 for TOS; 0.62 for MSCS score). The TOS and change in MSCS score were moderately to highly correlated with a Global Improvement Measure at 4 h (TOS: r = 0.90; MSCS: r = -0.59). Anchor- and distribution-based analyses suggested that conservative estimates for MID are 30 points for TOS and -0.30 points for 4-h change in MSCS score.

    CONCLUSIONS: The psychometric tests performed here provide evidence of the reliability and validity of the TOS and MSCS for evaluating symptom severity and change in HAE patients. The TOS and MSCS score provide an example of measurement methodology that may be used to precisely capture symptom severity and change in a disease characterized by acute attacks.

    Sep;18(7):929-939

    Available online at: http://link.springer.com/article/10.1007%2Fs11136-009-9509-8 (small fee)

    Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits

    Bygum A, Andersen KE, Mikkelsen CS 3/2009 European Journal of Dermatology

    Hereditary angioedema (HAE) is often debilitating with a serious effect on quality of life (QOL). Treatment of acute HAE attacks is usually with C1 esterase inhibitor (C1-INH) concentrates; however, treatment can be delayed by patients’ travel time for attending emergency units. We assessed the impact of self-administered home therapy with intravenous C1-INH concentrate on QOL in patients with HAE. Nine patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate. QOL was assessed prior to and following home therapy using the Dermatology Life Quality Index (DLQI) and 36-Item Short Form Survey (SF-36) questionnaires. Seven patients were recruited into the study. QOL was assessed at baseline and after 3 to 48 months of home therapy. The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (P < 0.001). Mean SF-36 scores for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions caused by the condition.

    Mar-Apr;19(2):147-151

    Available online at: http://www.researchgate.net/publication/24180431_Self-administration_of_intravenous_C1-inhibitor_therapy_for_hereditary_angioedema_and_associated_quality_of_life_benefits

    Update on therapeutic developments for hereditary angioedema

    Christiansen SC, Zuraw BL 9/2009 Allergy & Asthma Proceedings

    Remarkable progress has been made in understanding the molecular mechanisms underlying attacks of swelling in hereditary angioedema (HAE). Treatment options in the United States for this potentially life-threatening disease had remained essentially static, however, over the past 40 years. Prophylactic therapy had relied on attenuated androgens or antifibrinolytic agents. Although demonstrably effective, these drugs have been fraught with side effects. Acute therapy has been largely relegated to supportive care. In this article we discuss emerging treatments that have evolved from the recognition that kinin generation is the fundamental abnormality leading to attacks of angioedema. We will review the newly approved replacement therapy for prophylaxis of HAE attacks with C1 inhibitor (C1INH). Potential options for the acute treatment of HAE will be discussed including purified C1INH, recombinant C1INH, an inhibitor of plasma kallikrein, and a B2-receptor antagonist. The arrival of these novel therapies promises to transform the future management of HAE. [References: 44].

    Sep-Oct;30(5):500-505

    Available online at: http://www.ingentaconnect.com/content/ocean/aap/2009/00000030/00000005/art00006 (small fee)

    Usefulness of abdominal ultrasonography in the follow-up of patients with hereditary C1-inhibitor deficiency

    Pedrosa M, Caballero T, Gomez-Traseira C, Olveira A, Lopez-Serrano C 6/2009 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema (HAE) is caused by the deficiency of functional C1 inhibitor. Symptoms of this disease include cutaneous angioedema, abdominal pain, and even laryngeal edema. OBJECTIVE: To evaluate the usefulness of abdominal ultrasonography in patients with hereditary C1-inhibitor deficiency in diagnosing acute abdominal edema attacks and possible adverse effects of long-term prophylaxis with attenuated androgens. METHODS: Fifty-nine adult patients with HAE regularly observed in our department were included whether they were symptomatic or not and whether they received long-term androgen prophylaxis or not. We evaluated the ultrasonographic findings in the assessments performed routinely or in the moment of an acute abdominal attack. RESULTS: Of the 59 patients, 55 ever had any symptom due to HAE (abdominal location, 78% of the symptomatic patients); 4 patients were asymptomatic. In 11 cases, ultrasonography was performed during acute attacks. Ascites and intestinal wall swelling were found in 7 of these 11 cases and, thus, diagnosis was confirmed. Of the 59 patients, 33 were or had been receiving androgen prophylaxis. Abdominal ultrasonographic assessments were performed routinely in 31 of these patients. Four cases of angiomas, 4 of steatosis, and 1 each of portal hypertension, hepatic cysts, and hepatomegaly were found. Assessments were also performed in 17 patients who did not receive androgen prophylaxis; there were no findings in any of these patients. CONCLUSION: Abdominal ultrasonography has been proved useful as an early tool for diagnosing the adverse effects of therapy and for confirming diagnosis in the case of an acute abdominal attack.

    Jun;102(6):483-486

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960121-4/fulltext (small fee)

    When is prophylaxis for hereditary angioedema necessary?

    Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al 5/2009 Annals of Allergy, Asthma, & Immunology

    OBJECTIVE: To determine when newer agents, such as C1 esterase inhibitor protein (C1-INH), should be considered as prophylaxis to decrease hereditary angioedema (HAE) attacks as an alternative to androgens, which have significant adverse events.

    DATA SOURCES: A literature review (PubMed, Google, and Ovid), guideline review, expert panel meeting, and group discussion were performed to decide when prophylaxis is indicated.

    STUDY SELECTION: Articles addressing HAE therapy published in the peer-reviewed literature were selected.

    RESULTS: The retrieved studies demonstrate that C1-INH is effective and that the half-life makes it attractive for prophylactic use. The short half-lives of ecallantide, icatibant, and recombinant human C1-INH limit their use as prophylactic agents. Patients with severe anxiety, more than 1 attack per month, rapid progression of attacks, limited access to health care, more than 10 days lost from work or school per year, previous laryngeal swelling, more than 3 emergency department visits per year, more than 1 hospitalization per year, previous intubation, previous intensive care unit care, significant compromise in quality of life, or narcotic dependency should be considered for androgen or C1-INH prophylaxis therapy.

    CONCLUSION: Patients with HAE with frequent attacks, severe attacks, past laryngeal attacks, excessive loss of work or school, significant anxiety, and poor quality of life should be considered for C1-INH prophylaxis, especially those who fail, are intolerant of, have adverse reactions to, or are not candidates for androgen therapy. [References: 28].

    May;102(5):366-372

    Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960506-6/fulltext (small fee)

    2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema

    Tom Bowen, Marco Cicardi, Henriette Farkas, Konrad Bork, Hilary J Longhurst, Bruce Zuraw, Emel Aygoeren-Pürsün, Timothy Craig, Karen Binkley, Jacques Hebert, Bruce Ritchie, Laurence Bouillet, Stephen Betschel, Della Cogar, John Dean, Ramachand Devaraj, Azza Hamed, Palinder Kamra, Paul K Keith, Gina Lacuesta, Eric Leith, Harriet Lyons, Sean Mace, Barbara Mako, Doris Neurath, Man-Chiu Poon, Georges-Etienne Rivard, Robert Schellenberg, Dereth Rowan, Anne Rowe, Donald Stark, Smeeksha Sur, Ellie Tsai, Richard Warrington, Susan Waserman, Rohan Ameratunga, Jonathan Bernstein, Janne Björkander, Kristylea Brosz, John Brosz, Anette Bygum, Teresa Caballero, Mike Frank, George Fust, George Harmat, Amin Kanani, Wolfhart Kreuz, Marcel Levi, Henry Li, Inmaculada Martinez-Saguer, Dumitru Moldovan, Istvan Nagy, Erik W Nielsen, Patrik Nordenfelt, Avner Reshef, Eva Rusicke, Sarah Smith-Foltz, Peter Späth, Lilian Varga and Zhi Yu Xiang 07/2010 Allergy, Asthma & Clinical Immunology

    Background
    We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.

    Objective
    To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010).

    Methods
    The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) http://www.haecanada.com webcite and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review.

    Results
    This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference.

    Conclusions
    Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/24

    Acquired angioedema

    Marco Cicardi, Andrea Zanichelli 07/2010 Allergy, Asthma & Clinical Immunology

    Acquired angioedema (AAE) is characterized by acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and angioedema symptoms mediated by bradykinin released by inappropriate activation of the contact-kinin system. Angioedema recurs at unpredictable intervals, lasts from two to five days and presents with edema of the skin (face, limbs, genitals), severe abdominal pain with edema of the gastrointestinal mucosa, life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue. AAE recurs in association with various conditions and particularly with different forms of lymphoproliferative disorders. Neutralizing autoantibodies to C1-INH are present in the majority of patients. The therapeutic approach to a patient with AAE should first be aimed to avoid fatalities due to angioedema and then to avoid the disability caused be angioedema recurrences. Acute attacks can be treated with plasma-derived C1-INH, but some patients become non-responsive and in these patients the kallikrein inhibitor ecallantide and the bradykinin receptor antagonist icatibant can be effective. Angioedema prophylaxis is performed using antifibrinolytic agents and attenuated androgens with antifibrinolytic agents providing somewhat better results. Treatment of the associated disease can resolve AAE in some patients.

    Available online at: http://www.aacijournal.com/content/6/1/14

    Advances in basic and clinical immunology in 2009

    Chinen J, Shearer WT. 3/2010 Journal of Allergy and Clinical Immunology

    In 2009, reports on basic and clinical immunology had an increased focus on human disease mechanisms and management. The molecular pathogenesis of familial angioedema associated with estrogen was further explored to find possible factors affecting severity, including polymorphisms in enzymes and receptors related to bradykinin pathways. A placebo-controlled clinical trial of C1 esterase inhibitor concentrate in patients with hereditary angioedema demonstrated the safety of its use and its efficacy to reduce the duration of angioedema attacks. The interaction of innate immunity and adaptive responses was further examined in several reports, establishing the significant role of Toll-like receptor stimulation for the development of optimal specific antibody responses. The 2009 update of the classification of primary immunodeficiencies introduced more than 15 new genetic defects related to the immune response, including of dedicator of cytokinesis 8 (DOCK8) mutations, which are responsible for the autosomal recessive form of the hyper-IgE syndrome. Other reports expanded the clinical spectrum of disease and improved the characterization of conditions such as warts, hypogammaglobulinemia, and myelokathexis syndrome or the occurrence of mucormycosis and Serratia species infections in patients with chronic granulomatous disease. The frequent presentation of gastrointestinal disorders in patients with humoral immunodeficiencies was recognized, and recommendations for management were reviewed. Clinical research focused on severe combined immunodeficiency included the development and implementation of a state-wide newborn screening program for this condition, a desired goal considering the significant reduction of mortality rate when the diagnosis is made early before opportunistic infections occur. [References: 41].

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841291/

    An overview of novel therapies for acute hereditary angioedema

    Firszt R, Frank MM. 12/2010 American Journal of Clinical Dermatology

    Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin. Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

    Available from: https://www.ncbi.nlm.nih.gov/pubmed/20866113

    Angioedema due to C1 inhibitor deficiency in 2010

    Cicardi M, Zanichelli A. 12/2010 Internal and Emergency Medicine

    Angioedema is a recurrent, non-pitting, non-pruritic, self-limiting swelling due to transient increase of endothelial permeability in the capillaries of the deep cutaneous and mucosal layers. Two main groups of angioedema should be distinguished based on the response to treatment: those responding to antihistamine and those that do not. Among the last ones, angioedema due to inherited (hereditary angioedema) and acquired (acquired angioedema) C1 inhibitor deficiency are the best defined, and are known to be mediated by bradykinin. The clinical picture is characterized by cutaneous, abdominal, and laryngeal symptoms that are highly disabling, and can be lethal when they affect the larynx, or if they are not promptly and adequately treated. Important advances in diagnosis and treatment of C1 inhibitor deficiency have been made in recent years, and today, we can rely on different therapeutic options to prevent symptoms or to treat those already present. Because of these advances, in patients properly diagnosed and treated, the mortality for the disease has dropped close to zero, and the quality of life for patients approaches that of normal subjects.

    Available from: http://link.springer.com/article/10.1007%2Fs11739-010-0408-3

     

     

    C1 inhibitor, a multi-functional serine protease inhibitor

    Davis AE 3rd, Lu F, Mejia P. 11/2010 Thrombosis and Haemostasis

    C1 inhibitor (C1INH) is a serpin that regulates both complement and contact (kallikrein-kinin) system activation. It consists of a serpin domain that is highly homologous to other serpins and an amino terminal non-serpin mucin-like domain. Deficiency of C1INH results in hereditary angioedema, a disease characterised by episodes of angioedema of the skin or the mucosa of the gastrointestinal tract or the oropharynx. Although early data suggested that angioedema was mediated via complement system activation, the preponderance of the data indicate that bradykinin is the mediator. In the past few years, it has become apparent that C1INH has additional anti-inflammatory functions independent of protease inhibition. These include interactions with leukocytes that may result in enhanced phagocytosis, with endothelial cells via E- and P-selectins that interfere with leukocyte rolling and in turn results in suppression of transmigration of leukocytes across the endothelium, and interactions with extracellular matrix components that may serve to concentrate C1INH at sites of inflammation. In addition, C1INH suppresses gram negative sepsis and endotoxin shock, partly via direct interaction with endotoxin that interferes with its interaction with macrophages, thereby suppressing tumour necrosis factor-a and other inflammatory mediators. C1INH treatment improves outcome in a number of disease models, including sepsis and other bacterial infections, possibly malaria, ischaemia-reperfusion injury (intestinal, hepatic, muscle, cardiac, brain), hyper-acute transplant rejection, and other inflammatory disease models. Recent data suggest that this effectiveness is the result of mechanisms that do not require protease inhibition, in addition to both complement and contact system activation.

    Available from: www.schattauer.de/index.php?id=5236&mid=13518

     

    Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate

    Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kreuz W. 8/2010 American Journal of Obstetrics and Gynecology

    OBJECTIVE: The objective of the study was to investigate the rates and characteristics of hereditary angioedema (HAE) attacks associated with pregnancy, delivery, and the postpartum period and their treatment with C1 esterase inhibitor (INH) concentrate.

    STUDY DESIGN: This was an observational study including 22 women with type I HAE, with data collected before, during, and after 35 pregnancies (37 children) based on patient diaries, interviews, and case report forms.

    RESULTS: In 83% of pregnancies, attack rates increased during pregnancy; highest mean rates occurred in the second and third trimesters. C1-INH concentrate effectively controlled attacks and was safe for mothers and children. Low-plasma C1-INH activity during pregnancy tended to be associated with an increased chance of giving birth to a child with HAE.

    CONCLUSION: Increased attack rates during pregnancy in women with HAE are well controlled with C1-INH concentrate, indicating the clear benefit of integrating the availability of C1-INH concentrate into the management plan for these women during pregnancy and delivery.Copyright (c) 2010 Mosby, Inc. All rights reserved.

    Current treatment of hereditary angioedema: An update on clinical studies

    Banerji A. 9/2010 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare, potentially life-threatening disease that manifests as recurrent episodes of nonpruritic swelling that may affect the extremities, face, genitalia, gastrointestinal tract, and/or larynx. HAE is the result of a deficiency of functional C1-esterase inhibitor (C1-INH), a key regulator of the complement, coagulation, and kallikrein-kinin cascades. In HAE patients, overactivation of the kallikrein-kinin cascade results in excessive release of bradykinin, the mediator of the pain and swelling that is characteristic of HAE. Historically, treatment options for HAE have been limited, but newly approved and emerging therapies, such as C1-INH replacement products, a plasma kallikrein inhibitor, and a bradykinin B2-receptor antagonist, appear to provide safe and effective relief for a significant proportion of patients with HAE. Because they may have therapeutic and practical advantages over existing HAE therapies, the new agents have the potential to improve the overall management of patients with HAE. This article reviews the results from recent clinical trials of these drugs and considers their role in clinical practice.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2010/00000031/00000005/art00012

     

    Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor

    Konrad Bork 07/2010 Allergy, Asthma & Clinical Immunology

    Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/15

    Ecallantide for the treatment of acute attacks in hereditary angioedema

    Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. 08/2010 New England Journal of Medicine

    BACKGROUND: Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema.

    METHODS: In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement.

    RESULTS: A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events.

    CONCLUSIONS: Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.).

    Available from : http://www.nejm.org/doi/full/10.1056/NEJMoa0905079#t=article

    Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema

    Stolz LE, Horn PT. 8/2010 Drugs of Today

    Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE.Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

    Available from: https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=4&p_RefId=1507205&p_IsPs=N

    Ecallantide: in acute hereditary angioedema

    Garnock-Jones KP. 7/2010 Drugs

    Ecallantide, a recombinant protein that is a selective, highly potent and reversible inhibitor of human plasma kallikrein, is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged >or=16 years. In the randomized, double-blind, placebo-controlled, multicentre, phase III trial EDEMA3, mean symptom response to treatment at 4 hours (assessed using the Treatment Outcome Score [TOS]; primary endpoint) was significantly greater with a single subcutaneous dose of ecallantide 30 mg than with placebo in patients with acute, moderate to severe attacks of HAE. In addition, the mean change from baseline in symptom severity at 4 hours (assessed using the Mean Symptom Complex Severity [MSCS] scale) was significantly greater with ecallantide than with placebo. At 4 hours in the similarly designed EDEMA4 trial, the mean change from baseline in MSCS score (primary endpoint) and mean TOS were both significantly greater in recipients of a single subcutaneous dose of ecallantide 30 mg than in placebo recipients. Subcutaneous ecallantide 30 mg was generally well tolerated in patients with acute attacks of HAE in the EDEMA3 and EDEMA4 trials. Adverse events were mostly of mild to moderate severity, and no event that was more common in ecallantide than placebo recipients occurred in >10% of patients. [References: 22].

    Available from: http://link.springer.com/article/10.2165%2F11205850-000000000-00000

     

    Ecallantide: its pharmacology, pharmacokinetics, clinical efficacy and tolerability

    Bernstein JA, Qazi M. 1/2010 Expert Review of Clinical Immunology

    Ecallantide (Kalbitor, Dyax Corporation) is a highly specific recombinant plasma kallikrein inhibitor developed for treatment of hereditary angioedema (HAE). Advantages of this agent over plasma-derived treatments are that it poses no risk of viral contamination, is highly selective, has a quick onset of action and can be administered subcutaneously. In clinical trials, ecallantide appears to be a safe and effective drug useful for the treatment of HAE patients suffering from an acute attack. Ecallantide was found to be superior compared with placebo in relieving symptoms, decreasing the severity of attacks and shortening the duration of attacks. The primary safety concern appears to be related to hypersensitivity reactions. Phase IV postmarketing surveillance studies to monitor the incidence of these reactions will be implemented by the company now that the drug has been US FDA approved. [References: 22].

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.09.60

    EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema

    Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, et al. 6/2010 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder resulting from low levels of C1-inhibitor activity that manifests as acute attacks of variable and sometimes life-threatening edema. Ecallantide is a novel potent inhibitor of human plasma kallikrein, a key mediator of the excessive formation of bradykinin associated with the signs and symptoms of an HAE attack.

    OBJECTIVE: To evaluate the efficacy and safety of ecallantide in the treatment of acute HAE attacks.

    METHODS: In this double-blind, placebo-controlled study, patients with a moderate to severe HAE attack were randomized 1:1 to receive 30 mg of subcutaneous ecallantide or placebo. The primary efficacy end point was change from baseline in mean symptom complex severity score 4 hours after dosing. Additional end points included treatment outcome score 4 hours after dosing and maintenance of significant overall improvement through 24 hours.

    RESULTS: Ninety-six patients were enrolled. Mean (SD) change from baseline in mean symptom complex severity score 4 hours after dosing was significantly greater with ecallantide use (-0.8 [0.6]) compared with placebo use (-0.4 [0.8]) (P = .01 comparing distributions). Ecallantide therapy was also associated with a significantly larger mean (SD) treatment outcome score 4 hours after dosing vs placebo use (ecallantide: 53.4 [49.7]; placebo: 8.1 [63.2]; P = .003 comparing distributions). The benefit of ecallantide was apparent within 2 hours after dosing and was maintained through 24 hours after dosing. The safety profile was similar between the treatment groups.

    CONCLUSION: Ecallantide appears to be an effective and safe treatment for acute attacks of HAE.

     

    Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy

    Kaplan AP. 11/2010 Journal of Allergy and Clinical Immunology

    A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH.Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

    Available from: http://www.jacionline.org/article/S0091-6749%2810%2901197-8/fulltext

     

    Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions

    Karen E Binkley 07/2010 Allergy, Asthma & Clinical Immunology

    The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management.

    The electronic version of this article is the complete one and can be found online at:http://www.aacijournal.com/content/6/1/16

    HAE international home therapy consensus document

    Hilary J Longhurst, Henriette Farkas, Timothy Craig, Emel Aygören-Pürsün, Claire Bethune, Janne Bjorkander, Konrad Bork, Laurence Bouillet, Henrik Boysen, Anette Bygum, Teresa Caballero, Marco Cicardi, John Dempster, Mark Gompels, Jimmy Gooi, Sofia Grigoriadou, Ursula Huffer, Wolfhart Kreuz, Marcel M Levi, Janet Long, Inmaculada Martinez-Saguer, Michel Raguet, Avner Reshef, Tom Bowen and Bruce Zuraw 07/2010 Allergy, Asthma & Clinical Immunology

    Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks (‘self or assisted administration’) and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/22

    HAE therapies: past present and future

    Bruce L Zuraw 07/2010 Allergy, Asthma & Clinical Immunology

    Advances in understanding the pathophysiology and mechanism of swelling in hereditary angioedema (HAE) has resulted in the development of multiple new drugs for the acute and prophylactic treatment of patients with HAE. This review will recap the past treatment options, review the new current treatment options, and discuss potential future treatment options for patients with HAE.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/23

    Hereditary Angioedema Consensus 2010

    Tom Bowen 07/2010 Allergy, Asthma & Clinical Immunology

    The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was arrived at during the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) second meeting held May 15th/16th, 2010, Toronto, Canada and was cosponsored by CHAEN/RCAH, the Canadian Society of Allergy and Clinical Immunology, and the University of Calgary and was funded through an unrestricted educational grant from CSL Behring. This is the third international consensus and is meant to be a living document requiring continual updating and rethinking. The first consensus conference was scheduled for Toronto, Ontario, Canada in April 2003 but was SARSed out. That conference was rescheduled and held in Toronto in October 2003 and published in 2004. The next consensus was again held in Toronto Canada in 2006 and rediscussed in Budapest in 2007 and published in 2008. This third consensus conference was in danger of being ashed out from the volcanic activity in Iceland making planning of such meetings a challenge.

    Rare disorders such as Hereditary Angioedema require international collaboration to push ahead with progress in the management of the disorders. The Hungarian group under Dr. Henriette Farkas and the Italian group under Dr. Marco Cicardi have certainly led the way in organizing these essential get-togethers. Patient Group participation in these discussions has been strongly encouraged and the Consensus Algorithms have been signed off by various National Patient Organizations. The patients should decide how they wish to be treated. I usually bore audiences with my motto: It can be done – It must be done for the sake of our patients. This concept continues in this third consensus algorithm development. We have moved from 2003 from only a few controlled trials in prophylaxis and treatment in HAE-Types I and II to now several clinical trials in various stages of publication. Prophylaxis options have moved from anti-fibrinolytics and androgens to include consideration of plasma-derived C1-inhibitor (pdC1INH) prophylaxis. Therapy options have broadened from pdC1INH to now include bradykinin receptor antagonist Icatibant and kallikrein antagonist Ecallantide and recombinant C1INH under clinical trial. These phase III clinical trials will move this current consensus algorithm approach to evidence-based approach and Dr. Marco Cicardi is moving this along with an important meeting in Italy in September 2010.

    Clinical trials in rare disorders are difficult at the best of times but exceptionally difficult in HAE where swelling events are unpredictable and require quick intervention at all hours of day, night, weekends. These clinical trials are difficult for patients and clinic staff alike and it is to the credit of the Patients and the Research Clinics that these studies have moved along and are either now published or in stages of publication. However, phase IV clinical trials and head-to-head evaluation of prophylactic and therapeutic approaches including cost benefit and quality of life are still lacking. To date, the clinical trials have been small and these data may change when larger trials are undertaken. For example, for many years Berinert (Berinert P in the past and now just called Berinert) has been used for therapy at doses of one or two vials (500 to 1000 units; close to 10 units per kg) in thousands of infusions and appear safe and appear to have successfully treated most HAE episodes with second infusions uncommon. However, when the small clinical phase III trial was conducted, results showed benefit from 20 units/kg but not 10 units/kg. Since this was the phase III clinical trial, dose licensing for this drug is 20 units/kg. This recommendation has great economic impact on the therapy of this disorder increasing the cost of treatment by considerable amount. It is essential for national and international networks of clinics to undertake phase IV clinical trials to retest this dose-finding. Plasma derivatives such as pdC1INH are precious resources donated from dedicated blood donors needing conservation when possible and such products are costly for individual patients or treatment programs. The extensive European clinical experience in hundreds of thousands of infusions would indicate a lower dose used early in a swelling event may suffice. With the availability of new non blood product treatments, these treatments need head-to-head comparison with the gold standard pdC1INH and each other so that patients and clinics and payers can make appropriate cost benefit quality of life based analyses to strengthen the evidence based recommendations for management of this disorder.

    HAE-Type III has become recognized but whereas the genetic defect and pathophysiology of Types I and II are well worked out, the pathophysiology of Type III is still in its infancy. This group of manuscripts is meant to discuss the differential diagnosis of hereditary versus acquired angioedema, help understand the clinical differences and approaches to the three types of Hereditary Angioedema with nuances in females, pregnancy, pediatrics, and then adults. These manuscripts are from the presenters at the 2010 Consensus Conference held in Toronto Canada and represent some of the background for discussion for the patient and care teams present as they discussed the consensus algorithms. The Consensus Manuscript draft was discussed at the meeting and then circulated to the other international authors including patient groups and treatment team leaders. The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema is the result. We have chosen to publish in an on line open journal to allow wide and timely full free distribution of the consensus. We hope this generates further thoughts and discussions and that Dr. Cicardi will move the consensus forward to evidence-based approach as the various trials become published. This is but an algorithm approach in evolution changing as evidence becomes available. We look forward to the phase IV clinical phase and much larger clinical trials to further investigate the most cost effective approach leading to the best quality of life for all HAE patients.

    I would like to congratulate the many Patients who participate in these very difficult clinical trials and further congratulate the clinic teams who undertake these stressful trials requiring 24/7 research team availability in this unpredictable swelling disorder HAE. There is much more work to do! Keep up the good work. I would like to thank the Canadian Society of Allergy and Clinical Immunology and the University of Calgary for taking HAE under their wing and supporting these international consensus meetings.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/13

    Hereditary angioedema in women

    Laurence Bouillet 07/2010 Allergy, Asthma & Clinical Immunology

    Women with hereditary angioedema (HAE) are more likely to be symptomatic that men. Hormonal factors (puberty, contraception, pregnancy,….) play a significant role in the precipitation or worsening of the condition in women. So, combined contraceptive pills are not indicated and progestogen pill must be preferred. During pregnancy, attack rate can increase (38-48% of women). C1Inhibitor concentrate and tranexamic acid can be used during pregnancy. Attenuated androgens for long term prophylaxis are effective but side effects appear more often in female patients. These side effects are dose dependant and can be attenuated by titrating the dose down the lowest effective level.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/17

    Hereditary angioedema: an update on available therapeutic options

    Maurer M, Magerl M. 9/2010 Journal der Deutschen Dermatologischen Gesellschaft

    There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short-term prophylaxis before surgery, and long-term prophylaxis for those with frequent and severe attacks. In Germany, C1-INH concentrate and icatibant are licensed for acute therapy. C1-INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1-INH activity. This therapy, which has been available for decades, is effective and well-tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well-tolerated, even on repeated administration. An additional human C1-inhibitor, a recombinant human C1-inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long- and short-term prophylaxis. Androgen derivatives are established in long-term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1610-0387.2010.07450.x/full

    Icatibant

    11/2010 Prescrire International

    Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.

     

    Icatibant

    Deeks ED. 01/2010 Drugs

    Icatibant is a selective antagonist of the bradykinin type 2 receptor. In the randomized, double-blind, multicentre, FAST-1 trial, the difference in the median time to the onset of symptom relief (primary endpoint) did not reach statistical significance between a single dose of subcutaneous icatibant 30 mg and placebo in adults with moderate to very severe acute abdominal or cutaneous episodes of hereditary angioedema. However, icatibant was effective with regard to several other endpoints, providing significantly greater reductions from baseline in symptom severity scores 4 and 12 hours after administration, and eliciting significantly shorter times to both first symptom improvement and overall patient improvement than placebo. In the similarly designed, active comparator-controlled, FAST-2 trial, a single dose of subcutaneous icatibant 30 mg was associated with a significantly shorter median time to onset of symptom relief (primary endpoint) than oral tranexamic acid in adults with acute abdominal or cutaneous episodes of hereditary angioedema, and was also more effective than tranexamic acid in terms of most other endpoints. Across both FAST-1 and -2, the efficacy of subcutaneous icatibant 30 mg in the treatment of laryngeal episodes of hereditary angioedema was generally consistent with that seen for abdominal and cutaneous episodes, with a median time to first symptom improvement of 0.6-1.0 hours. Subcutaneous icatibant was generally well tolerated in adult patients with hereditary angioedema in the FAST trials, with the most common adverse events being injection-site reactions that were generally of mild severity, transient in nature and resolved spontaneously without treatment.

    Available from: http://link.springer.com/article/10.2165%2F11204500-000000000-00000

     

    Icatibant

    Dubois EA, Cohen AF. 5/2010 British Journal of Clinical Pharmacology

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856042/

    Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema

    Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, et al. 8/2010 New England Journal of Medicine

    BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.

    METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.

    RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.

    CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.).

    Available from : http://www.nejm.org/doi/full/10.1056/NEJMoa0906393#t=article

    Is there a need for clinical guidelines in the United States for the diagnosis of hereditary angioedema and the screening of family members of affected patients?

    Lunn ML, Santos CB, Craig TJ. 3/2010 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency of C1 esterase inhibitor (C1 INH) protein or function. Guidelines do not exist regarding diagnostic criteria or routine testing of family members of patients with HAE. Laboratory data for diagnosis include complement factor 4 level; C1 INH antigenic protein level, which is reduced in approximately 85% of patients with HAE; and C1 INH functional assay, which is considered an unreliable test in the United States secondary to inconsistent standardization of assays.

    OBJECTIVES: To assess the shortcomings of diagnosing HAE and to determine whether family members of patients with HAE are being adequately screened.

    METHODS: The top physician prescribers of danazol in the United States were screened via an Internet questionnaire focusing on the diagnosis and current management of HAE. To assess the patient perspective on HAE, affected individuals in the United States, the United Kingdom, France, Germany, and The Netherlands participated in the Web-based International Survey of Patient Experience of Hereditary Angioedema.

    RESULTS: All 80 physicians who completed the survey were allergist or immunologists with a mean of 7 patients with C1 INH deficiency in their practices. Almost 84% of physician respondents used C1 INH level and function for diagnosis, and 63.8% used complement factor 4 levels. A total of 313 patients with HAE completed the survey. Respondents noted that only 48% of immediate family members and 26% of extended family members had been tested.

    CONCLUSION: Guidelines could potentially alleviate delays in diagnosis and incorrect diagnoses and could lead to adequate screening of family members.

    Kinins, airway obstruction, and anaphylaxis

    Kaplan AP. /2010 Chemical Immunology and Allergy

    Anaphylaxis is a term that implies symptoms that are present in many organs, some of which are potentially fatal. The pathogenic process can either be IgE-dependent or non-IgE-dependent; the latter circumstance may be referred to as anaphylactoid. Bradykinin is frequently responsible for the manifestations of IgE-independent reactions. Blood levels may increase because of overproduction; diseases such as the various forms of C1 inhibitor deficiency (hereditary or acquired) or hereditary angioedema with normal C1 inhibitor are examples in this category. Blood levels may also increase because of an abnormality in bradykinin metabolism; the angioedema due to ACE inhibitors is a commonly encountered example. Angioedema due to bradykinin has the potential to cause airway obstruction and asphyxia as well as severe gastrointestinal symptoms simulating an acute abdomen. Formation of bradykinin in plasma is a result of a complex interaction among proteins such as factor XII, prekallikrein, and high molecular weight kininogen (HK) resulting in HK cleavage and liberation of bradykinin. These proteins also assemble along the surface of endothelial cells via zinc-dependent interactions with gC1qR, cytokeratin 1, and u-PAR. Endothelial cell expression (or secretion) of heat-shock protein 90 or prolylcarboxypeptidase can activate the prekallikrein-HK complex to generate bradykinin in the absence of factor XII, however factor XII is then secondarily activated by the kallikrein that results. Bradykinin is destroyed by carboxypeptidase N and angiotensin-converting enzyme. The hypotension associated with IgE-dependent anaphylaxis maybe mediated, in part, by massive proteolytic digestion of HK by kallikreins (tissue or plasma-derived) or other cell-derived kininogenases.Copyright 2010 S. Karger AG, Basel. [References: 102].

    Available from: http://www.karger.com/Article/Abstract/315938

     

    Management of acute attacks of hereditary angioedema: potential role of icatibant

    Longhurst HJ. /2010 Vascular Health and Risk Management

    Icatibant (Firazyr()) is a novel subcutaneous treatment recently licensed in the European Union for acute hereditary angioedema. Hereditary angioedema, resulting from inherited partial C1 inhibitor deficiency, is a disabling condition characterized by intermittent episodes of bradykinin-mediated angioedema. Icatibant blocks bradykinin B2 receptors, attenutating the episode. Randomized double-blind, placebo-controlled trials of icatibant, showed significant superiority over oral tranexamic acid in 74 European patients and a trend to improvement in a similar US trial comparing icatibant with placebo in 55 patients. Outcomes for several endpoints did not reach significance in the US trial, perhaps because of low participant numbers and confounding factors: a further trial is planned. Open label studies have shown benefit in multiple treatments for attacks at all sites. Approximately 10% of patients require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial treatment. Its subcutaneous route of administration, good tolerability and novel mode of action make icatibant a promising addition to the limited repertoire of treatments for hereditary angioedema.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941790/

    Management of hereditary angioedema: 2010 Canadian approach

    Tom Bowen, John Brosz, Kristylea Brosz, Jacques Hebert and Bruce Ritchie 07/2010 Allergy, Asthma & Clinical Immunology

    C1-inhibitor (C1-INH) deficiency is a rare blood disorder resulting in angioedema attacks that are debilitating and may be life-threatening. Prophylaxis and therapy of events has changed since our first Canadian Consensus Conference on the diagnosis, therapy and management of HAE. We have formed the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’Angioédème Héréditaire (RCAH) http://www.haecanada.com webcite to advance care of patients with this disorder in Canada. We here present a review of management of HAE in Canada.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/20

    Management of upper airway edema caused by hereditary angioedema

    Henriette Farkas 07/2010 Allergy, Asthma & Clinical Immunology

    Hereditary angioedema is a rare disorder with a genetic background involving mutations in the genes encoding C1-INH and of factor XII. Its etiology is unknown in a proportion of cases. Recurrent edema formation may involve the subcutis and the submucosa – the latter can produce obstruction in the upper airways and thereby lead to life-threatening asphyxia. This is the reason for the high, 30-to 50-per-cent mortality of undiagnosed or improperly managed cases. Airway obstruction can be prevented through early diagnosis, meaningful patient information, timely recognition of initial symptoms, state-of-the-art emergency therapy, and close monitoring of the patient. Prophylaxis can substantially mitigate the risk of upper airway edema and also improve the patients’ quality of life. Notwithstanding the foregoing, any form of upper airway edema should be regarded as a potentially life-threatening condition. None of the currently available prophylactic modalities is capable of preventing UAE with absolute certainty.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/19

    Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema

    Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, et al. 8/2010 New England Journal of Medicine

    BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening.

    METHODS: We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control.

    RESULTS: In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling.

    CONCLUSIONS: In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.).

    Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa0805538#t=article

    New insights into hereditary angio-oedema: Molecular diagnosis and therapy

    Nagy N, Grattan CE, McGrath JA. 8/2010 Australasian Journal of Dermatology

    Hereditary angio-oedema (HAE) is a rare but potentially life-threatening condition. Three types are now recognized. Types I and II HAE involve mutations in the C1NH (SERPING1) gene, encoding the C1 inhibitor protein, whereas type III HAE involves mutations in the F12 gene, encoding coagulation factor XII (Hageman factor). They share a common final pathway leading to increased bradykinin formation. HAE must be distinguished from acquired angio-oedema with C1 esterase inhibitor deficiency, angiotensin-converting enzyme inhibitor-induced angio-oedema and the much more common histaminergic angio-oedema, occurring with or without weals. Understanding the pathogenesis of HAE is leading to the introduction of new therapies that target the bradykinin receptor or inhibit kallikrein activity, innovations that will hopefully reduce morbidity and mortality in this group of severe genetic disease.

     

    Novel and recurrent mutations in the C1NH gene of Arab patients affected with hereditary angioedema

    Faiyaz-Ul-Haque M, Al-Gazlan S, Abalkhail HA, Al-Abdulatif A, Toulimat M, Peltekova I, et al. 1/2010 International Archives of Allergy and Immunology

    BACKGROUND: Autosomal dominant hereditary angioedema (HAE) results in episodes of subcutaneous edema in any body part and/or submucosal edema of the upper respiratory or gastrointestinal tracts. This disorder is caused by mutations in the C1NH gene, many of which have been described primarily in European patients. However, the genetic cause of HAE in Middle Eastern Arab patients has not yet been determined.

    METHODS: Four unrelated Arab families, in which 15 patients were diagnosed with HAE, were studied. DNA from 13 patients was analyzed for mutations in the C1NH gene by DNA sequencing.

    RESULTS: Three novel and 2 recurrent mutations were identified in the C1NH gene of HAE patients. In family 1, the patient was heterozygous for a novel c.856C>T and a recurrent c.1361T>A missense mutation encoding for p.Arg264Cys and p.Val432Glu, respectively. In patients from family 2, a novel c.509C>T missense mutation encoding for a p.Ser148Phe was identified. In patients from family 3, a novel c.1142delC nonsense mutation encoding for a p.Ala359AlafsX15 was discovered. In family 4, a recurrent c.1397G>A missense mutation encoding for a p.Arg444His was present.

    CONCLUSION: This is the first ever report of C1NH gene mutations in Middle Eastern Arab patients. Our study suggests that, despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in HAE patients of non-European origin. We conclude that the spectrum of C1NH gene mutations in HAE patients is wider due to the likely presence of novel and recurrent mutations in patients of other ethnicities.Copyright 2009 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/Abstract/236005

     

    On demand treatment and home therapy of hereditary angioedema in Germany – the Frankfurt experience

    Emel Aygören-Pürsün, Inmaculada Martinez-Saguer, Eva Rusicke, Thomas Klingebiel and Wolfhart Kreuz 07/2010 Allergy, Asthma & Clinical Immunology

    Background
    Manifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed.

    Methods
    We describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany).

    Results
    The HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment.

    Conclusions
    In conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/21

    Pediatric hereditary angioedema due to C1-inhibitor deficiency

    Henriette Farkas 07/2010 Allergy, Asthma & Clinical Immunology

    Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor (C1-INH) is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children) may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/18

    Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study

    Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, von Hentig N, Klingebiel T, Kreuz W. 2/2010 Transfusion

    BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH).

    STUDY DESIGN AND METHODS: This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate.

    RESULTS: The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT.

    CONCLUSIONS: pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.

    Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks

    Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. 8/2010 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available.

    OBJECTIVE: To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE.

    METHODS: Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model.

    RESULTS: The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h).

    CONCLUSIONS: The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.Copyright 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2810%2900602-2/fulltext

    Prospective study of rapid relief provided by C1 esterase inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema

    Craig TJ, Wasserman RL, Levy RJ, Bewtra AK, Schneider L, Packer F, et al. 11/2010 Journal of Clinical Immunology

    INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema that can be life-threatening if they occur in the laryngeal region. We assessed the efficacy of C1-INH concentrate in the emergency treatment of rarely occurring acute laryngeal HAE attacks in a prospective, open-label clinical study.

    METHODS: Acute laryngeal attacks were each treated with C1-INH concentrate (Berinert) at a single dose of 20 U/kg body weight. Efficacy endpoints included time to onset of symptom relief and time to complete resolution of all symptoms, each based on the patient’s assessment.

    RESULTS: All 39 laryngeal attacks in 16 patients were treated successfully. The median time to onset of symptom relief was 15 min. The median time to complete resolution of all symptoms was 8.25 h. No treatment-related serious adverse events occurred, and the treatment was well tolerated. The administration of C1-INH concentrate was not associated with any viral infections.

    CONCLUSION: C1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970824/

    Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema

    Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, Visscher S, et al. 4/2010 Journal of Allergy and Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE.

    OBJECTIVE: Analysis of pooled study results.

    METHODS: Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH.

    RESULTS: rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. CONCLUSION: Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

    Available from : http://www.jacionline.org/article/S0091-6749%2810%2901128-0/fulltext

    Replacement therapy with C1 esterase inhibitors for hereditary angioedema

    Cicardi M, Zanichelli A. 11/2010 Drugs of Today

    Angioedema due to hereditary C1 inhibitor deficiency (HAE) is a highly disabling and potentially lethal disease with an estimated prevalence of 1:50,000 in the general population worldwide. Treatment of this condition by replacing the deficient protein started shortly after discovery of the underlying genetic defect. Along with other therapeutic approaches developed over the years, C1 inhibitor replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Two plasma-derived C1 inhibitors and a recombinant form, produced in transgenic rabbits, have successfully completed controlled trials that reinforced the evidence of the safety and efficacy of this treatment.Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

    Available from: http://europepmc.org/abstract/MED/21225025

     

    Response time for ecallantide treatment of acute hereditary angioedema attacks

    Riedl M, Campion M, Horn PT, Pullman WE. 12/2010 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, and potentially fatal disease characterized by acute attacks of swelling that can affect the abdomen/gastrointestinal tract, larynx, face, genitals, and extremities. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks.

    OBJECTIVE: To examine the speed of effect of ecallantide vs placebo.

    METHODS: Data were integrated from 2 randomized, double-blind, placebo-controlled phase 3 trials of ecallantide in patients with HAE. Eligible patients presented within 8 hours of onset of a moderate to severe HAE attack for 1:1 randomization to receive a single dose of 30 mg of subcutaneous ecallantide or placebo. End points included time to beginning of improvement, time to sustained overall improvement, and time to significant overall improvement.

    RESULTS: A total of 143 participants (70 receiving ecallantide and 73 receiving placebo) were included. The distribution curves for time to beginning of improvement demonstrated a trend in favor of ecallantide vs placebo within 4 hours (P(log rank) = .09). For time to onset of sustained improvement, the difference in the distribution of the curves between the 2 groups reached significance by 2 hours after dosing (P(log rank) = .04). For time to significant overall improvement, the difference in the distribution of the curves reached significance in favor of ecallantide by 90 minutes (P(log rank) = .04). The beneficial effect of ecallantide was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks.

    CONCLUSIONS: Ecallantide provides relief of acute HAE attack symptoms, with rapidity of response commensurate with therapeutic needs for HAE attack locations.Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(10)00815-X/fulltext

     

    Subcutaneous infusion of human C1 inhibitor in swine

    Jiang H, Zhang HM, Frank MM. 9/2010 Clinical Immunology

    Hereditary angioedema afflicts patients with unpredictable episodes of swelling that can be life threatening. Treatments approved by the Food and Drug Administration for routine prophylaxis include danazol given orally and the nanofiltered human C1 esterase inhibitor, CINRYZE, which is approved for intravenous administration. Approved for the treatment of acute attacks are the C1 esterase inhibitor, Berinert, given intravenously, and the kallikrein inhibitor, KALBITOR, given subcutaneously. C1 inhibitor has generally been non-toxic and neither pro-inflammatory nor pro-fibrotic, suggesting that it may be suitable for subcutaneous infusion. The current study used a swine model to compare blood levels of human C1 inhibitor following intravenous and subcutaneous infusion, and the effect of infusion route on heart and skin pathology. Levels of C1 inhibitor achieved with SC infusion compared favorably with levels achieved after IV infusion and were relatively more stable than those after IV infusion. Neither cardiac nor skin toxicity was observed.Copyright 2010 Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1521661610005784 (small fee)

    Summary of the International Multicenter Prospective Angioedema C1-inhibitor Trials 1 and 2 (IMPACT1 and 2)

    Krassilnikova S, Craig ET, Craig TJ. 5/2010 Expert Review of Clinical Immunology

    Hereditary angioedema (HAE) is an autosomal dominant disease characterized by deficiency of C1 inhibitor (C1-INH) that commonly presents with recurrent swelling affecting different parts of the body. Supplementation with C1-INH is successfully used to treat HAE in selected countries, mostly in Europe. Berinert P (CSL Behring, Marburg, Germany), a human plasma-derived C1-INH, was studied in the International Multicenter Prospective Angioedema C1-inhibitor Trial 1 (IMPACT1) that was completed in 2007. It was the first safety and dose-finding study of C1-INH in patients with acute abdominal and facial angioedema. IMPACT2 was the extension of the first trial to study C1-INH efficacy and safety in multiple treatments of acute HAE attacks in various areas of the body. Berinert P has excellent potential to become a first-line therapy for treating patients with acute HAE attacks in the USA and other countries involved in the IMPACT trials. While final data from the IMPACT2 trial are not yet released, this article reviews currently available data from previous reports and abstract presentations.

    The bradykinin-forming cascade and its role in hereditary angioedema

    Kaplan AP, Joseph K. 3/2010 Annals of Allergy, Asthma, and Immunology

    OBJECTIVE: To review the mechanisms by which bradykinin is generated in hereditary angioedema (HAE) (C1 inhibitor deficiency), including the role of human plasma proteins and endothelial cells.

    DATA SOURCES: Published articles in reviewed journals that address (1) the fundamentals of bradykinin formation, (2) interactions between kinin-forming proteins and endothelial cells, (3) clinical evidence that bradykinin causes swelling in HAE, and (4) therapeutic options focused on inhibition of the plasma kallikrein-kinin cascade.

    STUDY SELECTION: Historical articles that have made fundamental observations. Recent articles that address evolving concepts of disease pathogenesis and treatment.

    RESULTS: C1 inhibitor deficiency causes dysregulation of the plasma bradykinin-forming cascade with overproduction of bradykinin due to uninhibited effects of activated factor XII and plasma kallikrein. Swelling in HAE and production of bradykinin are localized (and may then disseminate); activation along the endothelial cell surface involves cell membrane ligands of factor XII and high-molecular-weight kininogen, release of endothelial cell heat shock protein 90, activation of the high-molecular-weight kininogen-prekallikrein complex, and endothelial cell activation at the B2 receptor. Attacks of swelling may be terminated by treatment with a kallikrein inhibitor or B2 receptor blockade. Replenishing C1 inhibitor can abort attacks of swelling and provide prophylaxis with intravenous administration. CONCLUSIONS: Bradykinin is the mediator of swelling in types I and II HAE and is overproduced because of a deficiency in C1 inhibitor. Inhibition of bradykinin formation by novel agentscan provide targeted therapeutic approaches that address the pathophysiologic abnormalities. [References: 103].

    Available from: http://www.annallergy.org/article/S1081-1206%2810%2900173-0/fulltext

     

    The burden of hospitalizations and emergency department visits with hereditary angioedema and angioedema in the United States, 2007

    Zilberberg MD, Jacobsen T, Tillotson G. 11/2010 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. HAE is frequently confused with angioedema (AE), and little is known about emergency department (ED) or hospital utilization by patients with attacks in the United States. We examined hospitalizations and ED utilization for HAE and AE in two large nationally representative databases. We evaluated annual rate and resource use of HAE (International Classification of Diseases, Version 9, Clinical Modification [ICD-9-CM] code 277.6) and AE (ICD-9-CM code 995.1) hospitalizations within Nationwide Inpatient Sample (NIS), part of the Agency of Healthcare Research and Quality’s Healthcare Costs and Utilization Project (AHRQ-HCUP), for 2007. We also used AHRQ-HCUP’s 2007 Nationwide Emergency Department Sample (NEDS) to study annual rates of ED visits and subsequent hospitalizations with these conditions. There were 1691 hospitalizations with HAE and 22,572 with AE (4.25 HAE and 57.08 AE cases/100,000 hospitalizations). HAE was the principal diagnosis (PD) in 46.0% and AE in 62.5%. In aggregate, HAE and AE PD hospitalizations accrued 35,000 hospital days and hospital costs of $63 million. There were 2282 ED visits with HAE and 112,105 ED visits with AE (1.87 HAE and 91.64 AE cases/100,000 ED visits). HAE occurred as a PD in 51.2% and AE occurred as a PD in 80.0%. Forty-five percent of HAE patients and 18.3% of AE patients required hospitalization. HAE and AE ED use and hospitalization burden are substantial. Because diagnostic uncertainty is likely, HAE-related proportion of patients and resource use are probably underestimated. Clinical validation of current case definition would be useful, because administrative data may present an attractive source for investigating these populations.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2010/00000031/00000006/art00014

    The effect of long-term danazol prophylaxis on liver function in hereditary angioedema-a longitudinal study

    Farkas H, Czaller I, Csuka D, Vas A, Valentin S, Varga L, et al. 4/2010 The European Journal of Clinical Pharmacology

    BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients.

    METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively.

    RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study.

    CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

     

    The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey

    Czaller I, Visy B, Csuka D, Fust G, Toth F, Farkas H. 10/2010 European Journal of Obstetrics, Gynecology, and Reproductive Biology

    OBJECTIVE: The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE.

    STUDY DESIGN: Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries.

    RESULTS: HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed.

    CONCLUSIONS: Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

    Available from: http://www.ejog.org/article/S0301-2115(10)00227-7/abstract

    Therapeutic complement inhibition: new developments.

    Emlen W, Li W, Kirschfink M. 9/2010 Seminars in Thrombosis and Hemostasis

    Activation of the complement system significantly contributes to the pathogenesis of various acute and chronic inflammatory diseases. Current strategies to inhibit complement include the replacement or substitution of endogenous soluble complement inhibitors (e.g., C1 inhibitor [C1 inh], recombinant soluble complement receptor 1, TP10), the administration of antibodies to block key proteins of the cascade reaction (e.g., C5) or to neutralize the action of the complement-derived anaphylatoxins, or blockade of complement receptors (e.g., C5aR, CD88). The recent approvals of anti-C5 for the treatment of paroxysmal nocturnal hemoglobinuria as well as of C1 inh for the treatment of hereditary angioedema beyond European countries have provided a resurgence of interest in the potential of complement therapeutics for the treatment of disease.Copyright © Thieme Medical Publishers.

    Available from: https://www.thieme-connect.com/DOI/DOI?10.1055/s-0030-1262888

     

    Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series

    Bas M, Greve J, Stelter K, Bier H, Stark T, Hoffmann TK, et al. 9/2010 Annals of Emergency Medicine

    STUDY OBJECTIVE: The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema most likely resembles that of hereditary angioedema, ie, it is mainly mediated by bradykinin-induced activation of vascular bradykinin B2 receptors. We hypothesize that the bradykinin B2 receptor antagonist icatibant might be an effective therapy for ACEi-induced angioedema.

    METHODS: Eight patients with acute ACEi-induced angioedema were treated with a single subcutaneous injection of icatibant. The outcome was assessed by the time to first improvement of symptoms, complete symptom relief, and drug safety. In addition, we retrospectively assessed the clinical course of 47 consecutive patients of our clinic with ACEi-induced angioedema.

    RESULTS: First symptom improvement after icatibant injection occurred at a mean time of 50.6 minutes (standard deviation [SD] 21 minutes) and complete relief of symptoms at 4.4 hours (SD 0.8 hours). No patient received tracheal intubation, other drug treatment, tracheotomy, or a second icatibant injection. There were no adverse effects except erythema occurring at the injection site. In the historical comparison group treated with methylprednisolone and clemastine, the mean time to complete relief of symptoms was 33 hours (SD 19.4 hours). Some of these patients received a tracheotomy (3/47), were intubated (2/47), or received a second dose of methylprednisolone (12/47).

    CONCLUSION: Although sample size limits the external validity of our results, the substantial decrease of time to complete symptom relief suggests that this new treatment is likely effective as a pharmacotherapeutic approach to treat ACEi-induced angioedema.Copyright (c) 2009 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

    Available from: http://www.annemergmed.com/article/S0196-0644%2810%2900279-9/fulltext

    Treatment of Hereditary Angioedema: items that need to be addressed in practice parameter

    Callie Dagen, Timothy J Craig 05/2010 Allergy, Asthma & Clinical Immunology

    Background
    Hereditary Angioedema (HAE) is a rare, autosomal dominant (AD) disorder caused by a C1 esterase inhibitor (C1-inh) deficiency or qualitative defect. Treatment of HAE in many parts of the world fall short and certain items need to be addressed in future guidelines.

    Objective
    To identify those individuals who should be on long-term prophylaxis for HAE. Additionally, to determine if prodromal symptoms are sensitive and specific enough to start treatment with C-1 INH and possibly other newly approved therapies. Also, to discuss who is appropriate to self-administer medications at home and to discuss training of such patients.

    Methods
    A literature review (PubMed and Google) was performed and articles published in peer-reviewed journals, which addressed HAE prophylaxis, current HAE treatments, prodromal symptoms of HAE and self-administration of injected home medications were selected, reviewed and summarized.

    Results
    Individuals whom have a significant decrease in QOL or have frequent or severe attacks and who fail or are intolerant to androgens should be considered for long-term prophylaxis with C1INH. Prodromal symptoms are sensitive, but non-specific, and precede acute HAE attacks in the majority of patients. Although the treatment of prodromal symptoms could lead to occasional overtreatment, it could be a viable option for those patients able to adequately predict their attacks. Finally, self-administration, has been shown to be feasible, safe and effective for patients who require IV therapy for multiple other diseases to include, but not limited to, hemophilia.

    Conclusions
    Prophylactic therapy, treatment at the time of prodromal symptoms and self-administration at home all should allow a reduction in morbidity and mortality associated with HAE.

    The electronic version of this article is the complete one and can be found online at: http://www.aacijournal.com/content/6/1/11

    Type III hereditary angio-oedema: clinical and biological features in a French cohort

    Vitrat-Hincky V, Gompel A, Dumestre-Perard C, Boccon-Gibod I, Drouet C, Cesbron JY, et al. 10/2010 Allergy

    BACKGROUND: Hereditary angio-oedema (HAE) has been associated with C1inhibitor deficiency. The first cases of type III HAE were described in patients with normal C1Inh antigenic protein level and function and normal C4 levels in 2000. This finding has been reported mostly in women with a family history and may be influenced by exogenous oestrogen exposure.

    OBJECTIVES: The purpose of this article is to describe the clinical, biological and genetic characteristics of a French population suffering from type III HAE.

    PATIENTS AND METHODS: We conducted a retrospective analysis of angio-oedema (AE) cases seen in the National Reference Centre of AE between 2000 and 2009.

    RESULTS: We found 26 patients (from 15 unrelated families) with type III HAE. All but four were women and presented with typical AE attacks, exacerbated by pregnancy or oral contraceptives containing oestrogens (OC). We also found that 54.5% of women were worsened with oestrogen and 23% were oestrogen dependent. All patients improved on long-term prophylactic tranexamic acid treatment; some acute attacks improved with C1Inh concentrate infusion. All of the patients had normal C1Inh and C4 levels. C1Inh function was also normal, except in women receiving OC or during a pregnancy: transient, moderately low levels (32-74% of the normal range) were found in 18 patients tested (67%). No SERPING1 gene mutation was found. Six patients from three unrelated families were heterozygous for an F12 gene variant.

    CONCLUSION: Diagnosis of type III HAE should be based on clinical (typical attacks, often hormonally influenced), laboratory (normal C1Inh antigenic protein) and genetic (F12 gene mutation) evidence.

    Available from : http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2010.02368.x/full

    Upper airway considerations in hereditary angioedema

    Papadopoulou-Alataki E. 2/2010 Current Opinion in Allergy and Clinical Immunology

    PURPOSE OF REVIEW: The purpose of the present review is to outline the clinical aspects and management of the upper airway involvement in the patients suffering from hereditary angioedema.

    RECENT FINDINGS: Molecular mechanisms of hereditary angioedema reviewed in the literature conclude that it is an autosomal dominant disorder, characterized by the deficiency of C1 inhibitor due to mutations of its gene (SERPING). Hereditary angioedema manifests as episodes of localized swelling in any site of the body from skin, gastrointestinal tract to the upper airway, where it is severe and life-threatening. The age of onset, frequency of attacks and the factors triggering upper airway swelling in hereditary angioedema are variable among different patients. Acute laryngeal edema should be managed in emergency with monitoring of airway patency. To avoid airway obstruction, therapy should begin early either with current treatment (C1 inhibitor concentrate) or with new drugs developed recently. In patients with recurrent upper airway swelling attacks, long-term prophylaxis is recommended.

    CONCLUSION: The use of old and new treatment in acute attacks as well as in prophylaxis (long and short-term) has changed the outcome of patients with hereditary angioedema who present upper airway swelling. [References: 37].

    Available from:
    http://journals.lww.com/co-allergy/Abstract/2010/02000/Upper_airway_considerations_in_hereditary.5.aspx%20(small%20fee)

    Advances in basic and clinical immunology in 2010

    Chinen J, Shearer WT. 2/2011 Journal of Allergy and Clinical Immunology

    Reports in basic and clinical immunology in 2010 reflected the use of state-of-the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti-CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T-cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease.Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

    Available from: http://www.jacionline.org/article/S0091-6749%2810%2901864-6/fulltext

    Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort?

    Csuka D, Kelemen Z, Czaller I, Molnar K, Fust G, Varga L, et al. 3/2011 European Journal of Gastroenterology and Hepatology

    OBJECTIVE: Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases.

    METHODS: One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up.

    RESULTS: Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema.

    CONCLUSION: Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

    Available from: http://journals.lww.com/eurojgh/pages/articleviewer.aspx?year=2011&issue=03000&article=00007&type=abstract (small fee)

    Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia

    Blankart CR, Stargardt T, Schreyogg J. 1/2011 Pharmacoeconomics

    BACKGROUND: Market authorization does not guarantee patient access to any given drug. This is particularly true for costly orphan drugs because access depends primarily on co-payments, reimbursement policies and prices. The objective of this article is to identify differences in the availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US.

    METHODS: Four rare diseases were selected for analysis: pulmonary arterial hypertension (PAH), Fabry disease (FD), hereditary angioedema (HAE) and chronic myeloid leukaemia (CML). Indicators for availability were defined as (i) the indications for which orphan drugs had been authorized in the treatment of these diseases; (ii) the application date; and (iii) the date upon which these drugs received market authorization in each country. Indicators of patient access were defined as (i) the outcomes of technology appraisals; (ii) the extent of coverage provided by healthcare payers; and (iii) the price of the drugs in each country. For PAH we analysed bosentan, iloprost, sildenafil, treprostinil (intravenous and inhaled) as well as sitaxentan and ambrisentan; for FD we analysed agalsidase alfa and agalsidase beta; for HAE we analysed icatibant, ecallantide and two complement C1s inhibitors; for CML we analysed imatinib, dasatinib and nilotinib.

    RESULTS: Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country. The broadest range of indications was found in Australia, and the largest variations in indications were found for PAH drugs. Authorization process speed (the time between application and market authorization) was fastest in the US, with an average of 362 days, followed by the EU (394 days). The highest prices for the included drugs were found in Germany and the US, and the lowest in Canada, Australia and England. Although the prices of all of the included drugs were high compared with those of most non-orphan drugs, most of the insurance plans in our country sample provided coverage for authorized drugs after a certain threshold.

    CONCLUSIONS: Availability of and access to orphan drugs play a key role in determining whether patients will receive adequate and efficient treatment. Although the present study showed some variations between countries in selected indicators of availability and access to orphan drugs, virtually all of the drugs in question were available and accessible in our sample. However, substantial co-payments in the US and Canada represent important barriers to patient access, especially in the case of expensive treatments such as those analysed in this study. Market exclusivity is a strong instrument for fostering orphan drug development and drug availability. However, despite the positive effect of this instrument, the conditions under which market exclusivity is granted should be reconsidered in cases where the costs of developing an orphan drug have already been amortized through the use of the drug’s active ingredient for the treatment of a common indication.

    Available from: http://link.springer.com/article/10.2165%2F11539190-000000000-00000

    C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks–final results of the I.M.P.A.C.T.2 study

    Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, et al. 12/2011 Allergy

    BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks.

    METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies.

    RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient.

    CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.Copyright © 2011 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2011.02702.x/full

    Cinryze (C1-inhibitor) for the treatment of hereditary angioedema

    Gompels MM, Lock RJ. 9/2011 Expert Review of Clinical Immunology

    Cinryze is a pasteurized, nanofiltered plasma derived concentrate of C1-inhibitor (pdC1-INH) licensed for the prophylactic treatment of hereditary angioedema. In a double-blind placebo-controlled crossover trial to evaluate Cinryze as prophylaxis, the frequency of attacks was halved (6.26 per 12 weeks on Cinryze versus 12.73 per 12 weeks on placebo). Furthermore, attacks were generally milder and of shorter duration. For treatment of acute attacks in patients receiving Cinryze, 1000 units, within 4 h of the start of an attack, the estimated time to the onset of unequivocal relief was reduced to 2 h, compared with more than 4 h in those treated with placebo. Cinryze and other similar products are going to change the future management of hereditary angioedema and have potential in other areas of medicine.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.11.50

    Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis

    Caballero T, Baeza ML, Cabanas R, Campos A, Cimbollek S, Gomez-Traseira C, et al. /2011 Journal of Investigational Allergology and Clinical Immunology

    BACKGROUND: There are no Spanish guidelines or consensus statement on bradykinin-induced angioedema.

    AIM: To review the pathophysiology, genetics, and clinical symptoms of the different types of bradykinin-induced angioedema and to draft a consensus statement in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals.

    METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings of the SGBA were held in Madrid to reach the consensus.

    RESULTS: The pathophysiology, genetics, and clinical symptoms of the different types of angioedema are reviewed. Diagnostic approaches are discussed and the consensus reached is described.

    CONCLUSIONS: A review of bradykinin-induced angioedema and a consensus on diagnosis are presented.

     

    Available from : http://www.jiaci.org/issues/vol21issue5/vol21issue05-1.htm

     

    Current medical management of hereditary angioedema: results from a large survey of US physicians

    Riedl M, Gower RG, Chrvala CA. 4/2011 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a potentially life-threatening condition that affects approximately 1 in 50,000 persons. There are no known surveys of US physicians’ knowledge and experience regarding the epidemiology, diagnosis, and management of HAE.

    OBJECTIVE: This survey of physicians treating patients with HAE assessed physician characteristics, diagnostic and treatment practices, factors that influence physician and patient treatment choices, and physician awareness of new therapies.

    METHODS: From October 2009 to February 2010, physicians (N = 172) voluntarily completed an online survey developed by physician-investigators. Data were analyzed with descriptive statistics.

    RESULTS: Most physicians (73.8%) managed 5 patients or fewer in diverse practice settings. Laboratory testing was considered most important in establishing a diagnosis. Fresh frozen plasma and C1 esterase inhibitors were the most frequently administered treatments for acute events; nearly 50% of respondents prescribed C1 esterase inhibitor for acute attacks. More than 80% of respondents prescribed androgens for long-term prophylaxis. Approximately half of respondents were aware of, and likely to use, new therapies for HAE. Other than efficacy, adverse effects were the most important factor that influenced physicians’ treatment recommendations, whereas physicians perceived that patients were most influenced by adverse effects and cost.

    CONCLUSIONS: Wide variability exists in the treatment of patients with HAE. Many patients experience acute attacks that require emergency care or hospitalization. Androgens and fresh frozen plasma are frequently used despite recent availability of effective condition-specific agents, and many physicians are only somewhat aware of medications newly approved by the US Food and Drug Administration. Because the survey was completed shortly after approval of additional HAE therapies by the US Food and Drug Administration, these data will be useful for tracking changes in HAE treatment over time.Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2810%2901215-9/abstract

    Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies

    Sheffer AL, Campion M, Levy RJ, Li HH, Horn PT, Pullman WE. 7/2011 Journal of Allergy and Clinical Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks.

    OBJECTIVE: We sought to further characterize the safety and efficacy of ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies.

    METHODS: An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age >10 years) received 30 mg of subcutaneous ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS).

    RESULTS: Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (ecallantide [mean +/- SD], -0.97 +/- 0.78; placebo, -0.47 +/- 0.71; P < .001) and a significantly greater increase in TOSs at 4 hours (ecallantide, 55.5 +/- 46.5; placebo, 20.0 +/- 58.9; P < .001). Significantly greater symptomatic improvement over placebo occurred through 24 hours after dosing (MSCS score, P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups.

    CONCLUSIONS: This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks.Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

    Available from: http://www.jacionline.org/article/S0091-6749%2811%2900375-7/fulltext

    Hereditary angioedema: a clinical review for the otolaryngologist

    Anon JB. 1/2011 Ear Nose and Throat Journal

    Hereditary angioedema (HAE) is a relatively rare genetic disorder that is usually characterized by either low levels of C1 esterase inhibitor (C1-INH) or the presence of dysfunctional C1-INH. It can present with relatively mild and self-limiting symptoms, but it is also potentially fatal; the most common cause of death is asphyxiation secondary to edema of the upper airway. The diagnosis of HAE, especially in the emergency situation, is not straightforward. HAE must be distinguished from several other types of angioedema that require different management approaches. Management approaches include trigger avoidance and pharmacologic therapy; the latter has traditionally involved the administration of attenuated androgens and antifibrinolytics. Recently, a new class of agent-C1-INH-has been introduced in the United States. This article provides an update on the pathophysiology, clinical picture, diagnosis, prophylaxis, and acute treatment of HAE. We must keep HAE in mind as a possible diagnosis whenever we are faced with a case of unexplained angioedema if we are to take advantage of the effective and more specific therapies that are becoming available.

     

    Hereditary angioedema: diagnosis and management-a perspective for the dermatologist

    Parish LC. 10/2011 Journal of the American Academy of Dermatology

    Hereditary angioedema (HAE) is a relatively rare, but potentially life-threatening genetic disorder characterized by marked, diffuse mucosal edema that, in extreme cases, can affect the airway leading to asphyxiation. The clinical picture is similar to that of other forms of angioedema; therefore, misdiagnosis or delayed diagnosis is common. HAE is caused by a deficiency in, or a dysfunction of, C1 esterase inhibitor, which has a wide variety of physiologic functions, of which regulation of the contact (kallikrein-kinin) system is most relevant to this condition. Effective management of HAE must consider routine/long-term prophylaxis, short-term prophylaxis (in advance of predicted trauma, eg, surgical or dental procedures), and treatment of acute attacks. Historically, treatment options have been limited to controlling symptoms, but progress in understanding the pathophysiology of HAE has facilitated development of treatments, such as C1 inhibitor therapy, or drugs targeted at the bradykinin pathway, which address the underlying pathologic process.Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

    Available from: http://www.jaad.org/article/S0190-9622%2810%2901801-3/abstract

    Hereditary angioedema: long-term treatment with one or more injections of C1 inhibitor concentrate per week

    Bork K, Hardt J. 12/2011 International Archives of Allergy and Immunology

    BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is characterized by recurrent edema attacks in various organs. The objective of the present study was to assess the efficacy and safety of weekly long-term replacement treatment with one or more injections of plasma-derived C1-INH concentrate per week (WLTC) in patients with HAE-C1-INH.

    METHODS: Nineteen patients with HAE-C1-INH underwent WLTC for 9 years on average. The benefits and risks were determined based on regular recording by the patients of the severity and number of attacks at the beginning and the end of the study.

    RESULTS: All patients reported that all or most of their attacks were much less severe: the percentage of severe attacks was 93.3% without and 3.8% with treatment. In 8 of the 14 patients undergoing WLTC, the monthly number of attacks was lower at the end of the study than before the study, higher in 5 patients, and unchanged in 1 patient. The mean number of attacks per week in 6 patients (1 patient initially received weekly on-demand treatment for 2 years and then shifted to WLTC) with weekly on-demand treatment was 4.3 (SD 1.9) at the beginning and 8.0 (SD 3.1) at the end of the study.

    CONCLUSIONS: HAE-C1-INH can be significantly improved by one or more injections of C1-INH concentrate per week. However, patients have to accept a large number of intravenous injections and, in some cases, an increase in disease activity.Copyright © 2010 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/Abstract/319213

    Hereditary angioedema: management of laryngeal attacks

    Christiansen SC, Zuraw BL. 11/2011 American Journal of Rhinology and Allergy

    BACKGROUND: Hereditary angioedema (HAE) patients suffering from laryngeal attacks in the United States faced severely limited treatment options until 2008. These potentially life-threatening episodes occur in over one-half of the patients affected by HAE during their lifetimes. Acute therapy had been relegated to supportive care, intubation, and consideration of fresh frozen plasma (FFP)–the latter with the potential for actually accelerating the speed and severity of the swelling.

    METHODS: In this article we will review the recently approved and emerging HAE treatments that have evolved from the recognition that bradykinin generation is the fundamental abnormality leading to attacks of angioedema.

    RESULTS: Acute therapy for laryngeal attacks will be discussed including purified plasma-derived C1 inhibitor (C1INH), recombinant C1INH, an inhibitor of plasma kallikrein (ecallantide), and a B2 receptor antagonist (icatibant). Prophylactic care has also been transformed from a reliance on attenuated androgens with their attendant side effects to C1INH replacement.

    CONCLUSION: The arrival of these novel therapies promises to transform the future management of HAE.

    Available from: http://www.ingentaconnect.com/content/ocean/ajra/2011/00000025/00000006/art00016

    Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity

    Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. 1/2011 Allergy and Asthma Proceedings

    Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2011/00000032/00000001/art00006

    Human pasteurized C1-inhibitor concentrate for the treatment of hereditary angioedema due to C1-inhibitor deficiency

    Bork K. 11/2011 Expert Review of Clinical Immunology

    Hereditary angioedema is a relatively rare genetic disorder affecting between one in 10,000 and one in 50,000 individuals worldwide. The most common clinical symptoms observed are relapsing swelling of the skin and abdominal pain attacks. However, more serious and potentially fatal laryngeal attacks can also occur. Hereditary angioedema is most frequently caused by a deficiency of C1-inhibitor. Replacement therapy with Berinert, an intravenous pasteurized C1-inhibitor concentrate derived from human plasma, is a recommended treatment for rapid resolution of acute attacks of hereditary angioedema due to C1-inhibitor deficiency. Prophylactic therapy with C1-inhibitor is also available. Future advances may improve morbidity and mortality associated with hereditary angioedema.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.11.72

    Icatibant in hereditary angioedema: news and challenges

    Bouillet L. 5/2011 Expert Review of Clinical Immunology

    Hereditary angioedema (HAE) is a rare condition. Its prognosis depends on whether there is laryngeal involvement with a risk of asphyxia, which is present in 25% of such cases. Improved understanding of the pathophysiology of this disease has resulted in the development of targeted therapies including icatibant, which acts as an antagonist at bradykinin B2 receptors. This agent has been shown to be effective in the treatment of attacks of HAE in three Phase III randomized double-blind published studies. Efficacy data have been collected in all types of attack: cutaneous, abdominal and laryngeal. Safety data are also encouraging. Icatibant is administered subcutaneously, with the potential for patients to self-administer. In the future, this therapy may offer increased independence for HAE patients.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.11.16

    In brief: icatibant (Firazyr) for hereditary angioedema.

    11/2011 Medical Letter on Drugs and Therapeutics

    Available from : http://secure.medicalletter.org/w1378d

    Insurers will find icatibant lifesaving but expensive treatment. Managed care once again faces the all-too-familiar debate about cost and benefit

    Investigating recurrent angio-oedema

    Fitzharris P, Jordan A. /2011 BMJ

    Available from: http://www.bmj.com/content/343/bmj.d6607

    Long-term efficacy of danazol treatment in hereditary angioedema

    Fust G, Farkas H, Csuka D, Varga L, Bork K. 3/2011 European Journal of Clinical Investigation

    BACKGROUND: No systematic study has been published yet on the long-term efficacy of attenuated androgens in hereditary angioedema (HAE). Our aim was to conduct a follow-up study in two (German and Hungarian) cohorts of HAE patients (45 and 39 patients, respectively) undergoing uninterrupted treatment for 6 years with similar (starting dose 128 +/- 78 mg per day and 136 +/- 70 mg per day, respectively) and constant doses of danazol.

    DESIGN: The frequencies of subcutaneous, abdominal and laryngeal attacks were recorded each year.

    RESULTS: The annual frequency of all the three types of attacks was significantly lower during the first year of danazol treatment, compared to the last year before baseline. During subsequent years in Hungarian patients, the frequency of both subcutaneous and abdominal attacks – but not that of laryngeal attacks – increased significantly. In the case of abdominal attacks, a significant increase in the attack frequency was observed only in female patients. In the German cohort, by contrast, no change in the frequency of either type of attack was found during the 6-year study period.

    CONCLUSIONS: The differences observed between these cohorts cannot be related to drug dose, the age or gender distribution of subjects or the age at the onset of symptoms or the length of diagnostic delay in the patients. There were, however, marked differences in the baseline pattern of attacks: significantly – 3 times – more abdominal attacks were recorded in German patients. Further studies are necessary to clarify the mechanism of these findings.Copyright © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2010.02402.x/full

    Long-term follow up analysis of nadroparin for hereditary angioedema. A preliminary report

    Majluf-Cruz A, Nieto-Martinez S. 8/2011 International Immunopharmacology

    Hereditary angioedema is caused by a C1-inhibitor deficiency. It is a life-threatening disease. Its management includes treating acute attacks, short-term prophylaxis, and long-term prophylaxis. We report our experience with nadroparin for the short-term prophylaxis and treatment of angioedema attacks. We indicated treatment with nadroparin 0.3-0.6 mL SC 20 min after the onset of prodromes, then every 8-12 h for 1 day; short-term prophylaxis with 0.3-0.6 mL 1 h before a triggering event and then every 12-24 h for 1 more day. For children, treatment included 0.3 mL SC 20 min after the onset of prodromes, then every 12-24 h for 1 day; short-term prophylaxis was 0.3 mL 1 h before a triggering event and 1 more dose after 24 h. For the treatment, a complete response was considered when nadroparin totally stopped an acute attack within 2 h after injection. Partial response was considered if after 2 h analgesics and/or other therapy were required. Failure was established if after 4 h no response was obtained and fresh frozen plasma and other in-patient measures were required. For short-term prophylaxis, only complete responses and failures were considered. We included 29 adults and 5 children. Functional C1-inhibitor and C4 levels rose after nadroparin. We recorded 256 treatments (89.8% complete responses, 8.2% partial responses, and 1.9% failures), and 102 short-term prophylactic regimens (90.2% complete responses, and 9.8% failures). We found 38 mild adverse events without severe hemorrhagic episodes. If our results are reproduced subsequently, nadroparin may be an alternative for the treatment and short-term prophylaxis of angioedema attacks.Copyright © 2011 Elsevier B.V. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1567576911000786 (small fee)

    Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives

    Maurer M, Magerl M. 2/2011 Journal der Deutschen Dermatologischen Gesellschaft

    Androgen derivatives are regarded as standard in the long-term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long-term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off-label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1-INH and – since 2008 – subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand-oriented acute treatment using C1-INH or icatibant.Copyright © The Authors * Journal compilation © Blackwell Verlag GmbH, Berlin.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1610-0387.2010.07546.x/full

    Nanofiltered human C1 inhibitor concentrate (Cinryze): in hereditary angioedema

    Lyseng-Williamson KA. 10/2011 Biodrugs

    Intravenous nanofiltered human C1 inhibitor (C1-INH NF) concentrate (Cinryze) is used as a direct replacement of deficient levels of plasma C1 inhibitor in patients with hereditary angioedema (HAE). In the EU, C1-INH NF concentrate 1000U is indicated in the treatment, pre-procedural prevention, and routine prevention of angioedema attacks in adults and adolescents with HAE. Intravenous C1-INH NF concentrate 1000U effectively relieved angioedema attacks in patients with HAE. In a randomized, double-blind trial in pediatric and adult patients, the median time to onset of unequivocal relief from an attack was significantly shorter with C1-INH NF concentrate than with placebo. In an open-label trial, both unequivocal relief and clinical relief were shown in the majority of attacks within 1 and 4 hours of infusion of C1-INH NF concentrate, regardless of the site (i.e. gastrointestinal, cutaneous, laryngeal, or genitourinary) of the defining symptom. When administered prior to a procedure, open-label intravenous C1-INH NF concentrate 1000U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE. Routine preventative treatment with intravenous C1-INH NF concentrate 1000U every 3 or 4 days reduced the number of angioedema attacks. In a randomized, double-blind, crossover trial in pediatric and adult patients with HAE, the mean normalized number of attacks per 12-week period was significantly lower during routine prevention with C1-INH NF concentrate than with placebo. Routine prevention with C1-INH NF concentrate reduced the median monthly attack rate from baseline in an open-label trial. Intravenous C1-INH NF concentrate was well tolerated in clinical trials in patients with HAE. No cases of viral transmission were reported.

    Available from: http://link.springer.com/article/10.2165%2F11208390-000000000-00000

    New treatment options for acute edema attacks caused by hereditary angioedema

    Thomas MC, Shah S. 11/2011 American Journal of Health-System Pharmacy

    PURPOSE: New treatment options for acute edema attacks caused by hereditary angioedema (HAE) are reviewed.

    SUMMARY: HAE is characterized by mutations in the C1 inhibitor gene leading to either a reduced expression of C1 inhibitor in the plasma or expression of a functionally impaired C1 inhibitor. HAE is classified into two major types based on the cause of the C1 inhibitor deficiency. Type I HAE is defined by a reduced expression of C1 inhibitor in the plasma, whereas type II HAE is characterized by the expression of a dysfunctional C1 inhibitor protein. Clinical data were reviewed for C1 inhibitor, ecallantide, and icatibant in the treatment of acute edema attacks caused by HAE. C1 inhibitor leads to a faster onset of edema relief and is effective in decreasing the duration of edema. Dosing strategies include fixed dosing and weight-based dosing. Optimal dosing strategies have not been established, but fixed dosing (500-1000 units) or 20 units/kg has been effective in clinical trials and reports. No comparative trials suggest that one strategy is superior to another; however, the approved labeling for acute treatment is based on weight. Ecallantide is also efficacious for treating acute episodes; however, the available evidence is limited to a single published trial. Icatibant has shown variable effects in two trials with placebo and active controls.

    CONCLUSION: In patients with HAE, most edema episodes only involve the skin and gastrointestinal tract, though airway obstruction caused by laryngeal angioedema is the most common cause of death. I.V. C1 inhibitor should be considered first-line treatment for acute edema attacks because of its fast onset of action and effectiveness, though it is not clear whether fixed or weight-based dosing is preferred. Ecallantide can be considered as a second-line treatment option.

    Available from: http://www.ajhp.org/content/68/22/2129.long?hw-tma-check=true (small fee)

    Pathophysiology of hereditary angioedema

    Zuraw BL, Christiansen SC. 11/2011 American Journal of Rhinology and Allergy

    BACKGROUND: Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema.

    METHODS: A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.

    RESULTS: The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor-associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability.

    CONCLUSION: Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.

    Available from: http://www.ingentaconnect.com/content/ocean/ajra/2011/00000025/00000006/art00015

    Prominent features of allergic angioedema on oral mucosa

    Duvancic T, Lugovic-Mihic L, Brekalo A, Situm M, Sinkovic A. 12/2011 Acta Clinica Croatica

    Angioedema indicates acute subcutaneous edema that characterizes improperly restricted cutaneous or mucous membrane swelling, which can occur only once or be relapsing. Edema usually occurs in the periorbital area, lips, tongue, extremities and intestinal wall. It has turned out that angioedema is usually caused by the use of angiotensin-converting enzyme inhibitors (ACE) or allergies to certain allergens (allergic or IgE-mediated angioedema), followed by C1 inhibitor deficiency (hereditary and acquired angioedema), or the cause is unknown (idiopathic angioedema). It has been shown that patients with angioedema often have urticaria, which is noted in approximately 50% of cases. Usually there is a type I allergic reaction to some food allergens or drugs or insect stings. The most common causes of allergic angioedema are bee and wasp stings, reactions to medications or injections for sensitivity testing, and certain foods (especially eggs, shellfish and nuts). In diagnostic terms, it is important to determine the potential allergen, which is commonly performed with cutaneous tests, such as prick test, etc. The main risk of angioedema is swelling of the tongue, larynx and trachea, which can lead to airway obstruction and death, therefore tracheotomy is indicated in such cases. The initial treatment of patients with most forms of angioedema included administration of antihistamines and glucocorticoids, while epinephrine is given if there is fear from laryngeal edema.

    Available from: http://hrcak.srce.hr/index.php?show=clanak&id_clanak_jezik=125833 (small fee)

    Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks

    Wasserman RL, Levy RJ, Bewtra AK, Hurewitz D, Craig TJ, Kiessling PC, et al. 1/2011 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: hereditary angioedema (HAE) is a rare disorder characterized by a quantitative or functional deficiency of C1 esterase inhibitor (C1-INH), resulting in periodic attacks of acute edema at various body locations. The symptoms of these painful attacks can be treated effectively with C1-INH concentrate.

    OBJECTIVE: to document the efficacy and safety of a weight-based dose of C1-INH concentrate in the treatment of successive HAE attacks at abdominal and facial locations.

    METHODS: acute facial and abdominal attacks were each treated with C1-INH concentrate using a single intravenous dose of 20 U/kg body weight. Efficacy end points included patient-reported time to onset of symptom relief and time to complete resolution of all symptoms. Safety was assessed by monitoring adverse events and assaying for markers of viral infection.

    RESULTS: we treated 663 abdominal attacks in 50 patients and 43 facial attacks in 16 patients (a total of 706 attacks in 53 patients). The median time to onset of relief for all attacks was 19.8 minutes, with a median time to complete resolution of 11.0 hours. The median time to onset of relief was 19.8 minutes for abdominal attacks and 28.2 minutes for facial attacks, indicating efficacy for both types of attack. No treatment-related serious adverse events occurred, and C1-INH concentrate was well tolerated. No human immunodeficiency virus, hepatitis virus, or parvovirus B19 infections arose during the study.

    CONCLUSION: the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations.

    Available from: http://www.annallergy.org/article/S1081-1206%2810%2900956-7/abstract

    Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial

    Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, et al. 12/2011 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II).

    OBJECTIVE: To investigate icatibant efficacy and safety in subjects with acute HAE attacks.

    METHODS: Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.

    RESULTS: Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.

    CONCLUSIONS: FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks.

    TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00912093.Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2811%2900658-2/fulltext

    Recent advances in management and treatment of hereditary angioedema

    Sardana N, Craig TJ. 12/2011 Pediatrics

    CONTEXT: Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurrent self-limiting episodes of skin and mucosal edema. Morbidity and mortality are significant, and new and pending therapies are now available to reduce the risk associated with the disease.

    OBJECTIVE: To update the reader on new advances in HAE to improve patient care.

    METHODS: We performed a literature search of Ovid, PubMed, and Google to develop this review. Articles that are necessary for the understanding and use of the new therapeutic options for HAE were chosen, and studies of high quality were used to support the use of therapies, and in most cases, results from phase III studies were used.

    RESULTS: Until recently, therapy for HAE attacks in the United States consisted of symptom relief with narcotics, hydration, and fresh-frozen plasma, which contains active C1 inhibitor. Therapy to prevent HAE attacks has been confined to androgens and, occasionally, antifibrinolytic agents; however, both drug groups have significant adverse effects. The approval of C1-inhibitor concentrate for prevention and acute therapy has improved efficacy and safety. Ecallantide has also been approved for therapy of attacks, and icatibant is expected to be approved in the next few months for attacks. Recombinant C1 inhibitor is presently in phase III studies and should be available for attacks in the near future.

    CONCLUSION: In this article we review the changing therapeutic options available for patients in 2011 and beyond.

    Available from: http://pediatrics.aappublications.org/content/128/6/1173

    Response to ecallantide treatment of acute attacks of hereditary angioedema based on time to intervention: results from the EDEMA clinical trials

    Banta E, Horn P, Craig TJ. 7/2011 Allergy and Asthma Proceedings

    Hereditary Angioedema (HAE) is a rare, debilitating, genetic disorder characterized by acute attacks of edema without urticaria. Ecallantide, a direct plasma kallikrein inhibitor, is approved for treatment of acute HAE attacks. This article addresses the efficacy of ecallantide in the treatment of moderate-to-severe attacks of HAE based on time to treatment. A post hoc integrated analysis of the EDEMA4 and EDEMA3-DB clinical trials was performed based on the time to patient’s treatment, defined as the time from initial recognition of moderate-to-severe symptoms to dosing (cohort, 0-2, >2-4, >4-6, >6-8, and >8 hours). Mean symptom complex severity (MSCS) score and treatment outcome score (TOS) were analyzed. Complete or near-complete resolution of symptoms was assessed at 4 and 24 hours. In this analysis, 70 patients received 30 mg of subcutaneous (s.c.) ecallantide and 73 patients received placebo. Change from baseline in MSCS score and TOS at 4 hours revealed significantly better response to ecallantide versus placebo for patients treated >2-4 (n = 46; p = 0.002; p = 0.003) or >4-6 (n = 47; p = 0.044; p = 0.043) hours after symptom onset. Fewer patients were treated within 2 hours of symptom onset; for these patients (n = 10; p = 0.752; p = 0.422) treatment did not achieve statistical significance. For overall response, complete or near-complete resolution was greatest within the 0- to 2-hour cohort (71.4%). As with other therapies for HAE early ecallantide therapy is optimal. Treatment with ecallantide within 6 hours of symptom onset leads to more rapid and sustained improvement of symptoms.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2011/00000032/00000004/art00009

    rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency

    Varga L, Farkas H. 3/2011 Expert Review of Clinical Immunology

    Recombinant human C1 esterase inhibitor (rhC1INH) (Ruconest(), Pharming) is a new drug developed for the relief of symptoms occurring in patients with angioedema due to C1-inhibitor deficiency. Pertinent results have already been published elsewhere; this article summarizes the progress made since then. Similar to the purified C1-inhibitor derived from human plasma, the therapeutic efficacy of rhC1INH results from its ability to block the actions of enzymes belonging to the overactivated bradykinin-forming pathway, at multiple locations. During clinical trials into the management of acute edema, a total of 190 subjects received recombinant C1-inhibitor by intravenous infusion on 714 occasions altogether. Dose-ranging efficacy studies established 50 U/kg as the recommended dose, and demonstrated the effectiveness of this agent in all localizations of hereditary angioedema attacks. Studies into the safety of rhC1INH based on 300 administrations to healthy subjects or hereditary angioedema patients followed-up for 90 days have not detected the formation of autoantibodies against rhC1INH or IgE antibodies directed against rabbit proteins, even after repeated administration on multiple occasions. These findings met favorable appraisal by the EMA, which granted European marketing authorization for rhC1INH. Pharming is expected to file a biological licence with the US FDA by the end of 2010 to obtain marketing approval in the USA. The launch of rhC1INH onto the pharmaceutical market may represent an important progress in the management of hereditary angioedema patients.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.11.5

    Risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioedema with and without prophylaxis with C1 inhibitor concentrate: a retrospective study

    Bork K, Hardt J, Staubach-Renz P, Witzke G. 7/2011 Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology & Endodontology

    OBJECTIVE: Tooth extractions may trigger clinical symptoms of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH). The aim of this study was to determine how many tooth extractions were followed by symptoms of HAE-C1-INH in patients with and without preoperative short-term prophylaxis with C1 inhibitor concentrate.

    STUDY DESIGN: Tooth extractions and clinical symptoms of HAE-C1-INH were determined from clinical record files of 171 patients with HAE-C1-INH.

    RESULTS: Facial swelling or potentially life-threatening laryngeal edema, or both, occurred in 124/577 tooth extractions (21.5%) without prophylaxis. Similar symptoms occurred in a fewer proportion of patients undergoing extractions (16/128; 12.5%) after short-term prophylaxis with C1 inhibitor concentrate. The graded dose-response relationship was significant at P < .05.

    CONCLUSIONS: Short-term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis.Copyright © 2011 Mosby, Inc. All rights reserved. : Short-term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis.Copyright © 2011 Mosby, Inc. All rights reserved.

    Available from: http://www.oooojournal.net/article/S1079-2104(11)00108-9/fulltext

    Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients

    Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. 2/2011 Allergy

    BACKGROUND: Hereditary angioedema (HAE) due to the deficiency of C1 inhibitor (C1-INH) causes chronically recurrent cutaneous, abdominal and laryngeal angioedema that are disabling and potentially life-threatening.

    OBJECTIVE: We designed a prospective study to quantify the residual disease in patients with HAE treated according to the existing consensus documents.

    METHODS: Data were collected from diaries recording occurrence, duration, location and treatment of acute angioedema attacks. A total of 386 semesters properly completed were analyzed. Forty-seven of 103 patients were on prophylactic treatment, 41 with attenuated androgens and six with tranexamic acid. A total of 1532 angioedema attacks (one every 45.3 days) were registered.

    RESULTS: Peripheral attacks were the most frequent (698), followed by abdominal (503) and combined locations (232), laryngeal edema was less common (99). Patients on prophylaxis with attenuated androgens had 7.7 attacks/year lasting 1.47 days, those on tranexamic acid had 8.1 attacks/year lasting 1.59 days, and those without prophylaxis had 8.9 attacks/year lasting 1.68. Plasma-derived C1-INH was used by 44 patients to treat a total of 376 acute attacks that resolved faster (1.1 day) than those not treated (1.85 day) or treated with tranexamic acid (1.79 day). No adverse events related to C1-INH infusion were reported.

    CONCLUSION: Our data demonstrate that tranexamic acid is not effective in the treatment of acute attacks and indicate that under the current therapeutic approach, the HAE related disability is effectively but partially reduced. Incomplete success does not appear to depend on limited efficacy of the drugs but on their limited use that can be overcome by implementing specific treatment strategies.Copyright © 2010 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2010.02433.x/full

    The Turkish Hereditary Angioedema Pilot Study (TURHAPS): the first Turkish series of hereditary angioedema

    Kesim B, Uyguner ZO, Gelincik A, Mete Gokmen N, Sin AZ, Karakaya G, et al. 11/2011 International Archives of Allergy and Immunology

    BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients.

    METHODS: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE.

    RESULTS: The majority of patients were female (60%), the mean age was 37.7 +/- 14.1 years. The mean age at the time of first angioedema symptom was 12.5 +/- 9.2 years. Mean time lag between first symptom and diagnosis was 26 +/- 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described.

    CONCLUSION: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.Copyright © 2011 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/Abstract/323915

    Therapeutic approaches in hereditary angioedema

    Antoniu SA. 8/2011 Clinical Reviews in Allergy and Immunology

    Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and others are under evaluation for this indication. Plasma-derived C1-INH, bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), or recombinant C1-INH is authorized on the market for HAE attack therapy or prophylaxis. Some of these compounds can be used exclusively to treat HAE attacks, whereas others can also be used as prophylactic therapies. Such therapies, although not available worldwide, can improve disease outcome due to their different mechanisms of action.

    Available from: https://scholar.google.ca/scholar?q=Therapeutic+approaches+in+hereditary+angioedema&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwi6y4O4x_nQAhVB1mMKHa71BQ0QgQMIGjAA

    Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Management of adult patients with icatibant in hereditary angioedema

    Drake D. 8/2011 Emergency Medicine Journal

    A short-cut review was carried out to establish whether icatibant is effective in the treatment of hereditary angioedema. A total of 168 papers were found using the reported search, of which one represented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of this best paper are tabulated. The clinical bottom line is there is promising evidence for the use of the bradykinin receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema.

    Available from: http://emj.bmj.com/content/28/8/720.full (small fee)

    Treatment with C1-inhibitor concentrate does not induce IgM type anti-C1 inhibitor antibodies in patients with hereditary angioedema

    Varga L, Fust G, Csuka D, Farkas H. 1/2011 Molecular Immunology

    BACKGROUND: Earlier, we found a higher frequency of IgM type C1-inhibitor autoantibodies (C1INH-Abs) in hereditary angioedema (HAE) patients, regardless of previous treatment with C1INH concentrate. The presence of C1INH-Abs correlated with disease severity in patients who have never been treated with C1INH concentrate. We revisited these topics by analyzing a larger patient population with a longer follow-up.

    METHODS: We tested IgM type C1INH-Abs (defined as 2 SD higher, than the mean of control, >5.1 AU/ml) in 1127 sera from 130 HAE patients followed up for 8.67 +/- 3.18 years. Most analysis was done in a subset of 75 patients, with a follow-up of 9-11 years.

    RESULTS: IgM C1INH-Abs were found in 178 sera from 69/130 patients and in 51/75 patients followed up on the long term. Twenty-three/75 (31%) patients had IgM type antibodies in more than 3 serum samples. Temporal changes in the titers of IgM type C1INH Abs followed different patterns. The occurrence of IgM type Abs clustered in some families; there was a highly significant (p = 0.0084) heterogeneity in the levels of IgM C1-INH Abs among the 10 families with at least 3 members. We did not find any significant difference between the frequency of IgM type anti-C1INH antibodies in patients who have never received (n = 15) and in those ever treated (n = 60) with C1INH concentrate. Similarly, no significant correlation was found between the mean dose (number of ampoules) of C1INH concentrate and the frequencies of the levels of IgM type C1INH-Abs. At variance with previous data, the frequency of C1INH-Abs did not correlate either with annual attack rate or with other indicators of the severe course of the disease. CONCLUSIONS: This study confirmed that the occurrence of IgM type C1INH-Abs in HAE is not related to previous treatment of attacks with C1-inhibitor concentrate. Familial clustering suggests underlying genetic factors presumably unrelated to HAE.Copyright © 2010 Elsevier Ltd. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S0161589010005924 (small fee)

    Update on angioedema: evaluation, diagnosis, and treatment

    Bernstein JA. 11/2011 Allergy and Asthma Proceedings

    Hereditary Angioedema (HAE) is a multisystem, autosomal dominant disease that affects ~1:10,000 to 1:50,000 individuals in the United States. The disease has several clinical characteristics that distinguish it from other forms of angioedema. Recurrent swelling attacks involve the abdomen, face, extremities, genitalia, oropharynx, or larynx without urticaria. The swelling attacks are typically unilateral, nonpitting, nonpruritic, and, although uncomfortable, are often painless. Other forms of isolated angioedema such as acquired angioedema and angiotensin-converting enzyme-induced angioedema have similar characteristics of HAE. Therefore, evaluation of patients with recurrent angioedema should be directed at excluding these different forms of angioedema before a diagnosis of idiopathic angioedema is made. The objective of this article is to provide an overview of the differential diagnosis of angioedema that reflects the angioedema guidelines that are currently in development.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2011/00000032/00000006/art00007

    Update on preventive therapy (prophylaxis) of hereditary angioedema

    Frank MM. 1/2011 Allergy and Asthma Proceedings

    The prophylaxis of patients with hereditary angioedema to prevent attacks has gone through major revision as new agents for prophylaxis have come on the market. Earlier treatments, developed empirically, included the fibinolysis inhibitors epsilon aminocaproic acid and tranexamic acid and attenuated androgens such as danazol. With the development of these agents, many patients had relief of severe symptoms, and drugs in these classes have been the only treatments available in America. Their major disadvantage has been their side effects, which range from minor to severe. In Europe various products containing C1 inhibitor, the serum protein deficient in this disease, were prepared from pooled donor plasma. They were reported to be effective in ending attacks and in prophylaxis, but these products in general were not used in prophylaxis, in part because of the short half life of the plasma protein. One such product, C1 esterase inhibitor, has now been shown in a rigorous double-blind study to be effective in prevention of hereditary angioedema attacks and has been approved by the US Federal Drug Administration for prophylaxis of the disease. Its use has been attended by few side-effects, reflecting the fact that it is the purified naturally circulating product.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2011/00000032/00000001/art00004

    Update on the acute treatment of hereditary angioedema

    Riedl MA. 1/2011 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a genetic autosomal dominant condition caused by C1-esterase inhibitor protein (C1INH) deficiency that results in episodic tissue angioedema. Recently, new therapies have been developed to more effectively manage this rare but serious condition. This review will provide a concise summary of HAE acute treatment options for the practicing allergist/immunologist. Clinical study data for emerging HAE therapies were reviewed and summarized. Based on efficacy and safety data from completed clinical studies, three new HAE treatments have recently been approved by the Food and Drug Administration: nanofiltered plasma-derived C1INH for prophylactic therapy, pasteurized plasma-derived C1INH for acute therapy, and ecallantide for acute therapy. Two other promising therapies, recombinant C1INH and icatibant, are in various stages of the U.S. regulatory process. The medical management of HAE is entering a new era with the availability of safe, effective condition-specific treatments. Clinicians should consider a number of patient- and medication-specific factors when designing individualized treatment plans for HAE patients.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2011/00000032/00000001/art00003

    ACE inhibitor-induced angioedema

    Vasekar M, Craig TJ. 2/2012 Current Allergy and Asthma Reports

    Much has been written about hereditary angioedema (HAE) in recent literature; however, the prevalence of angiotensin-converting enzyme inhibitor-induced angioedema (ACEiIA) far exceeds that of HAE. Similarly, multiple therapies have been developed for HAE, yet no definitive therapy is available for ACEiIA. In this article, we discuss the mechanism, prevalence, pathophysiology, and management of ACEiIA, with focus on newer therapies recently approved for HAE and how they may be effective for ACEiIA.

    Available from: http://link.springer.com/article/10.1007%2Fs11882-011-0238-z

    An update on hereditary angioedema

    Hsu D, Shaker M. 10/2012 Current Opinion in Pediatrics

    PURPOSE OF REVIEW: To review and update the management and understanding of hereditary angioedema (HAE), while integrating insights into pediatric subtleties that exist in practice.

    RECENT FINDINGS: Major advances have recently been made in HAE treatment. Ecallantide (a kallikrein inhibitor approved for use in the United States in December 2009) and icatibant (a selective bradykinin B2 receptor antagonist approved for use in the United States in August 2011) represent novel subcutaneous therapies for acute HAE exacerbations. Recombinant human C1 esterase inhibitor (C1INH) serves as a promising future alternative to current mainstay acute and prophylactic treatment with plasma-derived C1INH. Recent guidelines have outlined new algorithms for short-term and long-term prophylaxis against HAE exacerbations.

    SUMMARY: The evolving standard of care for HAE management involves not only treatment of acute exacerbations but also individualized patient preference-sensitive short-term and long-term prophylaxis. Updated international consensus guidelines provide useful protocols, whereas recent clinical reviews have raised awareness of HAE. Further advances will likely focus on improving patient access to convenient acute and prophylactic treatment with C1INH.

    Available from: http://journals.lww.com/co-pediatrics/pages/articleviewer.aspx?year=2012&issue=10000&article=00015&type=abstract (small fee)

    Assessment of rebound and relapse following ecallantide treatment for acute attacks of hereditary angioedema

    Bernstein JA, Shea EP, Koester J, Iarrobino R, Pullman WE. 9/2012 Allergy

    BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable and recurring attacks of angioedema. This study assessed potential attack rebound and relapse following treatment with ecallantide, a plasma kallikrein inhibitor approved for HAE attack treatment.

    METHODS: Results were integrated from 2 double-blind, placebo-controlled studies of ecallantide treatment for HAE: EDEMA3-DB and EDEMA4. Symptoms were assessed by treatment outcome score (TOS), mean symptom complex severity (MSCS) score, and global response. Patients with improvement at 4 h post-dosing in all three measures followed by any sign of worsening at 24 h were considered to show potential rebound if worsening was beyond baseline or potential relapse if not beyond baseline. Likeliness of rebound or relapse was determined by the number of measures showing worsening and the magnitude of worsening. Patients receiving placebo who met the criteria for rebound/relapse were evaluated for descriptive comparison only.

    RESULTS: Significantly more ecallantide-treated patients (42 of 70) compared to placebo (26 of 71) showed improvement in three measures at 4 h and were thus eligible for rebound/relapse (P = 0.006). Of the nine ecallantide-treated patients with signs of worsening at 24 h, none were likely rebound, one was assessed as possible rebound, one as likely relapse, and two as possible relapse. No patient with potential rebound/relapse experienced new symptoms after dosing. Medical intervention was required in one ecallantide-treated patient.

    CONCLUSION: Ecallantide was efficacious for treating acute HAE attacks. Relapse was observed in a small proportion of patients, and there was little evidence of rebound.Copyright © 2012 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2012.02864.x/full

    C1-inhibitor therapy for hereditary angioedema attacks: prospective patient assessments of health-related quality of life

    Bewtra AK, Levy RJ, Jacobson KW, Wasserman RL, Machnig T, Craig TJ. 9/2012 Allergy and Asthma Proceedings

    C1-inhibitor (INH) concentrate, which is recommended as first-line treatment for acute hereditary angioedema (HAE) attacks in many countries, was recently approved in the United States. We sought to solicit patients’ feedback about their health-related quality of life (HRQoL) while being treated with C1-INH concentrate for acute HAE attacks under real-world conditions, as well as the personal impact of the availability of C1-INH on lifestyle and mental health domains. Subjects enrolled in an open-label study of C1-INH at 20 U/kg for acute HAE attacks were invited to participate in a prospectively designed survey to solicit “real-time” patient responses that were collected via an interactive voice response service or online with a personal computer. Eighteen subjects submitted 60 quarterly HRQoL and treatment impact survey responses over 29 months. Seventeen of 18 patients responding reported mean short form 12 HRQoL scores that were within a normal range. More than one-half indicated that C1-INH availability made them feel somewhat or much better, and >80% reported having a better outlook on the future and feeling more secure about the danger of life-threatening attacks. These data confirm a high level of HRQoL and a positive impact in lifestyle and emotional domains among patients who were treated for acute attacks of HAE with C1-INH concentrate.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2012/00000033/00000005/art00008

    Chapter 25: Idiopathic anaphylaxis

    Blatman KH, Ditto AM. 5/2012 Allergy and Asthma Proceedings

    Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely but if elevated in the absence of anaphylaxis, should suggest alternative diagnoses including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient’s symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential because they do not usually accompany any of the aforementioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year or two or more episodes in 2 months are classified as IA-frequent (IA-F). Patients who experience fewer episodes are classified as IA-infrequent (IA-I). This distinction is important because IA-F patients initially will require prednisone as disease-modifying therapy whereas most IA-I patients will not. Patients with IA must carry and know when and how to self-administer epinephrine.

    Clinical efficacy of icatibant in the treatment of acute hereditary angioedema during the FAST-3 trial

    Bas M. 11/2012 Expert Review of Clinical Immunology

    Bradykinin is the key mediator of symptoms of hereditary angioedema (HAE), a rare genetic disorder characterized by recurrent episodes of edema of the skin, mucosa and muscle. Icatibant, a bradykinin B(2) receptor antagonist, is an effective and generally well-tolerated treatment option for acute attacks of type I and II HAE. A Phase III randomized, double-blind, placebo-controlled study, FAST-3 (NCT00912093), was designed to further evaluate the efficacy and safety of icatibant in patients presenting with moderate to very severe cutaneous and/or abdominal or mild-to-moderate laryngeal symptoms. Severe laryngeal attacks were treated with open-label icatibant. The controlled phase of FAST-3, completed in October 2010 with results published in December 2011, demonstrated that compared with placebo, icatibant evoked clinically meaningful and statistically significant efficacy across multiple end points in the treatment of type I and II HAE attacks. In addition, icatibant was generally well tolerated and no drug-related serious adverse events were experienced.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.12.67

    Clinical impact of peripheral attacks in hereditary angioedema patients

    Kusuma A, Relan A, Knulst AC, Moldovan D, Zuraw B, Cicardi M, et al. 9/2012 The American Journal of Medicine

    BACKGROUND: Episodes of acute subcutaneous angioedema affecting the extremities in patients with known hereditary angioedema are called peripheral attacks. These attacks are considered to be of limited clinical importance.

    OBJECTIVE: To evaluate the impact of peripheral attacks in patients with hereditary angioedema and to assess the response to treatment with recombinant human C1-inhibitor (rhC1INH).

    METHODS: Hereditary angioedema patients with a peripheral attack included in a clinical database of rhC1INH were analyzed. Visual analog scale (VAS) scoring was used to evaluate symptom severity and response to therapy. RESULTS: Sixty-five patients with a peripheral attack were identified. VAS scores for 64 patients were available. Twenty-nine (45%) patients reported a single peripheral location of the attack, the others multiple locations. Eight patients (13%) indicated moderate (VAS 20-50 mm) and 55 (86%) severe (VAS >50 mm) swelling, 17 (27%) had moderate and 35 (55%) severe pain, while 8 (13%) patients reported moderate and 51 (80%) severe dysfunction for the peripheral attack. Symptom VAS scores decreased over time more rapidly in patients treated with rhC1INH than in patients treated with placebo. Onset of relief was achieved in 95% of the rhC1INH-treated patients within 4 hours, whereas only 21% of saline-treated patients had relief in the same time period.

    CONCLUSION: Peripheral attacks in hereditary angioedema patients often are located at multiple anatomical locations and frequently have associated pain and dysfunction, in addition to swelling, as dominant symptoms. The medical need for treatment of these attacks may be underestimated. Treatment with rhC1INH constitutes a therapeutic option for acute peripheral hereditary angioedema attacks.Copyright © 2012 Elsevier Inc. All rights reserved.

    Available from: http://www.amjmed.com/article/S0002-9343%2812%2900122-2/fulltext

    Current management options for hereditary angioedema

    Bork K. 8/2012 Current Allergy and Asthma Reports

    The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma-derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor have been approved. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are permitted for self-administration and home therapy. The number of management options has increased considerably within the last few years, thus helping to diminish the burden of HAE.

    Available from: http://link.springer.com/article/10.1007%2Fs11882-012-0273-4

    Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project

    Prior N, Remor E, Gomez-Traseira C, Lopez-Serrano C, Cabanas R, Contreras J, et al. /2012 Health and Quality of Life Outcomes

    BACKGROUND: There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase.

    METHODS/DESIGN: Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains.

    DISCUSSION: To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489868/

    Diagnosis and treatment of hereditary angio-oedema attacks

    Longhurst HJ, Nzeako UC. 3/2012 British Journal of Hospital Medicine

    Available from: http://www.magonlinelibrary.com/doi/full/10.12968/hmed.2012.73.3.148 (small fee)

    Ecallantide for treatment of acute attacks of hereditary angioedema

    Martello JL, Woytowish MR, Chambers H. 4/2012 American Journal of Health-System Pharmacy

    PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, dosage, administration, adverse effects, and place in therapy of ecallantide, a kallikrein inhibitor for the treatment of hereditary angioedema (HAE), are reviewed.

    SUMMARY: Ecallantide is the first member of the kallikrein inhibitor class approved for the treatment of acute attacks of HAE. Ecallantide works by binding to kallikrein, preventing the conversion of kininogen to bradykinin, which reduces vascular permeability, thus reducing the swelling associated with acute attacks of HAE. Ecallantide has been studied for the treatment of HAE in three Phase II studies and two Phase III studies. These studies were collectively known as the EDEMA (Evaluation of DX-88’s Effect in Mitigating Angioedema) studies. Phase III clinical trials found that ecallantide is superior to placebo in ameliorating patient symptoms associated with acute attacks of HAE at any anatomical site. Ecallantide has a favorable safety profile, with the most common adverse effects being gastrointestinal effects, headache, and injection site reactions. The most severe adverse effects of ecallantide are the risk of anaphylaxis and the possible development of antiecallantide antibodies. A risk evaluation and mitigation strategy program has been approved by the Food and Drug Administration to help ensure the safety and efficacy of ecallantide use. The recommended dose is 30 mg given as three separate subcutaneous injections.

    CONCLUSION: Ecallantide is a novel agent approved for the treatment of acute attacks of HAE at any anatomical site. It is one of only three medications approved for this indication in the United States, presents a unique mechanism of action, and appears to be safe and effective when used for its labeled indication.

    Available from: http://www.ajhp.org/content/69/8/651

    Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics

    MacGinnitie AJ, Campion M, Stolz LE, Pullman WE. 3/2012 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2012/00000033/00000002/art00013

    Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study

    Moldovan D, Reshef A, Fabiani J, Kivity S, Toubi E, Shlesinger M, et al. 6/2012 Clinical and Experimental Allergy

    BACKGROUND: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma.

    OBJECTIVES: This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks.

    METHODS: An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (> 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h.

    RESULTS: A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity.

    CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.Copyright © 2012 Blackwell Publishing Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/j.1365-2222.2012.03984.x/full

    Efficacy assessments in randomized controlled studies of acute therapy for hereditary angioedema

    Caballero T. 12/2012 Journal of Clinical Immunology

    Hereditary angioedema (HAE) is a rare disorder caused by a deficiency of C1 esterase inhibitor, characterized by recurrent, highly variable attacks of subcutaneous or submucosal edema that may affect multiple body sites. Clinical studies of acute HAE therapies have required the use of assessment tools to evaluate both pretreatment attack severity (baseline severity) and changes in symptom severity following treatment (treatment response). This article reviews the range of assessment tools used for efficacy determination of acute HAE therapies, based on a review of relevant clinical studies. Because the goal is relief of symptoms (rather than cure), patient-reported outcomes (PROs) form the basis of these tools. Tools used to evaluate baseline severity typically employ location-specific assessment of symptom severity, using either categorical descriptions (which may be converted into numerical variables) or a visual analog scale (VAS). Some studies define the initial or most symptomatic site as an “index” site for purposes of efficacy determination, while others (such as the Mean Symptom Complex Severity score used in clinical studies of ecallantide) use a composite score that reflects all sites. Assessment of treatment response typically employs the same tool(s) to evaluate baseline severity, and may be either time-based (e.g., time to achievement of minimal or no symptoms) or symptom-based (e.g., degree of symptom relief at predetermined time points). Although it is unlikely that therapies will be compared using identical assessment tools, prospective or retrospective validation ensures the adequacy and relevance of such tools, which should be taken into consideration when therapies are compared.

    Available from: http://link.springer.com/article/10.1007%2Fs10875-012-9734-8

    Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group

    Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, et al. 2/2012 Allergy

    Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients’ associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.Copyright © 2011 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2011.02751.x/full

    Fresh frozen plasma for the treatment of hereditary angioedema acute attacks

    Tang R, Chen S, Zhang HY. 6/2012 Chinese Medical Sciences Journal

    OBJECTIVE: To determine the safety and efficacy of fresh frozen plasma (FFP) infusion for the treatment of hereditary angioedema (HAE).

    METHODS: The medical records of patients with HAE admitted to Peking Union Medical College Hospital who had received FFP infusion during 2004 and 2010 were reviewed and PubMed database from 1966 to the present were searched using the following hereditary angioedema and fresh frozen plasma. The patient’s age, sex, body location of HAE attacks, the dose of FFP infusion, time of beginning to improvement, time to complete remission, complication, C1 inhibitor activity, and outcome were analyzed.

    RESULTS: A total of 13 enrolled patients (7 male and 6 female) received 16 times of FFP infusion, including 2 patients undergoing FFP infusion in Peking Union Medical College Hospital and 11 patients reported in the literature. The mean dosage of FFP infusion was 586-/+337 mL. Two cases suffered from worsening abdominal pain and one case experienced skin rash. Only 1 patient had no improvement in symptom owing to transfusion related reaction. There was a definite improvement in symptom 49-/+19 minutes after beginning FFP infusion. The remission time decreased from 61.7-/+27.0 hours to 3.3 (2.0, 12.0) hours after FFP infusion. FFP infusion was effective for both type I and type II HAE.

    CONCLUSION: FFP seems to be safe and effective for acute attacks of HAE.

    Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist

    Cicardi M, Johnston DT. 5/2012 Acta Haematologica

    Hereditary angioedema (HAE), a rare autosomal dominant disorder, was first described in the late 19th century. The disease remained poorly understood and without therapeutic options until the latter half of the 20th century. Advances in the understanding of immunologic and hematologic pathways have shed light on HAE, a disease characterized by painful and unpredictable recurrent attacks of nonpitting edema without urticaria. Recognition that a deficiency of complement component 1 (C1) esterase inhibitor leads to overproduction of vasoactive kinins that cause angioedema paved the way for the development of early treatments. Increased understanding of the role of bradykinin in hereditary and acquired forms of C1 esterase inhibitor deficiency has led to the development of more targeted treatments for this painful, debilitating and potentially life-threatening disease.Copyright © 2012 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/FullText/336590

    Hereditary angioedema (HAE) in children and adolescents–a consensus on therapeutic strategies

    Wahn V, Aberer W, Eberl W, Fashauer M, Kuhne T, Kurnik K, et al. 9/2012 European Journal of Pediatrics

    Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419830/

    Hereditary angioedema therapies in the United States: movement toward an international treatment consensus

    Riedl M. 3/2012 Clinical Therapeutics

    BACKGROUND: Hereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant disease characterized by recurrent angioedema attacks that affect the skin, gastrointestinal tract, and airway, including the larynx. Pharmacologic developments in HAE treatment have culminated in the recent introduction of 4 new HAE-specific therapies in the United States.

    OBJECTIVES: In light of these new therapeutic options, this commentary outlines historical US HAE therapy choices, discusses the potential effect of the 4 recently approved HAE treatments, and considers strategies for optimizing their use in line with international treatment recommendations.

    DISCUSSION: Treatment options for HAE in the United States have been limited to attenuated androgens and antifibrinolytic agents for long-term prophylaxis and FFP and supportive therapy for the management of acute attacks. The 4 new therapies that have recently become available (ie, 2 plasma-derived C1 esterase inhibitor (C1-INH) concentrates, the kallikrein inhibitor ecallantide, and the bradykinin beta(2)-antagonist icatibant) have provided an opportunity to change routine HAE treatment. In 2009, despite the availability of 2 of the new treatments (ie, the plasma-derived C1-INH concentrates), a large survey of US physicians suggested that wide variability still existed in the treatment of patients with HAE. Since this survey was undertaken, clinical experience with all 4 new treatments has increased significantly, and because 3 of these agents (ie, 2 plasma-derived C1-INH concentrates and icatibant) can be self-administered by trained patients, physicians can now provide individualized care that is proven effective and more aligned with international guidance.Copyright A© 2012 Elsevier HS Journals, Inc. All rights reserved.

    Available from: http://www.clinicaltherapeutics.com/article/S0149-2918%2812%2900081-1/abstract

    Hereditary angioedema treatment options: the availability of new therapies

    Aberer W. 9/2012 Annals of Medicine

    Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disease characterized by recurrent episodes of oedema, commonly occurring in the skin, abdomen, and upper respiratory tract. After many years during which limited treatment options were available, a range of newer therapies with proven efficacy have been approved in Europe by the European Commission for the treatment of HAE attacks. However, due to differing legislation and financial restrictions, these treatment options are not available in all countries. Home therapy and self-administration of treatment are recommended in order to minimize the burden of disease upon the patient, with the ideal treatment option being effective, well-tolerated, and easy to prepare and administer. Recently, the Hereditary Angioedema International Working Group (HAWK) consensus recommended early, on-demand treatment for HAE. This article reviews the current treatment options available, and considers the need for treatment guidelines to recommend the appropriate therapy.

    Available from: http://www.tandfonline.com/doi/full/10.3109/07853890.2012.687833

    Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema

    Kreuz W, Rusicke E, Martinez-Saguer I, Aygoren-Pursun E, Heller C, Klingebiel T. 1/2012 Transfusion

    BACKGROUND: C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE).

    STUDY DESIGN AND METHODS: Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). RESULTS: The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes.

    CONCLUSION: As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.Copyright © 2011 American Association of Blood Banks.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2011.03240.x/full

    Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study

    Zanichelli A, Bova M, Coerezza A, Petraroli A, Triggiani M, Cicardi M. 8/2012 Allergy

    Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1-inhibitor (C1-INH) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1-INH deficiency (AAE). Forty-eight moderate-to-severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67-39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25-2.10) h and complete resolution in 6.75 (0.50-30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.Copyright © 2012 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2012.02853.x/full

    Immunogenicity assessment of recombinant human c1-inhibitor: an integrated analysis of clinical studies

    Hack CE, Mannesse M, Baboeram A, Oortwijn B, Relan A. 10/2012 Biodrugs

    BACKGROUND AND OBJECTIVE: Recombinant human C1-inhibitor (rhC1INH) is used to treat acute angioedema attacks in hereditary angioedema (HAE) due to a genetic C1INH deficiency. Recombinant proteins in general may induce antibody responses and therefore evaluation of such responses in the target population is an essential step in the clinical development program of a recombinant protein. Here we report the assessment of the immunogenicity of rhC1INH in symptomatic HAE patients.

    METHODS: Blood samples collected before and after administration of rhC1INH were tested for antibodies against plasma-derived (pd) or rhC1INH, or against host-related impurities (HRI). Above cut-off screening results were confirmed with displacement assays, and also tested for neutralizing anti-C1INH antibodies. Finally, the relation of antibodies to clinical efficacy and safety of rhC1INH was analyzed.

    RESULTS: Data from 155 HAE patients who received 424 treatments with rhC1INH were analyzed. 1.5% of all pre-exposure tests and 1.3% of all post-exposure tests were above the cut-off level in the screening assay for anti-C1INH antibodies. Six patients (3.9%) had anti-rhC1INH antibodies positive in the confirmatory assay. In two patients, confirmed antibodies were pre-existing with no increase post-exposure; in three patients, the antibodies occurred on a single occasion post-exposure; and in one patient, on subsequent occasions post-exposure. Neutralizing anti-pdC1INH antibodies were not found. Anti-HRI antibodies in the screening assay occurred in <0.7% of the tests before exposure to rhC1INH, in <1.9% after first exposure and in <3.1% after repeat treatment with rhC1INH. Five patients had anti-HRI antibodies positive in the confirmatory assay. In one patient, the antibodies were pre-existing, whereas in three of the 155 rhC1INH-treated patients (1.9%), confirmed anti-HRI antibodies occurred at more time points. Antibody findings were not associated with altered efficacy of rhC1INH or adverse events.

    CONCLUSION: These results indicate a reassuring immunosafety profile of rhC1INH as a treatment for acute HAE attacks.

    Available from: http://link.springer.com/article/10.1007/BF03261888

    Immunotherapy for primary immunodeficiency diseases

    Wood P. 5/2012 Medical Clinics of North America

    The 2 most commonly encountered primary immunodeficiency syndromes in adult practice are antibody deficiency disorders and hereditary angioedema.Immunologic therapy for these disorders has significantly improved patient management. Therapy with immunoglobulin leads to improvement in overall quality of life. With increasing survival rates and decreasing levels of life-threatening infections in patients with primary antibody deficiencies, disease complications are more commonly encountered. Treatment of these complications with monoclonal antibody therapy seems promising and is likely to increase in the future. More recently,several additional agents have become available, including novel drugs targeted at different elements of the disease process.Copyright © 2012 Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S0025712512000752 (small fee)

    Life with hereditary angioedema: then and now

    Lane CJ, Grant JA, Dougherty D 3rd. 1/2012 Postgraduate Medicine

    Originally identified in 1882, hereditary angioedema (HAE) is a debilitating and potentially fatal disorder. Although a number of therapies have been identified, many are relatively ineffective or are associated with significant side effect concerns that limit their efficacy. Fortunately, the 2008 approval of plasma-derived C1 esterase inhibitor concentrate for disease prophylaxis provides clinicians with a novel and effective treatment unencumbered with severe side effect concerns for those with this debilitating disorder. However, despite advances in modern medicine, HAE remains a condition marked by a myriad of symptoms that mimic a range of other disorders, from allergic angioedema to acute abdomen, and accurate diagnosis remains a concern. Using articles from the medical literature from the late nineteenth and early twentieth centuries documenting families with HAE, we will review its history and pathophysiology as well as describe current trends in its diagnosis and treatment. Additionally, we will emphasize the humanistic impact of the disorder by describing the real-life experiences of a contemporary family who has documented their experience with HAE across 7 generations.

    Available from: http://www.tandfonline.com/doi/abs/10.3810/pgm.2012.01.2527

    Many faces of angioedema: focus on the diagnosis and management of abdominal manifestations of hereditary angioedema

    Nzeako UC, Longhurst HJ. 4/2012 European Journal of Gastroenterology and Hepatology

    Angioedema of the intestinal tract is an infrequent but well-described cause of abdominal pain that can occur because of inherited, acquired, allergic, or drug-induced causes. Hereditary angioedema (HAE) is a genetic disorder that causes recurrent attacks of severe edema of various body parts, including the intestinal tract. Moderate to severe abdominal pain occurs in 43-93% of such attacks due to intestinal edema. Laryngeal edema is a potentially life-threatening manifestation. Failure to recognize and diagnose HAE or other causes of intestinal angioedema can lead to years of delay in diagnosis, and in the case of HAE, often to unnecessary abdominal surgeries. Recognizing the typical history of recurrent attacks of abdominal pain, oropharyngeal/laryngeal angioedema or cutaneous angioedema, family history of similar symptoms, association of attacks with stress or menses, and exacerbation of attacks after administration of estrogens or angiotensin-converting enzyme inhibitors will increase diagnostic accuracy. Interdisciplinary treatment is often necessary after the diagnosis of HAE, first with acute management in the emergency room or the intensive care unit, followed by either drug prophylaxis against future attacks using a C1-esterase inhibitor concentrate or attenuated androgens and discontinuation of medications known to trigger attacks. Newer drugs approved for treatment of acute attacks may have future roles in the prevention of attacks if further studies support their efficacy. Gastroenterologists in particular should maintain a high index of suspicion for the possibility of HAE or other causes of intestinal angioedema in patients with a history of recurrent abdominal pain.

    Available from: http://journals.lww.com/eurojgh/pages/articleviewer.aspx?year=2012&issue=04000&article=00001&type=abstract (small fee)

    Model-based evaluation of similarity in pharmacokinetics of two formulations of the blood-derived plasma product c1 esterase inhibitor

    Keizer RJ, Budde IK, Sprengers PF, Levi M, Beijnen JH, Huitema AD. 2/2012 The Journal of Clinical Pharmacology

    A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis. Copyright 2012 American College of Clinical Pharmacology.

    Available from: http://onlinelibrary.wiley.com/doi/10.1177/0091270010394446/full

    Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial

    Riedl MA, Hurewitz DS, Levy R, Busse PJ, Fitts D, Kalfus I. 1/2012 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare disease caused by C1INH gene mutations, which leads to a deficiency or dysfunction of C1 inhibitor (C1 INH), resulting in recurrent episodes of severe and potentially life-threatening edema.

    OBJECTIVE: To evaluate the efficacy and safety of repeat use of nanofiltered C1 esterase inhibitor (human) (C1 INH-nf) for the short-term treatment of HAE attacks. METHODS: In this open-label study, patients received C1 INH-nf, 1,000 U intravenously, for the treatment of HAE attacks. Efficacy end points included the proportion of attacks with unequivocal relief of the defining symptom within 1 and 4 hours after receiving study drug and time to beginning of relief of the defining symptom. Safety was monitored through adverse event reporting, vital signs measurements, and laboratory testing.

    RESULTS: A total of 113 patients were enrolled in the study from September 21, 2006, through March 31, 2009, and received 885 doses of C1 INH-nf. A total of 609 HAE attacks were treated with C1 INH-nf, and the numbers of attacks achieving unequivocal relief of the defining symptom within 1 and 4 hours after the start of the first dose were 412 (68%) and 529 (87%), respectively. Of 101 patients treated for an attack during the study period, 80 achieved unequivocal relief of their first attack within 4 hours after study medication (response rate, 79%); median time to the beginning of unequivocal relief was 0.75 hour. C1 INH-nf was safe and well tolerated.

    CONCLUSIONS: This open-label study demonstrates the efficacy and safety of C1 INH-nf for short-term treatment of HAE attacks.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00438815.Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2811%2900859-3/abstract

    Pathogen safety of human C1 esterase inhibitor concentrate

    Groner A, Nowak T, Schafer W. 10/2012 Transfusion

    BACKGROUND: Human plasma-derived products–such as C1 esterase inhibitor (C1-INH) concentrate, used to treat hereditary angioedema–carry with them the risk of transmitting blood-borne viruses and, theoretically, prion proteins. To minimize this risk, three complementary approaches are implemented: selection and testing of plasma donations for the absence of pathogenic blood-borne viruses, similarly testing and releasing the plasma pool for fractionation, and ensuring that the manufacturing process includes validated steps for pathogen inactivation and removal.

    STUDY DESIGN AND METHODS: This article describes the selection of plasma for the production of C1-INH and the studies used to confirm the pathogen reduction capacity of the manufacturing process: three independent virus reduction steps–pasteurization, hydrophobic interaction chromatography (HIC), and virus filtration–and two prion reduction steps. Samples of product intermediates from the manufacturing steps were spiked with a panel of enveloped and nonenveloped viruses and two prion preparations and subjected to a valid scaled-down version of the respective manufacturing steps resulting in the quantification of the pathogen reduction factors.

    RESULTS: Validation studies demonstrated overall virus reduction factors for all viruses of more than 15 log, considerably exceeding the potential amount of virus present in a plasma pool for fractionation. Prion proteins were also efficiently removed by the manufacturing process, as currently determined in evaluating the prion removal capacity of the ammonium sulfate precipitation and HIC steps.

    CONCLUSION: The pathogen reduction capacity demonstrated here indicates that the manufacturing process of the C1-INH Berinert is highly effective for reducing enveloped and nonenveloped viruses and prion proteins.Copyright © 2012 American Association of Blood Banks.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2012.03590.x/full

    Per-attack reporting of prodromal symptoms concurrent with C1-inhibitor treatment of hereditary angioedema attacks

    Prematta MJ, Bewtra AK, Levy RJ, Wasserman RL, Jacobson KW, Machnig T, et al. 10/2012 Advances in Therapy

    INTRODUCTION: Prodromal symptoms commonly precede hereditary angioedema (HAE) attacks. There is continuing interest in evaluating prodromes as treatment indicators, but a paucity of relevant data. This study was designed to prospectively identify prodomal characteristics in patients voluntarily reporting such information around the time of seeking treatment for an acute HAE attack.

    METHODS: Twenty-eight patients with HAE were enrolled in this survey, which was conducted in the context of an open-label study of treatment of HAE attacks with plasma-derived C1-inhibitor concentrate. At the time of treatment, patients were encouraged to answer survey questions about prodromal symptoms preceding that particular HAE attack.

    RESULTS: Twenty-one patients provided prodromal information for 253 treated HAE attacks. Seventy-one percent of patients (15/21) reported prodromes. Three patients accounted for approximately 80% of the attacks and 89% of the reported prodromal symptoms. Prodromes were experienced before 67.6% (171/253) of attacks, with a mean of 1.4 prodromes per attack. Fatigue was the most frequent prodrome (42% of attacks), followed by nausea (26%), and flu-like symptoms (22%). The median duration of a prodrome before an attack was 12 h (range, 0.33-24 h).

    CONCLUSIONS: Despite many limitations in the study design, these findings confirm that prodromes are frequently associated with HAE attacks in many patients and occur sufficiently early to allow time for treatment initiation. The frequency of “false positive” prodromal symptoms remains undetermined, and the authors captured data only on attacks severe enough to warrant treatment. Additional well-designed prospective studies are clearly needed to continue investigating the potential clinical relevance of prodromes.

    Available from: http://link.springer.com/article/10.1007%2Fs12325-012-0053-5

    Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks

    Grant JA, White MV, Li HH, Fitts D, Kalfus IN, Uknis ME, et al. 7/2012 Allergy and Asthma Proceedings

    Patients with hereditary angioedema (HAE) may have attacks triggered by dental, medical, or surgical procedures. This analysis evaluated the efficacy and safety of preprocedural administration of nanofiltered C1 esterase inhibitor (C1 INH-nf; human) for the prevention of HAE attacks during and after dental, medical, or surgical procedures. Data were reviewed retrospectively from two acute treatment trials in which at least 1000 U of C1 INH-nf was administered i.v. within 24 hours before an emergency or noncosmetic medical, surgical, or dental procedure. Dosing data, HAE attacks reported within 72 hours, and adverse events (AEs) reported within 7 days after a preprocedural dose of C1 INH-nf were analyzed to assess efficacy and safety. Forty-one unique subjects (8 children and 33 adults) received C1 INH-nf for 91 procedures (40 in children and 51 in adults). The majority of procedures (56%) involved dental work and 44% involved a variety of surgical or medical procedures. A single 1000-U dose of C1 INH-nf was administered for 96% of procedures. An HAE attack did not occur within 72 hours after C1 INH-nf dosing for 98% (89/91) of procedures. Two HAE attacks were reported after the procedure, and both were treated with C1 INH-nf and achieved relief. None of the reported AEs were judged to be related to C1 INH-nf or were associated with an HAE attack. This analysis supports the efficacy and safety of preprocedural administration of C1 INH-nf for the prevention of HAE attacks.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2012/00000033/00000004/art00008

    Progress in the emergency management of hereditary angioedema: focus on new treatment options in the United States

    Bernstein JA, Moellman JJ. 5/2012 Postgraduate Medicine

    Hereditary angioedema (HAE) is a rare disorder generally caused by a deficit in the activity of C1-esterase inhibitor (C1-INH). Symptoms manifest as recurrent episodes of nonallergic, nonpruritic, and nonpitting edema. Attacks commonly occur on the extremities, trunk, genitalia, abdomen, or head and neck–the latter 2 locations are associated with the greatest morbidity and mortality. In the United States, there has been a considerable void in effective HAE treatments and emergency management guidelines. Clinical outcomes using agents such as fresh-frozen plasma, attenuated androgens (danazol), or plasmin inhibitors (aminocaproic acid) have not been ideal. Recent years have seen progress with US Food and Drug Administration (FDA) approval of several products for acute HAE treatment. Plasma concentrate of C1-INH has long been the treatment of choice in many parts of the world, and a pasteurized formula received FDA approval in October 2009 for treating attacks. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a bradykinin receptor antagonist, were approved in December 2009 and August 2011, respectively, for treatment of acute attacks. A recombinant C1-INH product is in late development stages for treating acute attacks. These new treatments provide symptom relief within hours, dramatically shorten attack duration, and decrease mortality from airway compromise. For the first time, US physicians have rapid-acting and highly effective treatments for managing acute HAE attacks.

    Prospective, double-blind, placebo-controlled trials of ecallantide for acute attacks of hereditary angioedema

    Stolz LE, Sheffer AL. 1/2012 Expert Review of Clinical Immunology

    Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, episodic, incapacitating attacks of well-demarcated angioedema in the absence of urticaria and pruritus. HAE is due to deficient or dysfunctional C1-esterase inhibitor activity, which results in unopposed activation of plasma kallikrein, resulting in increased levels of bradykinin. Ecallantide is a potent and specific plasma kallikrein inhibitor approved for the treatment of acute attacks of HAE affecting any anatomic site. In Phase III clinical trials, subcutaneously administered ecallantide demonstrated significant, rapid and durable symptom relief. Ecallantide was effective for all attack types, including potentially life-threatening laryngeal attacks. The main safety concern is potentially serious hypersensitivity reactions, including anaphylaxis. Ecallantide represents an important treatment option for the management of acute attacks of HAE.

    Available from: http://www.tandfonline.com/doi/full/10.1586/eci.11.81

    Recombinant C1-inhibitor: effects on coagulation and fibrinolysis in patients with hereditary angioedema

    Relan A, Bakhtiari K, van Amersfoort ES, Meijers JC, Hack CE. 2/2012 Biodrugs

    BACKGROUND: Recombinant human C1-inhibitor (rhC1INH; Ruconest) has been developed for treatment of acute angioedema attacks in patients with hereditary angioedema (HAE) due to heterozygous deficiency of C1INH. Previous reports suggest that administration of plasma-derived C1INH products may be associated with an increased risk for thromboembolic complications.

    OBJECTIVES: Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients.

    METHODS: Levels of various coagulation and fibrinolytic parameters were determined in pre- and post-exposure plasma samples from HAE patients included in a randomized clinical trial. Patients were treated with either saline, or 50 or 100U/kg rhC1INH for an acute angioedema attack.

    RESULTS: Prior to rhC1INH treatment, the majority of patients had low to normal activated partial thromboplastin times (aPTT) and increased levels of prothrombin fragment 1+2, thrombin-antithrombin complexes, D-dimers and plasmin-antiplasmin complexes, all of which indicate activation of both coagulation and fibrinolysis. Infusion of rhC1INH at doses up to 100U/kg did not affect these parameters except for a dose-dependent prolongation of aPTT, confirming that rhC1INH is an inhibitor of the contact system, and that F1+2 levels decreased.

    CONCLUSION: Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1+2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients.

    Available from: http://link.springer.com/article/10.2165%2F11599490-000000000-00000

    Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema

    Plosker GL. 10/2012 Biodrugs

    Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation. The therapeutic efficacy of conestat alfa in the treatment of angioedema attacks in patients with HAE was evaluated in two similar randomized, double-blind, placebo-controlled trials conducted in North America and Europe. The randomized controlled phases of both studies were closed after interim analyses provided compelling evidence of statistically significant positive efficacy findings and showed no apparent adverse safety findings. Results of the pooled analysis of the two trials showed that conestat alfa provided significantly faster initial relief of symptoms than placebo. The median time to the beginning of relief of symptoms (primary endpoint) was 66 minutes with conestat alfa 100 units/kg, 122 minutes with conestat alfa 50 units/kg, and 495 minutes with placebo. Conestat alfa was also statistically superior to placebo for the secondary endpoint of median time to minimal symptoms, with values of 266, 247, and 1210 minutes for the respective treatment groups. On the basis of data from open-label extension studies and integrated analyses of clinical trial data, conestat alfa has demonstrated efficacy in the treatment of repeated HAE attacks and in patients with potentially life-threatening HAE attacks with involvement of the upper airways. Conestat alfa was generally well tolerated in clinical trials, with the most frequently reported adverse event being headache. In the two randomized controlled trials, headache and vertigo were the only adverse events deemed to be related to study treatment.

    Available from: http://link.springer.com/article/10.1007/BF03261889

    Safety and efficacy of icatibant self-administration for acute hereditary angioedema

    Boccon-Gibod I, Bouillet L. 6/2012 Clinical and Experimental Immunology

    We evaluated the efficacy and safety of icatibant self-administration in 15 patients with hereditary angioedema (HAE) types I or III, for 55 acute attacks (mostly severe or very severe). Icatibant self-administration was generally effective: first symptom improvement occurred in 5 min-2 h (HAE type I; n = 17) and 8 min-1 h (HAE type III; n = 9) for abdominal attacks and 5-30 min (HAE type I; n = 4) and 10 min-12 h (HAE type III; n = 6) for laryngeal attacks. Complete symptom resolution occurred in 15 min-19 h (HAE type I; n = 8) and 15 min-48 h (HAE type III; n = 9) for abdominal attacks and 5-48 h (HAE type I; n = 3) and 8-48 h (HAE type III; n = 5) for laryngeal attacks. No patient required emergency hospitalization. The only adverse events were mild, spontaneously resolving injection site reactions. Patients reported that carrying icatibant with them gave them greater confidence in managing their condition.Copyright © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390482/

    Safety and efficacy of physician-supervised self-managed C1 inhibitor replacement therapy

    Tourangeau LM, Castaldo AJ, Davis DK, Koziol J, Christiansen SC, Zuraw BL. 3/2012 International Archives of Allergy and Immunology

    BACKGROUND: C1 inhibitor (C1INH) has recently been approved in the USA for the treatment of acute attacks in hereditary angioedema (HAE) patients. The literature suggests that treatment with C1INH is most effective when administered early in an attack. Home infusion of C1INH allows for the earliest possible intervention since patients can initiate therapy at the first sign of symptoms.

    METHODS: We performed an observational, prospective study on 39 subjects with HAE utilizing two groups of patients: one receiving on-demand C1INH replacement therapy in a medical facility and the other self-managing on-demand C1INH replacement therapy in the home setting under the supervision of a treating physician. All subjects completed online questionnaires weekly for 8 weeks.

    RESULTS: There were statistically significant decreases in attack duration (p < 0.0001), pain medication use (p < 0.0001) and graded attack severity (p < 0.005) in the subjects who received C1INH in the home setting versus the clinic-based group. Attack frequency was similar between the groups. The home group experienced more frequent injection-related side effects; however, the clinic group noted more severe adverse events from C1INH.

    CONCLUSION: Physician-supervised self-managed C1INH replacement therapy is a safe and effective treatment for patients with HAE with potential benefits in diminishing attack duration and attack severity.Copyright © 2011 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/FullText/329635

    Safety and efficacy of prophylactic nanofiltered C1-inhibitor in hereditary angioedema

    Zuraw BL, Kalfus I. 9/2012 American Journal of Medicine

    OBJECTIVE: Nanofiltered C1-inhibitor (C1INH-nf) is approved for prophylactic treatment of hereditary angioedema. This study assessed the efficacy and safety of C1INH-nf as prophylactic therapy in a large cohort of patients with hereditary angioedema.

    METHODS: An open-label multicenter extension study was performed involving 146 subjects with hereditary angioedema who were treated with C1INH-nf for up to 2.6 years in centers throughout the United States. Subjects were to be treated with C1INH-nf 1000 units every 3 to 7 days. The primary efficacy variable was the number of attacks of angioedema experienced.

    RESULTS: Subjects experienced a 93.7% reduction in attacks while taking prophylactic C1INH-nf (0.19 attacks per month; interquartile range, 0.00-0.64) compared with the historical rate of attacks. Some 87.7% reported an attack frequency of 1 or less attack per month during prophylactic C1INH-nf and 34.9% had no attacks during the study. Some 7.5% of subjects experienced relatively frequent attacks despite twice-weekly C1INH-nf. Although twice-weekly dosing was highly effective in most subjects, once-weekly dosing provided adequate control in a subgroup of subjects. No clinical characteristics predicted the response to prophylactic C1INH-nf, including historical attack frequency. C1INH-nf was well tolerated.

    CONCLUSION: Prophylactic C1INH-nf is highly effective and safe, and provides durable prophylaxis in the majority of patients with hereditary angioedema. The recommended dose of C1INH-nf 1000 units twice weekly is supported by this open-label study. Individual patients may benefit from further dose adjustment on the basis of response to therapy and individual treatment goals.Copyright Published by Elsevier Inc.

    Available from: http://www.amjmed.com/article/S0002-9343%2812%2900381-6/fulltext

    Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor–a long-term survey

    Farkas H, Zotter Z, Csuka D, Szabo E, Nebenfuhrer Z, Temesszentandrasi G, et al. 12/2012 Allergy

    BACKGROUND: Hereditary angioedema is a potentially life-threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short-term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures.

    METHODS: We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1-INH concentrate, tranexamic acid, and danazol) administered for STP.

    RESULTS: Comparing surgical interventions performed without pre-event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher’s exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1-INH concentrate (Berinert() , CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher’s exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP.

    CONCLUSIONS: STP reduces the number of postprocedural edematous episodes. C1-INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions.Copyright © 2012 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12032/full

    Target levels of functional C1-inhibitor in hereditary angioedema

    Hack CE, Relan A, van Amersfoort ES, Cicardi M. 1/2012 Allergy

    BACKGROUND: Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks.

    METHODS: Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses.

    RESULTS: A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses >50 U/kg. This dose increases plasma C1INH activity in almost all patients to values >0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy.

    CONCLUSION: A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range.Copyright © 2011 John Wiley & Sons A/S.

     

    Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: investigation from the United States Food and Drug Administration adverse event reporting system database

    Gandhi PK, Gentry WM, Bottorff MB. 10/2012 Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy

    STUDY OBJECTIVE: To investigate reports of thrombotic events associated with the use of C1 esterase inhibitor products in patients with hereditary angioedema in the United States.

    DESIGN: Retrospective data mining analysis.

    SOURCE: The United States Food and Drug Administration (FDA) adverse event reporting system (AERS) database.

    MEASUREMENTS AND MAIN RESULTS: Case reports of C1 esterase inhibitor products, thrombotic events, and C1 esterase inhibitor product-associated thrombotic events (i.e., combination cases) were extracted from the AERS database, using the time frames of each respective product’s FDA approval date through the second quarter of 2011. Bayesian statistical methodology within the neural network architecture was implemented to identify potential signals of a drug-associated adverse event. A potential signal is generated when the lower limit of the 95% 2-sided confidence interval of the information component, denoted by IC025 , is greater than zero. This suggests that the particular drug-associated adverse event was reported to the database more often than statistically expected from reports available in the database. Ten combination cases of thrombotic events associated with the use of one C1 esterase inhibitor product (Cinryze) were identified in patients with hereditary angioedema. A potential signal demonstrated by an IC025 value greater than zero (IC025 = 2.91) was generated for these combination cases.

    CONCLUSION: The extracted cases from the AERS indicate continuing reports of thrombotic events associated with the use of one C1 esterase inhibitor product among patients with hereditary angioedema. The AERS is incapable of establishing a causal link and detecting the true frequency of an adverse event associated with a drug; however, potential signals of C1 esterase inhibitor product-associated thrombotic events among patients with hereditary angioedema were identified in the extracted combination cases.Copyright © 2012 Pharmacotherapy Publications, Inc.

    Available from: http://onlinelibrary.wiley.com/doi/10.1002/j.1875-9114.2012.01126/full

    Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis

    McCormack PL. 3/2012 Drugs

    Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving. In direct comparisons with other marketed agents, tranexamic acid was at least as effective as epsilon-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent.

    Available from: http://link.springer.com/article/10.2165%2F11209070-000000000-00000

    Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety

    Hofstra JJ, Kleine Budde I, van Twuyver E, Choi G, Levi M, Leebeek FW, et al. 3/2012 Clinical Immunology

    From 1997, plasma-derived C1-inhibitor concentrate (Cetor) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety.Copyright A© 2011 Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1521661611003330 (small fee)

    Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks

    Craig TJ, Bewtra AK, Hurewitz D, Levy R, Janss G, Jacobson KW, et al. 7/2012 Allergy and Asthma Proceedings

    Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981).

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2012/00000033/00000004/art00009

    Update on treatment of hereditary angioedema

    Buyantseva LV, Sardana N, Craig TJ. 6/2012 Asian Pacific Journal of Allergy and Immunology

    BACKGROUND: Hereditary Angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New therapies have recently emerged and are now available; however, many physicians are not aware of the new medications, and their indications and contraindications.

    OBJECTIVE: To update allergists and primary care physicians on new advances in HAE therapies.

    DATA SOURCES: A PubMed literature search was used to develop this manuscript.

    STUDY SELECTIONS: English language peer-reviewed angioedema articles were selected. High quality Phase II and III placebo-controlled clinical trials were reviewed and summarized.

    RESULTS: Until 2008, therapy for HAE consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side effects. Newer therapies include C1-inhibitor–both human plasma derived and recombinant–as well as contact system modulators such as ecallantide and icatibant. All of these products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis.

    CONCLUSION: New, disease-specific therapies have recently emerged which are more efficacious, are proven to work by placebo-controlled studies, have minimal adverse effects, and can be utilized for the treatment of HAE.

    Available from: thailand.digitaljournals.org/index.php/APJAI/article/viewFile/12235/11634

    Acute angioedema: recognition and management in the emergency department

    Jaiganesh T, Wiese M, Hollingsworth J, Hughan C, Kamara M, Wood P, et al. 2/2013 European Journal of Emergency Medicine

    Angioedema is characterized by localized swelling of subcutaneous tissues or mucosa of the upper respiratory or gastrointestinal tract. Laryngeal involvement may threaten airway patency and can be fatal if not addressed promptly. There are several distinct subtypes of angioedema, caused by different pathological processes involving a range of proinflammatory mediators. In the emergency department, it is essential not only that acute angioedema is identified as quickly as possible but also that the likely working diagnosis is established so that the most effective treatment may be administered to resolve potentially life-threatening swelling. In this paper, we present an overview of the various types of angioedema, and offer a practical diagnostic and therapeutic approach to their management.

    Available from: http://journals.lww.com/euro-emergencymed/Fulltext/2013/02000/Acute_angioedema___recognition_and_management_in.3.aspx

    Analysis of hereditary angioedema attacks requiring a second dose of ecallantide

    Li HH, Campion M, Craig TJ, Soteres DF, Riedl M, Lumry WR, et al. 3/2013 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Effective treatment of acute attacks is critical in managing hereditary angioedema (HAE). Ecallantide, a plasma kallikrein inhibitor, is approved for the treatment of HAE attacks. Occasionally, a second dose is needed when treating attacks of HAE.

    OBJECTIVE: To evaluate the characteristics of HAE attacks requiring a second dose (dose B) of ecallantide.

    METHODS: Data from all ecallantide clinical trials (EDEMA2, EDEMA4, and DX-88/19) that allowed an open-label dose B were included in this analysis. Patient and attack characteristics potentially predictive of dose B after ecallantide were analyzed by logistic regression. A multivariate model was built using a backward selection process, incorporating variables from the univariate model with P < .20 and removing factors with the highest P value until only significant (P < .05) factors remained.

    RESULTS: The analysis included 732 ecallantide-treated HAE attacks in 179 patients. Dose B was required in 88 attacks (12.0%), most (80.5%) for incomplete response. By attack location, 31 of 325 abdominal attacks (9.5%), 17 of 158 laryngeal attacks (10.8%), and 40 of 242 peripheral attacks (16.5%) required dose B. On the basis of the univariate analysis, baseline severity (odds ratio = 1.33, P = .15) and peripheral attack (odds ratio = 1.80, P = .01) were identified as potential predictive factors; abdominal attacks had an inverse correlation (odds ratio = 0.64, P = .055). However, the multivariate analysis identified only peripheral attacks as statistically significantly correlated (P < .05) with dose B requirement.

    CONCLUSION: A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE were more likely to require a second dose of ecallantide after 4 hours.

    TRIAL REGISTRATION: clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before registration requirements were implemented), NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2812%2900995-7/pdf

    Angio-oedema due to hereditary C1 inhibitor deficiency in children

    Caballero T. 1/2013 Allergol.Immunopathol.

    Hereditary angio-oedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare inherited disorder characterised by recurring and debilitating episodes of cutaneous swelling and abdominal pain and less frequent episodes of laryngeal oedema. Symptom onset is usually in childhood and early adolescence, with earlier disease onset associated with greater disease severity. Although HAE-C1-INH attacks are generally less frequent and less severe in children than in adults, they can cause significant physical and psychological impairment and affect advancement in school. There are often significant delays in the diagnosis of HAE-C1-INH due to its variable clinical presentation and because abdominal symptoms can often mimic other common paediatric gastrointestinal disorders. In recent years, several disease-specific agents have become available for the acute and prophylactic treatment of HAE-C1-INH. Although these treatments have not been evaluated rigorously in controlled clinical trials in children with HAE-C1-INH, paediatric data on efficacy and safety are available for some agents. Early diagnosis and initiation of appropriate therapy in children with HAE-C1-INH can help reduce the burden of this illness in the paediatric population. Copyright © 2011 SEICAP. Published by Elsevier Espana. All rights reserved.

    Available from: http://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-angio-oedema-due-to-hereditary-c1-90187212

    Assessment of hereditary angioedema treatment risks

    Kalaria S, Craig T. 11/2013 Allergy Asthma Proc.

    Therapies used for hereditary angioedema (HAE) have been associated with adverse events to include thrombosis, emboli, hepatocellular carcinoma (HCC), exacerbation of attacks, and anaphylaxis. It is difficult to determine incidence of these adverse events from the literature. For this reason we surveyed multiple HAE physicians to determine the risk associated with therapies used in HAE. This study was designed to determine by survey the risk of thrombosis associated with C1-inhibitor (C1-INH), worsening attacks with fresh frozen plasma (FFP), and carcinoma secondary to androgens (mainly danazol). An Internet-based survey was sent to physicians internationally who treat patients with HAE. The survey queried physicians about their observations while treating HAE. Of the 66 physicians who participated in the survey, 37 had patients (856 patients) who were on C1-INH but only 4 (total of 5 patients) had patients on C1-INH who experienced an thromboembolic episode. Of the 17 patients on C1 esterase inhibitor and an indwelling catheter, 3 experienced an embolic, thrombosis, or thromboembolic event. The likelihood of an abnormal event when a patient is on a C1-INH is 5/856 (0.6%), compared with 3/17 (18%) with a central catheter. The incidence of HCC is rare. The incidence of adverse effects to FFP is greater than the literature suggests. Patients with HAE should avoid indwelling catheters, use FFP only when other therapies are unavailable, and use androgens with caution. Most importantly, adverse events to drugs should be reported so that the true incidence of adverse events can be determined.

    2013 Nov-Dec;34(6):519-522

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000006/art00009 (small fee)

    Benefits of progestin contraception in non-allergic angioedema

    Saule C, Boccon-Gibod I, Fain O, Kanny G, Plu-Bureau G, Martin L, et al. 4/2013 Clinical and Experimental Allergy

    BACKGROUND: Hereditary angioedema attacks can be induced or worsened by oral contraceptive containing oestrogens.

    OBJECTIVES: The purpose of this study was to assess the impact of progestin contraceptives on angioedema attacks.

    METHODS: We conducted a French retrospective, multi-centre study of progestin contraception in women with non-allergic angioedema, including hereditary angioedema type I, II and III and idiopathic angioedema. Patients were classified into four groups according to frequency of attacks. We evaluated the effects of progestin on the mean number of attacks and compared the number of patients in each group before and under progestin contraception. The influence of hormonal factors on the course of angioedema was also assessed.

    RESULTS: Fifty-five women were included: mean age was 32.1 years (16-52) and mean follow-up 32.4 months (SD:29). Fourteen women were classified as type I (25.4%), two as type II (3.6%) and 19 as type III (34%) and 20 were idiopathic (36%). Seventeen patients were taking a low dose progestin-only pill (POP), 24 antigonadotropic progestins (AGP) and 14 both successively. Total or partial improvement was observed in 81.8% (45/55) of the patients and more frequently in those on an AGP agent (34 patients, 89.5%) than on POP (19 patients, 61.3%) (P = 0.013).

    CONCLUSIONS & CLINICAL RELEVANCE: This is the first study evaluating the interest of antigonadotropic progestin contraception in a series of women with non-allergic angioedema. Progestins, especially antigonadotropic progestins, appear to convey a marked benefit in most cases. Antigonadotropic progestins could thus be recommended as adjuvant treatment in childbearing women with non-allergic angioedema.Copyright © 2012 Blackwell Publishing Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/cea.12055/full

    C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies

    Schneider L, Hurewitz D, Wasserman R, Obtulowicz K, Machnig T, Moldovan D, et al. 2/2013 Pediatric Allergy and Immunology

    BACKGROUND: We analyzed the clinical response of pediatric and adolescent hereditary angioedema (HAE) patients to pdC1-INH in the International Multicenter Prospective Angioedema C1-INH Trials (I.M.P.A.C.T.) 1 and 2.

    METHODS: Patients included in this post hoc analysis of prospectively collected data were between 10 and 18 yr old with type I or II HAE and a documented history of abdominal or facial attacks. Patients received a single injection of pdC1-INH concentrate (Berinert() , CSL Behring, Marburg, Germany) 20 U/kg. Efficacy end-points were time from the administration of study drug to onset of symptom relief and time to complete relief of all symptoms.

    RESULTS: Seven pediatric patients were included in I.M.P.A.C.T.1 with only 1 attack analyzed per patient. Median time to onset of relief was 0.42 h and to complete resolution was 8.08 h. No patient experienced a worsening of symptoms during the 0-4-h assessment period. Nine patients who experienced a total of 115 attacks were included in the analysis of I.M.P.A.C.T.2. Abdominal attacks were rated as ‘severe’ more frequently than were other types of attacks. The number of attacks per patient ranged from 2 to 42, and study participation ranged from 1 to 38 months. Median times to onset of symptom relief and to complete symptom resolution were 0.49 h and 14.1 h, respectively. Of 4 treatment-emergent adverse events in both studies, only 2 were considered related to treatment.

    CONCLUSIONS: Study results showed that outcomes with pdC1-INH treatment of HAE in pediatric patients are comparable with outcomes in adults.Copyright © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/pai.12024/full

    Challenges of C1-inhibitor concentrate self-administration

    Boysen HB, Bouillet L, Aygoren-Pursun E. 5/2013 International Archives of Allergy and Immunology

    Self-administration of therapy can help hereditary angioedema (HAE) patients regain control of their disease or reduce its impact and improve the quality of their lives. However, data from a self-administration survey, and subsequent discussion at an international HAE expert meeting, identified several barriers to self-administration therapy. These barriers include difficulty in administration technique, availability of nursing resources and the mental capacity of the patient. Encouragingly, international HAE experts identified that once a patient has acquired self-administration skills, they generally retain them in the long-term. As patient uptake increases, it was recommended that follow-up management plans should be established to address any issues from the patient’s perspective.Copyright © 2013 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/FullText/351238

    Current pharmacotherapy of bradykinin-mediated angioedema

    Farkas H 4/2013 Expert Opinion on Pharmacotherapy

    INTRODUCTION: Bradykinin-mediated angioedema is characterized by subcutaneous and/or submucosal edema formation without wheals and pruritus. It is linked to bradykinin-enhanced vascular permeability and, therefore, it does not respond to conventional measures, but requires specific therapy.

    AREAS COVERED: This summary briefly reviews the different types of bradykinin-mediated angioedema and its remedies. Therapy focuses on relieving edema, as well as on decreasing its incidence and severity. The modes of the actions of attenuated androgens and antifibrinolytics are not precisely known – these agents have been introduced on an empirical basis. Contemporary treatments, by contrast, have been purposely developed to inhibit bradykinin. Most experience pertains to angioedema resulting from C1-inhibitor deficiency, and the controlled studies have focused on the hereditary form of this disease type (HAE). The pathomechanisms of HAE with normal C1-inhibitor activity, as well as of angiotensin-converting enzyme inhibitor-releated, and of non-histaminergic idiopathic sporadic angioedemas are largely unknown. Appropriate laboratory methods for the diagnosis, or specific interventions for the therapy of these conditions are not available or only available off-label.

    EXPERT OPINION: In this case, diagnosis and management are challenging. The range of targeted therapeutic options has increased in recent years and includes measures to handle emergencies, prevent edematous episodes and manage additional types of bradykinin-mediated angioedema.

    Available from: http://www.tandfonline.com/doi/full/10.1517/14656566.2013.778826

    Current status of implementation of self-administration training in various regions of Europe, Canada and the USA in the management of hereditary angioedema

    Caballero T, Sala-Cunill A, Cancian M, Craig TJ, Neri S, Keith PK, et al. 5/2013 International Archives of Allergy and Immunology

    Results from a 16-question survey about self-administration of hereditary angioedema (HAE) therapy, administered in Europe, Canada and the USA, were used to guide discussion at an international HAE expert meeting. The aim was to capture information about current practice in self-administered HAE therapy in these countries, including self-administration training, the key benefits of switching to self-administration, the barriers to self-administration and trends in self-administration. Overall, switching to self-administration therapy is looked upon favourably from both patient and clinician perspectives by virtue of the potential improvement in quality of life arising from optimisation of therapy and early intervention. The recent changes to product licences allowing self-administration provide additional options for the management of HAE.Copyright © 2013 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/FullText/35123

    Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks

    Craig TJ, Rojavin MA, Machnig T, Keinecke HO, Bernstein JA. 09/2013 Ann.Allergy Asthma Immunol.

    BACKGROUND: C1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation.

    OBJECTIVE: To assess the effect of time to treatment (6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy.

    METHODS: A post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open-label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies.

    RESULTS: In IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment.

    CONCLUSION: Early treatment with C1-INH (6 hours), supporting the international recommendation to treat HAE attacks as early as possible.

    TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981. Copyright 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    2013 Sep;111(3):211-215

    Available from: http://www.annallergy.org/article/S1081-1206%2813%2900440-7/fulltext (small fee)

     

    Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study

    Lumry WR, Bernstein JA, Li HH, MacGinnitie AJ, Riedl M, Soteres DF, et al. 3/2013 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with >12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000002/art00007?token=005114fbb74241333c4a2f7a6c38762c4b415d766634704f6d6222346b62687630502183342ef57eb (small fee)

    Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

    Riedl MA, Levy RJ, Suez D, Lockey RF, Baker JW, Relan A, et al. 4/2013 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: The efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies.

    OBJECTIVE: To assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE.

    METHODS: In this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events.

    RESULTS: Sixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH.

    CONCLUSION: The results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2813%2900101-4/abstract

    Factors associated with hospitalization of patients with angiotensin-converting enzyme inhibitor-induced angioedema

    Gang C, Lindsell CJ, Moellman J, Sublett W, Hart K, Collins S, et al. 05/2013 Allergy Asthma Proc.

    Angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema can be life-threatening without emergent intervention. The putative mediator is believed to be bradykinin, similar to hereditary angioedema, so these patients respond poorly to corticosteroids and antihistamines. This study was designed to determine characteristics and clinical outcomes of patients presenting to an emergency department (ED) with ACE-I angioedema. This was a retrospective chart review of 100 patients presenting to the ED from 2007 to 2008 with an ICD-9 code of 995.1 (angioedema) or 995.2 (drug-induced angioedema). Two hundred fifty-two patients with these ICD-9 codes were identified and placed in random order, and the first 100 meeting inclusion criteria were included. Statistical analysis was primarily descriptive. All 100 patients had an ICD-9 code of 995.1 (angioedema). Patients presented in every month, with spring months (April-June) having the most presentations (32%). The median age was 59 years, 75% were African American, and 66% were admitted to the hospital. Two patients (2%) required endotracheal intubation. Lisinopril was the most commonly prescribed ACE-I (84%). The most common symptom was moderate lip and tongue swelling (89%) followed by mild difficulty breathing (12%). Tongue swelling was significantly associated with admission. Time from symptom onset to ED presentation was not associated with need for admission. Concomitant medications did not differ between admitted and discharged patients. ACE-I angioedema is associated with significant morbidity and health care use because many patients require hospitalization, suggesting an unmet need for novel therapies targeted to treat this condition.

    2013 May-Jun;34(3):267-273

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000003/art00012 (small fee)

    Farkas H.

    Current pharmacotherapy of bradykinin-mediated angioedema. 4/2013 Expert Opinion on Pharmacotherapy

    INTRODUCTION: Bradykinin-mediated angioedema is characterized by subcutaneous and/or submucosal edema formation without wheals and pruritus. It is linked to bradykinin-enhanced vascular permeability and, therefore, it does not respond to conventional measures, but requires specific therapy.

    AREAS COVERED: This summary briefly reviews the different types of bradykinin-mediated angioedema and its remedies. Therapy focuses on relieving edema, as well as on decreasing its incidence and severity. The modes of the actions of attenuated androgens and antifibrinolytics are not precisely known – these agents have been introduced on an empirical basis. Contemporary treatments, by contrast, have been purposely developed to inhibit bradykinin. Most experience pertains to angioedema resulting from C1-inhibitor deficiency, and the controlled studies have focused on the hereditary form of this disease type (HAE). The pathomechanisms of HAE with normal C1-inhibitor activity, as well as of angiotensin-converting enzyme inhibitor-releated, and of non-histaminergic idiopathic sporadic angioedemas are largely unknown. Appropriate laboratory methods for the diagnosis, or specific interventions for the therapy of these conditions are not available or only available off-label.

    EXPERT OPINION: In this case, diagnosis and management are challenging. The range of targeted therapeutic options has increased in recent years and includes measures to handle emergencies, prevent edematous episodes and manage additional types of bradykinin-mediated angioedema.

    HAE update: determining optimal patient specific therapy

    Gower RG. 1/2013 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by deficient or dysfunctional C1 inhibitor (C1 INH). HAE patients experience recurrent episodes of angioedema affecting the extremities, face, genitalia or submucosal edema in the abdomen or upper airway. Laryngeal attacks can be fatal. The determination of optimal therapy should be based on individualization of patient history and preferences. The parameters include attack frequency, location, severity and burden of illness on quality of life. Patients with HAE need medications for acute attacks; some also require prophylaxis. This is an overview of HAE treatments currently available in the US and how to individualize therapy for patients based on their circumstances. A literature search was performed for HAE and therapeutic modalities currently available. HAE guidelines and randomized, controlled clinical trials were evaluated. There are several options for acute and prophylactic treatment of HAE that have been approved by the Food and Drug Administration. Acute treatments include C1 INH, a replacement therapy; ecallantide, a kallikrein inhibitor; and icatibant, a bradykinin-2 receptor antagonist. Prophylactic treatments include attenuated androgens and C1 INH. These options have been proven safe and effective in clinical trials. Optimal therapy is based on the individual patients need regarding on-demand therapy and/or prophylactic therapy, short-term or long-term. Patients with HAE have individual requirements, based on the nature and frequency of past attacks, occupation, proximity to trained medical personnel, and patient preference. These factors should be used to create a patient-centered approach to management of HAE.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000001/art00004?crawler=true&mimetype=application/pdf

    HAE update: special considerations in the female patient with hereditary angioedema

    Geng B, Riedl MA. 1/2013 Allergy and Asthma Proceedings

    This review on hereditary angioedema (HAE) focuses on special topics regarding HAE in female patients. HAE is a bradykinin-mediated disorder, and the role of hormonal regulation of disease expression will be discussed focusing on the effect of estrogen on disease mechanism. The impact of exogenous estrogen on symptom exacerbation leads to special consideration regarding choice of contraceptives and safety of hormone replacement therapy. The effects of pregnancy and childbirth will be examined on the course of disease control. Unique considerations regarding therapeutic management for female HAE patients will be addressed, including the role of C1 inhibitor (C1-INH), ecallantide, and icatibant. Finally, this review will provide an overview of the more recently characterized HAE with normal C1-INH (HAE type III) that predominantly affects women and is in some cases associated with factor XII gene mutations.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000001/art00006

    Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment

    Maurer M, Aberer W, Bouillet L, Caballero T, Fabien V, Kanny G, et al. 2/2013 PLoS ONE

    BACKGROUND: Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B(2) receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking.

    OBJECTIVE: To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks.

    METHODS: The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009-February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients.

    RESULTS: Attack duration was significantly shorter in patients treated 1 hour (6.1 hours versus 16.8 hours [p 1 hour (6.1 hours versus 16.8 hours [p 2 hours (7.2 hours versus 20.2 hours [p 2 hours (7.2 hours versus 20.2 hours [p 5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional.

    CONCLUSION: Early blockade of the bradykinin B(2) receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563637/

    Hereditary angioedema in women: specific challenges

    Bouillet L, Gompel A. 11/2013 Immunol.Allergy Clin.North.Am.

    Women with hereditary angioedema (HAE) present with more frequent and more severe attacks than men. The disease is often affected by estrogenic status. Estrogens increase kininogenase activities. Deliveries seem to be safe but it is advised to have C1 inhibitor (C1Inh) concentrate in the delivery room; in case of worsening during the pregnancy, it is recommended to use short-term prophylaxis with C1Inh concentrate. Women often badly tolerate attenuated androgen: 30% of women have weight gain, 30% irregular menstruations, and 6% virilization. Acid tranexamic and progestins are preferred for long-term prophylaxis for women with HAE. Copyright 2013 Elsevier Inc. All rights reserved.

    2013 Nov;33(4):505-511

    Available from: http://www.sciencedirect.com/science/article/pii/S088985611300057X (small fee)

    Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patients.

    Bouillet L. Launay D. Fain O. Boccon-Gibod I. Laurent J. Martin L. Montauban V. Finck K. Bouee S. Gompel A. Kanny G. French National Reference Center for Hereditary Angioedema (CREAK). 10/2013 Ann.Allergy Asthma Immunol

    BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. New specific treatments are available.

    OBJECTIVE: To identify patients’ features and patients’ best therapeutic option.

    METHODS: A 1-year, multicenter, retrospective study was performed. The primary objective was to examine the clinical presentation of HAE. Secondary objectives included patient characteristics, management of HAE over 12 months, and health-related quality of life using the SF-36v2 questionnaire.

    RESULTS: One hundred ninety-three patients were included, and 69.4% were women. In the 12-month period, the mean number of HAE attacks was 7.6. Among the 568 reported attacks, localizations were the abdomen (57.1%), peripheral limbs (42.5%), upper airway (7.9%), and face (6.9%); 31.6% of attacks were severe and occurred statistically more often in women (P < .02). Compared with a population of allergic patients, all age- and sex-adjusted scores were significantly lower in patients with HAE (P < .05) except for the physical component summary. Health-related quality of life negatively correlated with the annual number of attacks and was markedly altered for patients having more than 5 attacks per year (P < .05 for all dimensions).

    CONCLUSION: HAE is a severe disease that places a heavy burden on quality of life. Copyright 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    2013 Oct;111(4):290-294

    Available from: http://www.annallergy.org/article/S1081-1206%2813%2900491-2/fulltext (small fee)

    Hereditary angioedema: a bradykinin-mediated swelling disorder

    Bjorkqvist J, Sala-Cunill A, Renne T. 3/2013 Thrombosis and Haemostasis

    Edema is tissue swelling and is a common symptom in a variety of diseases. Edema form due to accumulation of fluids, either through reduced drainage or increased vascular permeability. There are multiple vascular signalling pathways that regulate vessel permeability. An important mediator that increases vascular leak is the peptide hormone bradykinin, which is the principal agent in the swelling disorder hereditary angioedema. The disease is autosomal dominant inherited and presents clinically with recurrent episodes of acute swelling that can be life-threatening involving the skin, the oropharyngeal, laryngeal, and gastrointestinal mucosa. Three different types of hereditary angiodema exist in patients. The review summarises current knowledge on the pathophysiology of hereditary angiodema and focuses on recent experimental and pharmacological findings that have led to a better understanding and new treatments for the disease.

    Available from: www.schattauer.de/index.php?id=5236&mid=19201

    How benign is hematuria? Using genetics to predict prognosis

    Gale DP. 08/2013 Pediatr.Nephrol.

    Hematuria is a common presenting feature of glomerular disease and is sometimes associated with kidney failure later in life. Where isolated microscopic hematuria occurs in children and young adults, an underlying monogenic disorder, such as Alport syndrome or thin basement membrane nephropathy, is frequently responsible. In this review, these and other diseases, which often present with isolated microscopic hematuria, including hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome, IgA nephropathy, and CFHR5 nephropathy, are discussed together with the associated molecular pathology, clinical features, and prognosis. Genetic testing for these conditions used in clinical practice can provide important diagnostic and prognostic information that is relevant to the patient and their family, particularly when kidney transplantation is considered.

    2013 Aug;28(8):1183-1193

    Available from: http://link.springer.com/article/10.1007%2Fs00467-012-2399-y (small fee)

    Icatibant for the treatment of hereditary angioedema

    Cole SW, Lundquist LM. 1/2013 Annals of Pharmacotherapy

    OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, and safety of icatibant, a recently approved bradykinin B(2) receptor antagonist for treatment of acute attacks of hereditary angioedema (HAE).

    DATA SOURCES: Articles indexed in MEDLINE (1948-June 2012), International Pharmaceutical Abstracts (1970-May 2012), and Cumulative Index to Nursing and Allied Health Literature (1981-June 2012) were identified using the search terms icatibant, bradykinin B(2) receptor antagonist, and hereditary angioedema. Additional references were identified from the reference lists of the articles identified.

    STUDY SELECTION AND DATA EXTRACTION: English-language articles were reviewed.

    DATA SYNTHESIS: Icatibant was evaluated in 3 Phase 3 clinical trials and found to be a safe and effective option for treatment of acute HAE. Icatibant was compared to placebo in 2 clinical trials (FAST-1 and FAST-3) and to tranexamic acid in the FAST-2 trial. Patients receiving icatibant in FAST-1 did not experience a significant improvement in median time to clinically significant relief of the index symptom (p = 0.14), whereas patients receiving icatibant in FAST-3 experienced a significant improvement in median time to at least 50% reduction in symptom severity (p < 0.001). When icatibant was compared to tranexamic acid in FAST-2, the median time to clinically significant relief of the index symptom was shorter for patients receiving icatibant (p < 0.001). The most common adverse events associated with the administration of icatibant were injection-site reactions, which were mild to moderate and transient. These data suggest that icatibant is a safe and effective treatment for acute attacks of HAE. Although direct comparisons of recently approved alternatives for treatment of acute attacks are lacking, there are administration advantages of icatibant over other agents. Additionally, the cost of icatibant is comparable to that of the C1 esterase inhibitor Berinert and less expensive than ecallantide.

    CONCLUSIONS: Available efficacy data support that icatibant should be considered a safe and effective treatment for acute attacks of HAE. Additionally, limited treatment options for this rare condition, ease of administration, and comparable cost profile support its consideration for formulary inclusion.

    Available from: http://aop.sagepub.com/content/47/1/49.long (small fee)

    Immunosafety of recombinant human C1-inhibitor in hereditary angioedema: evaluation of ige antibodies

    Hack CE, Relan A, Baboeram A, Oortwijn B, Versteeg S, van Ree R, et al. 4/2013 Clinical Drug Investigation

    BACKGROUND: Recombinant human C1-inhibitor (rhC1INH) purified from milk of transgenic rabbits is used for the treatment of acute attacks in patients with hereditary angioedema (HAE) due to C1-inhibitor (C1INH) deficiency.

    OBJECTIVE: The objective was to investigate the risk of rhC1INH inducing IgE antibodies or eliciting anaphylactic reactions.

    METHODS: In subjects treated with rhC1INH, we retrospectively analysed the frequency and clinical relevance of pre-exposure and potentially newly induced IgE antibodies against rabbit and other animal allergens including cow’s milk by the ImmunoCAP() Specific IgE blood test system.

    RESULTS: 130 HAE patients and 14 healthy subjects received 300 administrations of rhC1INH, 65 subjects (47.4 %) on one occasion; 72 (52.6 %) on at least two occasions (range 2-12; median 2). Five subjects had pre-existing anti-rabbit epithelium IgE; the subject with the highest levels and a previously undisclosed rabbit allergy developed an anaphylactic reaction upon first exposure to rhC1INH, whereas the other four subjects with lower pre-existing IgE levels (Class 1-3), did not. No other anaphylactic reactions were identified in any of the subjects exposed to rhC1INH. Analysis of post-exposure samples revealed that the risk of inducing new or boosting existing IgE responses to rabbit or cow’s milk allergens was negligible.

    CONCLUSION: The propensity of rhC1INH to induce IgE antibodies following repeated administration of rhC1INH is low. Subjects with substantially elevated anti-rabbit epithelium IgE antibodies and/or clinical allergy to rabbits may have an increased risk for an allergic reaction. No other risk factors for allergic reactions to rhC1INH have been identified.

    Available from: http://link.springer.com/article/10.1007%2Fs40261-013-0064-2

    Inhibition of the serine proteases of the complement system

    Gal P, Dobo J, Beinrohr L, Pal G, Zavodszky P. /2013 Advances in Experimental Medicine and Biology

    Proteases play important roles in human physiology and pathology. The complement system is a proteolytic cascade, where serine proteases activate each other by limited proteolysis in a strictly ordered manner. Serine proteases are essential in both the initiation and the amplification of the cascade. Since uncontrolled complement activation contributes to the development of serious disease conditions, inhibition of the complement serine proteases could be an attractive therapeutic approach. In this chapter, we give a brief overview of the major types of natural serine protease inhibitors and their role in controlling the complement cascade. A special emphasis is laid on C1-inhibitor, a natural complement protease inhibitor, which is approved for clinical use in hereditary angioedema (HAE). We also examine the potential of developing artificial complement protease inhibitors. Synthetic small-molecule drugs can be very efficient serine protease inhibitors, but they usually lack sufficient specificity. A promising approach to yield more specific compounds is the alteration of natural protease inhibitors through engineering or directed evolution resulting in new variants with fine-tuned specificity and enhanced affinity.

    Available from: http://link.springer.com/chapter/10.1007/978-1-4614-4118-2_2

    Leukocytosis and high hematocrit levels during abdominal attacks of hereditary angioedema

    Ohsawa I, Nagamachi S, Suzuki H, Honda D, Sato N, Ohi H, et al. 01/2013 BMC Gastroenterol.

    BACKGROUND: The diagnosis of hereditary angioedema (HAE) is often delayed due to the low awareness of this condition. In patients with undiagnosed HAE, abdominal symptoms often create the risk of unnecessary surgical operation and/or drug therapy. To explore the cause of misdiagnosis, we compared the laboratory findings of HAE patients under normal conditions with those during abdominal attacks.

    METHODS: Patient medical histories were analyzed and laboratory data at the first consultation with no symptoms and no medication were compared with those at visits to the emergency department during severe attacks.

    RESULTS: Fourteen HAE patients were enrolled. Initial HAE symptoms occurred at 20.2 + 9.4 years of age. The correct diagnosis of HAE was made 22.7 + 14.2 years after the initial symptoms. A common site of angioedema was the extremities. Half of the patients experienced a life-threatening laryngeal attack and/or severe abdominal pain. In the patients with severe abdominal pain, significant leukocytosis with neutrophilia along with increased levels of hematocrit were observed while levels of C-reactive protein (CRP) remained low. All severe attacks were alleviated with an infusion of C1-inhibitor concentrate.

    CONCLUSIONS: Consideration of the likelihood of a HAE attack is important when patients present with acute abdominal pain and leukocytosis without elevation of CRP.

    2013;13:123

    Available from: http://www.biomedcentral.com/1471-230X/13/123 (free)

    Management and prevention of hereditary angioedema attacks

    Lumry WR. 06/2013 Am.J.Manag.Care

    Hereditary angioedema (HAE) is a rare genetic syndrome caused by a deficiency in functional C1 inhibitor that results in recurrent episodes of nonpruritic swelling of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx beginning in childhood or adolescence and continuing throughout the patient’s lifetime. Treatment for acute HAE attacks in the United States has been transformed by new therapies that inhibit the underlying mechanisms of angioedema- notably ecallantide, a potent and specific inhibitor of plasma kallikrein, and icatibant, a selective bradykinin receptor antagonist. These treatments, combined with safer formulations of plasma-derived C1 esterase inhibitor concentrate for HAE prophylaxis and acute treatment, have greatly improved the quality of life for people with HAE, many of whom can now lead fairly normal lives. This article reviews the current therapeutic landscape for HAE, including treatment for acute angioedema attacks, short- and long-term HAE prophylaxis, and home-based therapy.

    2013 Jun;19(7 Suppl):s111-8

    Available from: http://www.ajmc.com/publications/supplement/2013/ACE010_13jun_HAE_CE/ACE010_Lumry2_S111to18/ (free)

    Management of dental-oral procedures in patients with hereditary angioedema due to C1 inhibitor deficiency

    Jurado-Palomo J, Munoz-Caro JM, Lopez-Serrano MC, Prior N, Cabanas R, Pedrosa M, et al. /2013 Journal of Investigational Allergology and Clinical Immunology

    BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH.

    MATERIAL AND METHODS: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. RESULTS: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P = .002, Fisher exact test).

    CONCLUSIONS: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity.

    Available from: http://www.jiaci.org/issues/vol23issue1/vol23issue01-1.htm

    Management of hereditary angioedema

    Dempster J. 5/2013 Nursing Standard

    Hereditary angioedema is characterised by unpredictable, painful and potentially life-threatening oedema. Recently, some C1 inhibitors have been approved for self-administration and/or routine prevention, enabling patients to be proactive in managing their disease and reducing the burden of illness. This article discusses the effect of these advances from a specialist nurse’s perspective.

    Available from: http://journals.rcni.com/doi/abs/10.7748/ns2013.05.27.37.35.e7336?journalCode=ns

    Management of hereditary angioedema in 2012: scientific and pharmacoeconomic perspectives

    Tilles SA, Borish L, Cohen JP. 2/2013 Annals of Allergy, Asthma, and Immunology

    Available from: http://www.annallergy.org/article/S1081-1206%2812%2900939-8/fulltext

    Managing hereditary angioedema patients undergoing otolaryngeal procedures.

    Bernstein JA. 11/2013 Am.J.Rhinol.Allergy

    BACKGROUND: Hereditary angioedema (HAE), a rare autosomal dominant disorder, is characterized by repeated attacks of swelling of the skin, gastrointestinal tract, face, larynx, and other organs. In most cases it is caused by low levels of functional C1 esterase inhibitor (C1-INH), a serine protease inhibitor that plays important regulatory roles in the complement, contact, and fibrinolytic pathways.

    METHODS: Lack of functional C1-INH results in excessive release of bradykinin, which triggers vasodilation, vascular permeability, and edema. Most attacks are mild and self-limiting, but untreated laryngeal attacks may cause rapid asphyxiation and death. Potential triggers of laryngeal attacks include trauma to or manipulation of the face, mouth, or upper airway. Therefore, before performing such a procedure in a patient with HAE, the otolaryngologist should consult with the patient, the physician managing the HAE, and the anesthesiologist and make appropriate preparations for prevention and/or treatment of an attack.

    RESULTS: Current World Allergy Organization and European guidelines recommend the use of i.v. plasma-derived C1-INH replacement for short-term prophylaxis of angioedema attacks. Other effective options include danazol given for several days before and after the procedure and fresh-frozen plasma, but these may not be as effective as C1-INH and may be associated with a high rate of adverse events.

    CONCLUSION: Acute attacks, which may occur many hours after a procedure, may be treated with C1-INH; icatibant, a bradykinin B2-receptor antagonist; or ecallantide, a kallikrein inhibitor, all of which have been shown to reduce the duration and severity of HAE attacks.

    2013 Nov-Dec;27(6):522-527

    Available from: http://www.ingentaconnect.com/content/ocean/ajra/2013/00000027/00000006/art00026 (small fee)

    Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women

    Baker JW, Craig TJ, Riedl MA, Banerji A, Fitts D, Kalfus IN, et al. 3/2013 Allergy and Asthma Proceedings

    Data are limited on hereditary angioedema (HAE) in pregnant women and the safety and efficacy of therapies for treatment and prevention of HAE attacks during pregnancy. Prospective studies are unlikely given the rarity of HAE and ethical considerations regarding enrollment of pregnant female subjects in clinical trials. A retrospective analysis of clinical trial and compassionate-use data was conducted to identify subjects who received nanofiltered C1 esterase inhibitor (C1 INH-nf; human) during pregnancy. This study evaluates the efficacy and safety of human C1 INH-nf for treatment and prevention of HAE attacks in pregnant women. Data from pregnant subjects enrolled in either open-label extensions of two randomized, double-blind, placebo-controlled trials of C1 INH-nf or in a compassionate-use program were retrospectively analyzed for efficacy (e.g., total attacks, attack frequency during prophylaxis, and monthly attack rates) and safety (e.g., pregnancy outcomes and adverse events). C1 INH-nf was administered as acute treatment, preprocedural prophylaxis, or routine prophylaxis. C1 INH-nf prophylaxis substantially reduced monthly attack rates. Of 16 subjects, 13 delivered 14 healthy neonates (1 set of twins). Two adverse fetal outcomes were reported; neither was considered by the principal investigator to be related to C1 INH-nf. One subject’s pregnancy outcome was unknown. This analysis shows a favorable risk-benefit profile for C1 INH-nf for managing HAE during pregnancy. NCT Identifier: NCT00438815; NCT00462709.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000002/art00008

    Nanofiltered C1 esterase inhibitor for treatment of laryngeal attacks in patients with hereditary angioedema

    Riedl MA, Lumry WR, Li HH, Craig TJ, Fitts D, Kalfus I, et al. 11/2013 The American Journal of Rhinology and Allergy

    BACKGROUND: Laryngeal edema is a life-threatening manifestation of hereditary angioedema (HAE), an autosomal-dominant disorder caused by quantitative or functional C1 esterase inhibitor (C1 INH) deficiency. The preparation of nanofiltered C1 INH (C1 INH-nf) used in this study is indicated for routine prophylaxis against angioedema attacks in the United States and for treatment, preprocedure prevention, and routine prevention of HAE in Europe. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when used for the treatment of laryngeal attacks.

    METHODS: A post hoc analysis of an open-label treatment study evaluated the effectiveness of C1 INH-nf in the treatment of laryngeal attacks in patients with HAE. Outcomes included unequivocal or clinical relief rates and time from treatment to onset of relief. Data were compiled from this and three other studies for post hoc dosing and tolerability analyses. In all studies, C1 INH-nf at 1000 U was administered i.v., with a second 1000-U dose given after 60 minutes if indicated.

    RESULTS: In the open-label treatment study, 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. Time to unequivocal relief was shorter with prompt treatment. When C1 INH-nf was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Of 265 attacks from the four studies, 62% received two 1000-U doses of C1 INH-nf. No serious adverse events occurring within 7 days after treatment were attributed to study drug, and only one patient required intubation after receiving C1 INH-nf (14.5 hours after symptom onset).

    CONCLUSION: This analysis supports that C1 INH-nf is an effective and well-tolerated therapy for laryngeal angioedema attacks.

    Available from: http://www.ingentaconnect.com/content/ocean/ajra/2013/00000027/00000006/art00025

    Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children

    Lumry W, Manning ME, Hurewitz DS, Davis-Lorton M, Fitts D, Kalfus IN, et al. 5/2013 Journal of Pediatrics

    OBJECTIVES: To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies.

    STUDY DESIGN: In the acute-attack treatment studies, the efficacy of 1000 U of C1 INH-nf (with an additional 1000 U given 1 hour later if needed) was assessed based on the time to the start of symptomatic relief and the proportion of patients experiencing relief within 4 hours of therapy. In the prophylaxis studies, C1 INH-nf 1000 U was given twice weekly, and efficacy was based on the frequency of attacks.

    RESULTS: Across 4 studies, 46 children received a total of 2237 C1 INH-nf infusions. The median time to the start of unequivocal relief in the acute-attack treatment study (n = 12) was 30 minutes with C1 INH-nf, compared with 2 hours for placebo. In the open-label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. In the prophylaxis study (n = 4), the number of attacks was reduced by approximately 2-fold with C1 INH-nf compared with placebo. In the prophylaxis open-label extension (n = 23), the median monthly attack rate decreased from 3.0 before treatment to 0.39 with C1 INH-nf use.

    CONCLUSION: In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks.Copyright © 2013 Mosby, Inc. All rights reserved.

    Available from: http://www.jpeds.com/article/S0022-3476%2812%2901364-9/fulltext

    New drugs to treat hereditary angioedema

    Scheinfeld N. 11/2013 Skinmed

    2013 Nov-Dec;11(6):357-359

    Available from: http://issuu.com/pulsemarketing/docs/skinmed_v11_i6?e=5397957/6430954 (free, starting on page 39 of 68)

    Ongoing contact activation in patients with hereditary angioedema

    Konings J, Cugno M, Suffritti C, Ten Cate H, Cicardi M, Govers-Riemslag JW. 01/2013 PLoS ONE

    Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.

    2013;8(8):e74043

    Available from: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0074043 (free)

    Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks

    Sheffer AL, MacGinnitie AJ, Campion M, Stolz LE, Pullman WE. 3/2013 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare disorder associated with episodic attacks of well-demarcated angioedema. Attacks that affect the larynx can result in life-threatening airway obstruction.

    OBJECTIVES: To examine efficacy and safety of ecallantide treatment for laryngeal HAE attacks.

    METHODS: Data were combined from 4 clinical studies (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) evaluating 30 mg of subcutaneous ecallantide for treatment of acute HAE attacks. Efficacy was assessed using 2 validated, HAE-specific, patient-reported outcome measures. The change in Mean Symptom Complex Severity (MSCS) score indicates change in symptom severity; a negative score indicates improvement. The calculated minimally important difference (MID) for change in severity is -0.30. The Treatment Outcome Score (TOS) measures treatment response. A positive score indicates improvement; the calculated MID is 30. RESULTS: Overall, 98 patients received ecallantide for 220 laryngeal attacks. The mean +/- SD change in MSCS score was -1.1 +/- 0.73 and -1.6 +/- 0.68 at 4 and 24 hours, respectively. The mean +/- SD TOS was 73.5 +/- 35.8 and 85.5 +/- 27.8 at 4 and 24 hours, respectively. Median time to significant improvement was 185 minutes (95% confidence interval, 167-226). One attack required intubation. Four treatment-emergent serious adverse events were reported, including 2 HAE attacks that resulted in hospitalization and 2 anaphylactic reactions. One of these reactions required treatment with epinephrine, but both patients recovered fully. There were no deaths.

    CONCLUSION: In this large attack series, ecallantide was effective for treatment of laryngeal HAE attacks. There is a risk of hypersensitivity, including anaphylaxis, consistent with product labeling. As such, ecallantide should be administered under the supervision of a health care professional.

    TRIAL REGISTRATION: clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before implementation of registration requirements); NCT00262080 for EDEMA3, NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(12)00998-2/fulltext

    Pharmacotherapy of chronic spontaneous urticaria

    Makris M, Maurer M, Zuberbier T. 12/2013 Expert Opin.Pharmacother.

    INTRODUCTION: Urticaria, by definition, is a disease presenting with wheals, angioedema or both. In patients with recurrent angioedema without wheals, urticaria needs to be distinguished from bradykinin-mediated angioedema, for example, hereditary angioedema or ACE inhibitor-induced angioedema. AREAS COVERED: Urticaria is comprised of acute and chronic forms. The latter group of chronic urticaria has many different subtypes needing partly different therapeutic approaches. However, all therapeutic approaches for symptomatic treatment center on reducing mast cell-mediator-release and preventing its effect.

    EXPERT OPINION: The current guidelines recommend non-sedating, second generation H1-antihistamines (nsAHs) as the first-line treatment. If needed, nsAHs are to be used at higher doses (up to fourfold the standard dose), and Omalizumab, Montelukast or Cyclosporin A (not in preferred order) are recommended as third-line options. Many alternative treatments have been reported but not tested in randomized controlled trials. These include among others dapsone, H2-antihistamines, anticoagulants and methotrexate. Some therapies should no longer be used according to current guidelines, since studies have shown their inefficacy or because new safety concerns have emerged. This mainly refers to the formally propagated use of sedating antihistamines at night, which change REM-sleeping-patterns and learning curves and have been shown in head-to-head trials to not be superior in efficacy to non-sedating antihistamines.

    2013 Dec;14(18):2511-2519

    Available from: http://informahealthcare.com/doi/abs/10.1517/14656566.2013.850490 (small fee)

    Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

    Farrell C, Hayes S, Relan A, van Amersfoort ES, Pijpstra R, Hack CE. 12/2013 Br.J.Clin.Pharmacol.

    AIMS: To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients.

    METHODS: Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme.

    RESULTS: A one-compartment model with Michaelis-Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839-0.968] and 0.176 U ml(-1) (95% CI: 0.154-0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68-3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml(-1) h(-1) (95% CI: 1.41-1.88) and 1.60 U ml(-1) (95% CI: 1.14-2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml(-1)) for at least 94% of all patients.

    CONCLUSIONS: The population PK model for C1INH supports a dosing scheme on a 50 U kg(-1) basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration. 2013 The British Pharmacological Society.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12132/full (small fee)

    Practical approach to self-administration of intravenous C1-INH concentrate: a nursing perspective

    Symons C, Rossi O, Magerl M, Andritschke K. 5/2013 International Archives of Allergy and Immunology

    At an international hereditary angioedema (HAE) expert meeting, results from a survey were used to guide discussion on how best to advise patients on self-administering intravenous C1 esterase inhibitor therapy. Treatment differences across Europe were highlighted, together with the practicalities of self-administration and useful resources for patients in the future. The international HAE experts noted an increase in the uptake of self-administration, with patients being trained by nursing staff. All patients who are willing and able to self-administer should be offered this treatment option and patients should be encouraged to treat attacks early. Several initiatives were suggested regarding support for patients who self-administer therapy, including a 24-hour helpline and home care agencies.Copyright © 2013 S. Karger AG, Basel.

    Available from : https://www.karger.com/Article/FullText/351236

    Recent advances in hereditary angioedema self-administration treatment: summary of an International Hereditary Angioedema Expert Meeting

    Craig TJ. 5/2013 International Archives of Allergy and Immunology

    Available from: https://www.karger.com/Article/FullText/351228

    Recent advances in the management of hereditary angioedema

    Hemperly SE, Agarwal NS, Xu YY, Zhi YX, Craig TJ. 07/2013  J.Am.Osteopath.Assoc.

    Hereditary angioedema (HAE) is a rare genetic condition that manifests as painful and potentially life-threatening episodic attacks of cutaneous and submucosal swelling. It results from functional deficiency of C1 inhibitor (C1 INH), which is a regulator of the complement, fibrinolytic, kinin (contact), and coagulation systems. In patients with HAE, the low plasma concentration of functional C1 INH leads to overactivation of the kinin cascade and local release of bradykinin. Bradykinin is responsible for the pain, vascular permeability changes, and edema associated with HAE. Until recently, therapeutic options for HAE have been very limited. Many new therapies have emerged, however, such as C1 INH replacement drugs and medications aimed at components of the contact system (eg, plasma kallikrein inhibitor and bradykinin B2 receptor antagonist). The authors review current and novel treatments for patients with HAE.

    2013 Jul;113(7):546-555

    Available from: http://www.jaoa.osteopathic.org/content/113/7/546.long (free)

    Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study

    Reshef A, Moldovan D, Obtulowicz K, Leibovich I, Mihaly E, Visscher S, et al. 1/2013 Allergy

    BACKGROUND: Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling affecting various body locations. Recent literature shows that patients with frequent attacks may benefit from long-term prophylaxis. This study evaluated the safety and prophylactic effect of weekly administrations of recombinant C1INH (rhC1INH).

    METHODS: Patients with a history of HAE attacks occurring >every 2 weeks received a once weekly administration of 50 U/kg rhC1INH. Hereditary angioedema attack history was collected at screening. Breakthrough attacks during the study were recorded at each visit. Following a 2-week run-in period, HAE patients received 8 weekly rhC1INH administrations and were followed-up for an additional 6 weeks. Efficacy was evaluated by comparing the HAE attack incidence during the treatment period to the historical attacks over the previous 2 years. Safety evaluation was based on clinical laboratory and adverse events (AEs) reports.

    RESULTS: The 25 participants reported a mean of 0.9 attacks/week over the past 2 years. The mean breakthrough attack rate during the treatment period was 0.4 attacks/week (95% CI 0.28-0.56). A total of 30 treatment-emergent-AEs were reported in 13 patients, all mild to moderate. One patient died from a laryngeal attack 25 days after last study drug administration. The only possible drug related AEs reported were dry mouth, dizziness and anxiety in one patient and hypotension in another. There were no allergic AEs and no neutralizing antibodies observed.

    CONCLUSIONS: Weekly administrations of 50 U/kg rhC1INH appeared to reduce the frequency of HAE attacks and were generally safe and well tolerated.Copyright © 2012 John Wiley & Sons A/S.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12060/full

    Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study

    Bas M, Greve J, Hoffmann TK, Reshef A, Aberer W, Maurer M 11/2013 Allergy

    BACKGROUND: The For Angioedema Subcutaneous Treatment (FAST)-2, a phase III, double-blind, randomized, multicenter, placebo-controlled study (ClinicalTrials.gov identifier: NCT00500656), established the efficacy and safety of single injections of icatibant, a bradykinin B2 receptor antagonist, in the treatment of hereditary angioedema (HAE) attacks. Here, we evaluate the efficacy and safety of repeated treatment with icatibant in adult patients experiencing HAE attacks during the FAST-2 open-label extension (OLE) phase.

    METHODS: Patients completing the controlled phase were eligible to participate in the OLE phase and receive open-label icatibant (30 mg subcutaneously) for the treatment of cutaneous, abdominal, and/or laryngeal HAE attack(s) severe enough to warrant treatment. Time to onset of symptom relief was calculated for each attack. Descriptive analyses (median, 95% CIs) were performed for all attacks; post hoc analyses were conducted in patients with at least five icatibant-treated attacks throughout the FAST-2 OLE phase. Safety was also monitored.

    RESULTS: Fifty-four patients received icatibant for 374 attacks (176 cutaneous, 168 abdominal, and 30 laryngeal). For cutaneous and/or abdominal attacks (attacks 2-5), the median times to onset of symptom relief ranged between 2.0 and 2.5 h. For all laryngeal attacks, the median times to regression (start of improvement) of symptoms ranged between 0.3 and 4.0 h. Post hoc analyses showed that the overall median time to onset of symptom relief was 2.0 h. Overall, 89.8% of attacks resolved with a single icatibant injection. No drug-related serious adverse events were reported.

    CONCLUSIONS: These findings have demonstrated the efficacy and safety of repeated icatibant treatment for HAE attacks.
    John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    2013 Nov;68(11):1452-1459

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12244/full (small fee)

    Review of recent guidelines and consensus statements on hereditary angioedema therapy with focus on self-administration

    Cicardi M, Craig TJ, Martinez-Saguer I, Hebert J, Longhurst HJ. 5/2013 International Archives of Allergy and Immunology

    Consensus meetings and the resulting recommendations shape treatment choices in rare diseases such as hereditary angioedema (HAE) because they combine the experience of prescribing physicians and the patients who are receiving therapy. Self-administration of HAE therapy was recognised as a potential treatment option in the first consensus publication in 2003. Recent studies have confirmed that self-administration of therapy resolves attacks quickly, safely and minimises burden of disease; however, the discovery of inconsistent treatment approaches is a concern and warrants investigation into the barriers that prevent adherence with current recommendations.Copyright © 2013 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/FullText/351232

    Riedl MA, Levy RJ, Suez D, Lockey RF, Baker JW, Relan A, et al. Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

    Riedl MA, Levy RJ, Suez D, Lockey RF, Baker JW, Relan A, et al. 4/2013 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: The efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies.

    OBJECTIVE: To assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE.

    METHODS: In this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events.

    RESULTS: Sixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH.

    CONCLUSION: The results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Risk of angioedema following invasive or surgical procedures in HAE type I and II–the natural history

    Aygoren-Pursun E, Martinez Saguer I, Kreuz W, Klingebiel T, Schwabe D. 08/2013 Allergy

    BACKGROUND: Hereditary angioedema (HAE), caused by deficiency in C1-inhibitor (C1-INH), leads to unpredictable edema of subcutaneous tissues with potentially fatal complications. As surgery can be a trigger for edema episodes, current guidelines recommend preoperative prophylaxis with C1-INH or attenuated androgens in patients with HAE undergoing surgery. However, the risk of an HAE attack in patients without prophylaxis has not been quantified. OBJECTIVES: This analysis examined rates of perioperative edema in patients with HAE not receiving prophylaxis. METHODS: This was a retrospective analysis of records of randomly selected patients with HAE type I or II treated at the Frankfurt Comprehensive Care Centre. These were examined for information about surgical procedures and the presence of perioperative angioedema.

    RESULTS: A total of 331 patients were included; 247 underwent 700 invasive procedures. Of these procedures, 335 were conducted in 144 patients who had not received prophylaxis at the time of surgery. Categories representing significant numbers of procedures were abdominal (n = 113), ENT (n = 71), and gynecological (n = 58) procedures. The rate of documented angioedema without prophylaxis across all procedures was 5.7%; in 24.8% of procedures, the presence of perioperative angioedema could not be excluded, leading to a maximum potential risk of 30.5%. Predictors of perioperative angioedema could not be identified.

    CONCLUSION: The risk of perioperative angioedema in patients with HAE type I or II without prophylaxis undergoing surgical procedures ranged from 5.7% to 30.5% (CI 3.5-35.7%). The unpredictability of HAE episodes supports current international treatment recommendations to consider short-term prophylaxis for all HAE patients undergoing surgery.

    2013 University Hospital Frankfurt, Goethe University. Allergy published by John Wiley & Sons Ltd.

    2013 Aug;68(8):1034-1039

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12186/full (free)

    Self-administration of intravenous C1 esterase inhibitor in hereditary angioedema

    Rizk C, Karsh J, Santucci S, Yang W. 6/2013 CMAJ Canadian Medical Association Journal

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680557/

    The dermatology view of hereditary angio-oedema: practical diagnostic and management considerations

    Maurer M, Parish LC. 2/2013 Journal of the European Academy of Dermatology and Venereology

    Hereditary angio-oedema (HAE) is characterized by recurrent, localized, non-pitting, non-pruritic, non-urticarial oedema. Nearly all patients experience skin swelling as a feature of HAE. There may be painful abdominal attacks, accompanied by nausea and vomiting. The disease is life-threatening should laryngeal oedema occur. HAE results from a deficiency or dysfunction of C1 inhibitor, a plasma protein with an important role in regulating the contact, complement and fibrinolytic systems. Effective management of HAE should include a plan for treatment of attacks, as well as routine and preprocedure prevention. Acute and prophylactic therapy with C1 inhibitor therapy for correcting the underlying deficiency in HAE is a valuable option.Copyright © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2012.04562.x/full

    Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency

    Zanichelli A, Mansi M, Periti G, Cicardi M. 05/2013  Expert rev.clin.immunol.

    Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients’ quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

    2013 May;9(5):477-488

    Available from: http://informahealthcare.com/doi/full/10.1586/eci.13.22 (small fee)

    Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients

    Farkas H, Csuka D, Zotter Z, Szabo E, Czaller I, Varga L, et al. 3/2013 Journal of Allergy and Clinical Immunology

    Available from: http://www.jacionline.org/article/S0091-6749%2812%2901451-0/fulltext

    Treatment with C1-esterase inhibitor concentrate in type I or II hereditary angioedema: a systematic literature review. 

    Bork K, Steffensen I, Machnig T.  07/2013 Allergy Asthma Proc.

    Hereditary angioedema (HAE) due to C1 esterase inhibitor (HAE-C1-INH) deficiency is a rare genetic disorder presenting with recurrent episodes of skin swellings, abdominal pain attacks, and potentially fatal laryngeal edema. This study was designed to review the efficacy and safety of pasteurized, human, plasma-derived C1-INH concentrate for the treatment of patients with HAE-C1-INH. A systematic search of electronic databases up to December 2011 was performed without language or date restrictions. Two reviewers completed the study selection using predefined inclusion criteria, tabulated, and analyzed the data. The data were inappropriate for meta-analysis; thus, a qualitative synthesis was performed. We identified 89 studies (2000 patients) that investigated C1-INH. Replacement therapy with C1-INH significantly shortened time to onset of symptom relief in HAE attacks compared with placebo in a randomized controlled trial, and similar improvements were consistently reported in observational and descriptive studies, accompanied by improvements in patients’ quality of life. C1-INH has been shown to be effective for patients receiving home therapy and short- and long-term prophylaxis. Treatment with C1-INH was generally well tolerated. Administration of C1-INH was not associated with transmission of viruses or development of autoantibodies irrespective of treatment duration. This research provides additional confirmation of the efficacy of C1-INH in the treatment and prevention of HAE attacks. C1-INH is generally safe and well tolerated and has an excellent safety record for over 25 years of clinical use.

    2013 Jul-Aug;34(4):312-327

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2013/00000034/00000004/art00002 (free)

    Update on treatment of hereditary angioedema

    Xu YY, Buyantseva LV, Agarwal NS, Olivieri K, Zhi YX, Craig TJ. Update on treatment of hereditary angioedema. Clinical & Experimental Allergy 2013 Apr;43(4):395-405. 4/2013 Clinical and Experimental Allergy

    Hereditary angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New research and therapies have recently emerged and are now available; however, many physicians are not aware of the new developments in HAE. To update immunologists and other health care providers on new advances in HAE therapies, a PubMed, OVID and Google literature search were used to develop this manuscript. English language peer-reviewed angioedema articles were selected. High quality clinical trials were reviewed and summarized. Acute therapy in the past often consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side-effects. Newer therapies include C1-inhibitor – both human plasma derived and recombinant – as well as contact system modulators such as ecallantide and icatibant. These newer products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis. These disease-specific therapies have proven to work by placebo-controlled studies, have minimal adverse effects and can be utilized for the treatment of HAE.Copyright © 2013 Blackwell Publishing Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/cea.12080/full

    Use of ecallantide in pediatric hereditary angioedema

    MacGinnitie AJ, Davis-Lorton M, Stolz LE, Tachdjian R. 08/2013 Pediatrics

    OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age.

    METHODS: Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined.

    RESULTS: Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (-1.4 + 0.9 ecallantide versus -0.9 + 0.6 placebo) and TOS (73.9 + 35.50 ecallantide versus 45.0 + 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed.

    CONCLUSIONS: Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.

    2013 Aug;132(2):e490-7

    Available from: http://pediatrics.aappublications.org/content/132/2/e490.long (free)

    A cross-sectional questionnaire assessing patient and physician use of short-term prophylaxis for hereditary angioedema

    Nanda MK, Singh U, Wilmot J, Bernstein JA. 08/2014 The Annals of Allergy, Asthma & Immunology (Ann.Allergy Asthma Immunol.)

    BACKGROUND: Current guidelines recommend short-term prophylaxis (STP) before invasive procedures to prevent hereditary angioedema (HAE) attacks; however, adherence to these guidelines may be variable because this indication lacks Food and Drug Administration approval in the United States. OBJECTIVE: To ascertain the STP experiences of patients with HAE and HAE-treating physicians.

    METHODS: Online questionnaires focusing on STP experiences were distributed by the US Hereditary Angioedema Association to the first 250 patients with HAE and to registered HAE-treating physicians. SAS 9.3 was used to perform descriptive statistics and to test the difference between patients who underwent procedures and those who did not using Pearson chi(2) test, Fisher exact test, and 2-sample t test.

    RESULTS: For the patient survey, 219 respondents met the criteria for HAE type 1 and 2; 37 (17%) underwent 66 invasive procedures, and all reported receiving STP. Eight patients (22%) reported failed STP, but only 3 required on-demand therapy. For STP, anabolic steroids and plasma-derived C1 inhibitor were the most and second-most commonly used, respectively. For the physician survey, 37 physicians reported caring for 433 patients with HAE. Depending on the procedure, 19% to 54% of physicians used STP and 30% to 86% prescribed on-demand therapy; 69% and 78% of physicians prescribed plasma-derived C1 inhibitor as STP for minimally invasive and invasive procedures, respectively. Physicians reported excellent efficacy for the STP treatments used.

    CONCLUSION: Physicians reported excellent outcomes using primarily newer STP therapies, namely plasma-derived C1 inhibitor, which was discordant to patient-reported outcomes using older STP therapies, namely anabolic steroids. Well-controlled STP studies are needed to clarify use for patients with HAE in the United States. Copyright 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    2014 Aug;113(2):198-203

    Available from: http://www.annallergy.org/article/S1081-1206%2814%2900309-3/fulltext (small fee)

    A phase 1 study investigating DX-2930 in healthy subjects

    Chyung Y, Vince B, Iarrobino R, Sexton D, Kenniston J, Faucette R, et al. 10/2014 Annals of Allergy, Asthma and Immunology

    BACKGROUND: DX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein under investigation for long-term prophylaxis of hereditary angioedema.

    OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DX-2930 in healthy subjects.

    METHODS: A single-center, double-blinded study was performed in 32 healthy subjects randomized 3:1 to receive a single subcutaneous administration of DX-2930 or placebo within 1 of 4 sequential, ascending dose cohorts (n = 8 each): 0.1, 0.3, 1.0, or 3.0 mg/kg.

    RESULTS: No dose-limiting toxicity was observed. Headache was the most commonly reported treatment emergent adverse event (AE), occurring at a rate of 25% in the DX-2930- and placebo-treated groups; none were severe and all resolved. There were no serious AEs, discontinuations owing to an AE, or deaths. Two subjects had a severe AE reported as related to treatment by the blinded investigator; the 2 AEs were asymptomatic creatinine phosphokinase elevations of 902 U/L in 1 subject receiving 0.1 mg/kg DX-2930 and 1,967 U/L in 1 subject receiving placebo. For the 0.1-, 0.3-, 1.0-, and 3.0-mg/kg dose groups, respectively, mean maximum plasma concentrations were 0.6, 1.4, 5.6, and 14.5 mug/mL and mean elimination half-lives were 20.6, 16.8, 17.6, and 21.2 days. Exploratory biomarker assays, involving ex vivo activation of the kallikrein pathway, showed dose- and time-dependent inhibition of plasma kallikrein, with evidence of sustained bioactivity consistent with the pharmacokinetics profile.

    CONCLUSION: A single administration of DX-2930 in healthy subjects up to doses of 3.0 mg/kg was well tolerated without dose-limiting toxicity. Pharmacokinetic and pharmacodynamic data provide evidence for a long-acting biological effect relevant to long-term prophylaxis for hereditary angioedema with C1-inhibitor deficiency.

    TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01923207.Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2814%2900377-9/fulltext

    Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency

    Rubinstein E, Stolz LE, Sheffer AL, Stevens C, Bousvaros A. 4/2014 BMC Gastroenterology

    BACKGROUND: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.

    METHODS: Information collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.

    RESULTS: Forty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 x 10(9)/L) in 23% of attacks (mean +/- SD: 15.1 +/- 11.27 x 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 +/- 33 versus 29 +/- 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.

    CONCLUSIONS: HAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.

    TRIALS REGISTRATION: The data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov.proxy1.lib.uwo.ca EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101849/

    An evidence based therapeutic approach to hereditary and acquired angioedema

    Bork K. 8/2014 Current Opinion in Allergy and Clinical Immunology

    PURPOSE OF REVIEW: Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH), HAE with normal C1-INH, and acquired angioedema due to C1-INH deficiency are rare but important diseases that can be associated with significant morbidity and mortality. Research into the pathogenesis of angioedema has expanded greatly and has led to new clinical trials with novel therapeutic agents and strategies.

    RECENT FINDINGS: Strategies for managing HAE-C1-INH are aimed at treating acute attacks or preventing attacks through the use of prophylactic treatment. Agents available in Europe for treating acute attacks include plasma-derived C1-INH concentrates, a bradykinin B2 receptor (B2R) antagonist, and a recombinant human C1-INH. In the USA, a plasma-derived C1-INH concentrate, a bradykinin B2R antagonist, and a plasma kallikrein inhibitor have been approved for the treatment of acute HAE-C1-INH attacks. C1-INH concentrates and attenuated androgens are used for short-term prophylactic treatment. Long-term prophylactic treatments include attenuated androgens, a plasma-derived C1-INH concentrate, and antifibrinolytics. Plasma-derived C1-INH and a bradykinin B2R antagonist are approved for self-administration at home.

    SUMMARY: The number of management options for HAE-C1-INH and similar conditions has increased considerably within the last few years, thus helping to alleviate the burden of these rare diseases.

    Available from: http://journals.lww.com/co-allergy/Abstract/2014/08000/An_evidence_based_therapeutic_approach_to.16.aspx  (small fee)

    Angioedema deaths in the United States, 1979-2010

    Kim SJ, Brooks JC, Sheikh J, Kaplan MS, Goldberg BJ. 12/2014 Ann.Allergy Asthma Immunol.

    BACKGROUND: Hospital admission data indicate that the angioedema incidence has increased during the past several decades. Little is known about mortality trends.

    OBJECTIVES: To count the number of deaths associated with angioedema in the United States, investigate correlations with age, sex, race, and other contributory causes, and analyze trends from 1979 to 2010. METHODS: All US death certificates in which angioedema was listed as an underlying or contributing cause of death during 1979 to 2010 were analyzed. Age-adjusted mortality rates were analyzed by age, sex, and race. Other conditions designated as the underlying cause of death were investigated.

    RESULTS: From 1979 to 2010, there were 5,758 deaths in which angioedema was listed as a contributing cause. The age-adjusted death rate for hereditary angioedema decreased from 0.28 (95% confidence interval [CI] 0.25-0.32) to 0.06 (95% CI 0.05-0.08) per million persons per year. Conversely, mortality for angioedema increased from 0.24 (95% CI 0.21-0.27) to 0.34 (95% CI 0.31-0.37) per million. Blacks constituted 55% of angioedema deaths that were associated with use of angiotensin-converting enzyme inhibitors. On death certificates that listed hereditary angioedema as the underlying cause of death, cancer (frequently lymphoma or leukemia) was the second most commonly listed cause.

    CONCLUSION: Angioedema-associated deaths were very rare from 1979 to 2010. Hereditary angioedema deaths became even more so, whereas nonhereditary angioedema deaths increased. Risks associated with angiotensin-converting enzyme inhibitors were higher in blacks. Lack of specific coding for acquired angioedema most likely explains the observed association between cancer and hereditary angioedema. In the future, more granular coding systems may help distinguish hereditary from acquired angioedema.Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1081120614006371 (small fee)

    Angiotensin-converting enzyme inhibitor-induced angioedema–a dangerous new epidemic

    Rasmussen ER, Mey K, Bygum A. 5/2014 Acta Dermato Venereologica

    Angioedema is a sudden localised and often asymmetric swelling of the skin or mucous membranes caused by transient increased endothelial permeability causing plasma extravasation. In the last decades the incidence of severe angioedema involving the upper airways and even fatal outcome due to asphyxia has increased. This is mainly due to pharmaceuticals such as angiotensin converting enzyme-inhibitors, which are extensively used worldwide. Some aspects of the pathophysiology have been elucidated and the vasoactive molecule bradykinin is shown to be one of the main causative agents. The diagnosis is often delayed and traditional treatment usually ineffective. Complement C1 inhibitor concentrate and bradykinin receptor antagonists, normally used to treat patients with hereditary angioedema, have shown good results when used in patients with bradykinin-mediated angioedema. This review discusses the disease, prognosis and treatment options.

    Available from: http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1760&html=1

    Biochemical comparison of four commercially available C1 esterase inhibitor concentrates for treatment of hereditary angioedema

    Feussner A, Kalina U, Hofmann P, Machnig T, Henkel G. 10/2014 Transfusion

    BACKGROUND: For safe and efficacious treatment of hereditary angioedema, C1 esterase inhibitor (C1-INH) concentrates should have high purity and high amounts of functional protein. As no pharmacopoeia requirements exist for C1-INH concentrate lot release, biochemical characteristics as declared by the manufacturers may not be compared directly. This study compared the characteristics and purity profiles of four commercially available C1-INH concentrates.

    STUDY DESIGN AND METHODS: The analysis included one transgenic (Ruconest) and three plasma-derived (Berinert, Cetor, Cinryze) C1-INH concentrates. C1-INH antigen concentration was determined by nephelometry, total protein (specific activity) with a Bradford assay, purity by size-exclusion chromatography and gel electrophoresis, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was performed.

    RESULTS: Functionality (inversely proportional to antigen-to-activity ratio) was lowest for Ruconest (1.67), followed by Cetor (1.42), Berinert (1.24), and Cinryze (1.22). Specific activity (U/mg) and purity (%) were highest in Ruconest (12.13; 98.6) and Berinert (11.57; 97.0), followed by Cinryze (10.41; 89.5) and Cetor (9.01; 88.6). Main protein bands were found for all plasma-derived products at approximately 105kDa, and for Ruconest, at approximately 98kDa. Additional bands in the plasma-derived products were alpha1-antichymotrypsin, ceruloplasmin, Factor C3 (Cinryze/Cetor), and immunoglobulin heavy constant mu (Berinert). C

    CONCLUSION: Ruconest has a very high purity profile but is not identical to the human C1-INH protein. Of the plasma-derived products, Berinert has the highest purity profile. The impact of the nontherapeutic proteins identified has not yet been evaluated. For harmonization of the analysis for drug release, we recommend the establishment of regulatory requirements for purity determination and the implementation of threshold levels in C1-INH concentrates.Copyright © 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

    Available from:  http://onlinelibrary.wiley.com/doi/10.1111/trf.12678/full

    Bradykinin-mediated diseases

    Kaplan AP. /2014 Chemical Immunology and Allergy

    Diseases which have been demonstrated to be caused by increased plasma levels of bradykinin all have angioedema as the common major clinical manifestation. Angioedema due to therapy with angiotensin-converting enzyme (ACE) inhibitors is caused by suppressed bradykinin degradation so that it accumulates. This occurs because ACE metabolizes bradykinin by removal of Phe-Arg from the C-terminus, which inactivates it. By contrast, angioedema due to C1 inhibitor deficiency (either hereditary types I and II, or acquired) is caused by bradykinin overproduction. C1 inhibitor inhibits factor XIIa, kallikrein and activity associated with the prekallikrein-HK (high-molecular-weight kininogen) complex. In its absence, uncontrolled activation of the plasma bradykinin cascade is seen once there has been an initiating stimulus. C4 levels are low in all types of C1 inhibitor deficiency due to the instability of C1 (C1r, in particular) such that some activated C1 always circulates and depletes C4. In the hereditary disorder, formation of factor XIIf (factor XII fragment) during attacks of swelling causes C4 levels to drop toward zero, and C2 levels decline. A kinin-like molecule, once thought to be a cleavage product derived from C2 that contributes to the increased vascular permeability seen in hereditary angioedema (HAE), is now thought to be an artifact, i.e. no such molecule is demonstrable. The acquired C1 inhibitor deficiency is associated with clonal disorders of B cell hyperreactivity, including lymphoma and monoclonal gammopathy. Most cases have an IgG autoantibody to C1 inhibitor which inactivates it so that the presentation is strikingly similar to type I HAE. New therapies for types I and II HAE include C1 inhibitor replacement therapy, ecallantide, a kallikrein antagonist, and icatibant, a B2 receptor antagonist. A newly described type III HAE has normal C1 inhibitor, although it is thought to be mediated by bradykinin, as is an antihistamine-resistant subpopulation of patients with ‘idiopathic’ angioedema. The mechanism(s) for the formation of bradykinin in these disorders is unknown.Copyright © 2014 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/Abstract/358619

    C-reactive protein levels in hereditary angioedema

    Hofman ZL, Relan A, Hack CE. 07/2014 Clinical & Experimental Immunology (Clin.Exp.Immunol)

    Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P=0049) and during the next 24h CRP rose significantly (P=0002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P=0034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset. 2014 British Society for Immunology.

    2014 Jul;177(1):280-286

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/cei.12314/full (small fee)

    C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk

    Schurmann D, Herzog E, Raquet E, Nolte MW, May F, Muller-Cohrs J, et al. 11/2014 Thrombosis and Haemostasis

    Human plasma-derived C1-esterase inhibitor (C1-INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1-INH at recommended or off-label, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1-INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1-INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1-INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1-INH at doses up to 800 IU/kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1-INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1-INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1-INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1-INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.

    Available from : http://th.schattauer.de/en/contents/archive/manuscript/22277.html

    Contact system activation on endothelial cells

    de Maat S, de Groot PG, Maas C. 11/2014 Seminars in Thrombosis and Hemostasis

    When the contact system assembles and activates on negatively charged surface materials, plasma coagulation rapidly follows. This mechanism is redundant for hemostasis but mediates pathological thrombus formation, as was reported in a multitude of in vivo studies. The epidemiological data are presently scarce to firmly support a role for the contact system in human thrombotic disease, while its physiological function and mode of activation remains mysterious. Besides its role in blood coagulation in vitro, the contact system is responsible for the production of bradykinin. This inflammatory peptide is involved in episodes of pathological tissue swelling in (hereditary) angioedema, but potentially also in the physiological regulation of vascular permeability. A body of evidence indicates that contact system factors are recruited to the surface of activated endothelial cells, where proteins that are locally released can activate them. Furthermore, clinical and biochemical studies indicate that plasmin, the effector enzyme of the fibrinolytic system, can evoke contact system activation. This auxiliary role for plasmin may so far not have been fully appreciated in pathophysiology. To conclude this review, we propose a complementary model for contact system activation on the endothelial cell surface that is initiated by plasmin activity. Copyright Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

    Available from: http://europepmc.org/abstract/med/25389102 (small fee)

    Does angiotensin-converting enzyme inhibitor use exacerbate hereditary angioedema?

    Hassen GW, Tu TJ, Wei DH, Hwang A, Lamothe R, Costea A, et al. 10/2014 J.Emerg.Med.

    BACKGROUND: Approximately 2% of angioedema (AE) patients have a hereditary or an acquired deficiency of the complement 1 (C1) esterase inhibitor (C1 INH) gene. Some case reports indicate an association between angiotensin-converting enzyme inhibitor (ACEI) use and exacerbation of hereditary AE (HAE).

    OBJECTIVE: The aim of this retrospective study is to investigate the association between HAE and ACEI use in a larger patient population.

    METHODS: A retrospective chart review of patients who presented with AE and patients with diagnostic serum assays for functional C1 INH, C1 INH antigenic protein, C1q, C1q immune complex (C1q IC), and complement 4 (C4) regardless of medical complaint. Descriptive statistics were used to analyze the data.

    RESULTS: A total of 1594 patients had complement levels measured (136 C1 INH, 55 C1q, 10 C1q IC, and 1500 C4), of which 156 (9.7%) patients presented with AE. Angiotensin-converting enzyme inhibitor use was documented in 747 (47%) patients. Low C1 INH was detected in one patient with recurrent AE who was not taking ACEI. Another patient who presented with recurrent AE was found to have systemic lupus erythematosus with abnormal C4, C1q, and C1q IC, but normal C1 INH. A low C4 level was present in 94 patients, 4 of which had AE.

    CONCLUSIONS: The risk of exacerbating HAE by ACEI might be present, but we did not find any association in this retrospective study. Further studies are needed to determine the existence of this association. Copyright 2013 Elsevier Inc. All rights reserved.

    2013 Oct;45(4):602-608

    Available from: http://www.jem-journal.com/article/S0736-4679%2813%2900577-5/fulltext (small fee)

    Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema.

    Bernstein JA, Manning ME, Li H, White MV, Baker J, Lumry WR, et al. 01/2014  J.Allergy Clin.Immunol.Pract.

    BACKGROUND: Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor.

    OBJECTIVE: To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days).

    METHODS: Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (1 attack/month were eligible for further escalation to 2000 U and then 2500 U.

    RESULTS: Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator’s discretion, or experienced a reduction in attacks of >1.0/month.

    CONCLUSIONS: Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients. Copyright 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    2014 Jan-Feb;2(1):77-84

    Available from: http://www.jaci-inpractice.org/article/S2213-2198%2813%2900383-8/fulltext (free)

    Evaluating the efficacy of subcutaneous C1-esterase inhibitor administration for use in rat models of inflammatory diseases

    Emmens RW, Naaijkens BA, Roem D, Kramer K, Wouters D, Zeerleder S, et al. 6/2014 Drug Deliv.

    CONTEXT: C1-esterase inhibitor (C1-inh) therapy is currently administered to patients with C1-inh deficiency through intravenous injections. The possibility of subcutaneous administration is currently being explored since this would alleviate need for hospitalization and increase mobility and well-being of patients. Recently, it was observed in pigs that C1-inh indeed can effectively be applied by subcutaneous injection. For studies on the effectiveness of C1-inh therapy for other indications than acquired and hereditary angioedema, rats are commonly used as model animal. For rats, however, subcutaneous C1-inh administration has never been investigated.

    OBJECTIVE: To evaluate the efficacy of subcutaneous C1-inh administration in rats.

    MATERIALS AND METHODS: Three boli of 100 U/kg human plasma-derived C1-inh were administered to Wistar rats on three consecutive days through subcutaneous injection or intravenous injection. Blood samples were collected from the tail veins 3, 4.5 or 6 h after C1-inh administration for measurement of C1-inh plasma levels. Antigen and activity levels of C1-inh of each plasma sample were determined by means of a specific ELISA.

    RESULTS: For both C1-inh antigen and C1-inh activity, 21- to 119-fold higher plasma levels were measured after intravenous administration compared with subcutaneous administration. Subcutaneous administration also resulted in C1-inh plasma levels that were less stable and with decreased relative activity.

    CONCLUSION: These combined results indicate that in rats, subcutaneous injections in the present formulation are not effective as alternative administration route for C1-inh.

    Available from: http://informahealthcare.com/doi/abs/10.3109/10717544.2013.853211

    Feasibility of home infusion and self-administration of nanofiltered C1 esterase inhibitor for routine prophylaxis in patients with hereditary angioedema and characterization of a training and support program

    Gregory C, Landmesser LM, Corrigan L, Mariano D. 1/2014 Journal of Infusion Nursing

    Hereditary angioedema (HAE) is a rare, chronic disease of C1 inhibitor deficiency. Study researchers evaluated the prevalence of home and self-administration of nanofiltered, human-derived C1 esterase inhibitor infusions and the implementation of a nursing training and support program. Home administration rate increased from 49.0% to 75.8%. The percentage who self-administered increased from 20.3% to 43.9%. Doses per week averaged 1.85 at home compared with 1.40 in infusion centers and physicians’ offices. Patients required an average of 5 visits to be trained. Self-administration is a viable, feasible option in the management of HAE, which is facilitated by a nurse-managed training and support program.

    Available from: http://journals.lww.com/journalofinfusionnursing/Citation/2014/01000/Feasibility_of_Home_Infusion_and.4.aspx (small fee)

    Frequency of the virilising effects of attenuated androgens reported by women with hereditary angioedema

    Zotter Z, Veszeli N, Csuka D, Varga L, Farkas H. 2/2014 Orphanet Journal of Rare Diseases

    BACKGROUND: Danazol, a drug extensively used in the management of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), has various side effects. This study investigated the virilizing actions of this drug in 31 danazol-treated female patients with HAE-C1-INH. We compared our findings with those of healthy controls and with literature data.

    METHODS: The patients were interviewed individually about the type and severity of the virilizing effects, as well as about their satisfaction with danazol therapy.

    RESULTS: The average duration of danazol treatment was 10.31 years [2 to 23] and its mean daily dose was 131.7 mg [33 to 200]. The most common adverse effects were hirsutism (n=14), weight gain (n=13), and menstrual disturbances (n=8). The severity of danazol adverse effects did not differ by duration of treatment or by daily drug dose. The mean level of patient satisfaction with the treatment was high. The comparison of age-matched healthy controls and of HAE-C1-INH patients receiving danazol did not demonstrate a statistically higher incidence of any of the monitored symptoms in the danazol group.

    CONCLUSIONS: Our findings indicate that long-term danazol treatment – using the lowest effective dose – has only a mild virilizing effect.

    Available from: http://link.springer.com/article/10.1186/s13023-014-0205-6/fulltext.html

    Hereditary angioedema – consequences of a new treatment paradigm in Denmark

    Bygum A. 7/2014 Acta Dermato Venereologica

    Experiences from a Danish patient cohort with hereditary angioedema are reported with focus on home therapy and burden of illness. Eighty patients have been prospectively followed over 11 years, having experienced a total of 7,809 attacks over 469 patient years. More than half of the patients stopped long-term prophylaxis with danazol or tranexamic acid and changed treatment regimen to on-demand treatment with C1 inhibitor concentrate or icatibant. At least 10% of the attacks remained un-treated. More than half of the patients felt that hereditary angioedema had a significant psychological impact on their lives and restricted their physical activities. By December 2012, a total of 39 patients (49%) were practicing home treatment of acute attacks. Home therapy reduced the mean number of acute hospital visits by 84% and significantly improved burden of illness items. In conclusion, home therapy has profoundly improved the lives of hereditary angioedema patients.

    Available from: http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1743&html=1

    Hereditary angioedema in Greece: the first results of the greek hereditary angioedema registry

    Psarros F, Koutsostathis N, Farmaki E, Speletas MG, Germenis AE. 10/2014 International Archives of Allergy and Immunology

    BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013).

    METHODS: A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients’ disease-specific quality of life.

    RESULTS: One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non-FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients.

    CONCLUSION: Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients’ quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics.Copyright © 2014 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/Abstract/366276

    Hereditary angioedema: a brief review of new developments

    Altman KA, Naimi DR. 5/2014 Current Medical Research and Opinion

    BACKGROUND: Angioedema is a serious medical condition characterized by recurrent non-pitting tissue edema. Hereditary (HAE) forms of this disorder are potentially fatal.

    METHODS: PubMED, Up to Date and Cochrane Library databases were used to identify scholarly peer reviewed original research or review articles on angioedema. Search terms used were: angioedema, HAE, ACE inhibitor induced angioedema, acquired angioedema, type III HAE (now termed HAE with normal C1-INH), diagnosis of HAE, and treatment of HAE. Inclusive dates of the search were 1946 through 2013. Articles on urticaria were excluded.

    RESULTS: The pathophysiology, clinical manifestations, differential diagnosis and treatments of angioedema are presented. Three variants of HAE are discussed and differentiated from acquired, ACE induced and allergic types of angioedema. Emphasis is placed on understanding that HAE is mediated by bradykinin, not histamine, and is therefore unresponsive to antihistamines, corticosteroids and epinephrine. In contrast, newer therapies that replace C1-INH or block bradykinin production or action are the appropriate treatments for prophylaxis and acute treatment of HAE.

    CONCLUSION: Recognition of HAE by primary care providers and distinguishing it from allergic histamine mediated angioedema is essential in preventing recurrent attacks and avoiding inappropriate therapy, and may be life-saving.

    Available from: http://informahealthcare.com/doi/abs/10.1185/03007995.2013.879441

    High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency

    Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M. 12/2014 Clinical and Experimental Allergy

    BACKGROUND: The inherited deficiency of C1-inhibitor (C1-INH), which can be quantitative (type I) or qualitative (type II), is characterized by recurrent attacks of oedema, and it is known as hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). The frequency of symptoms varies widely among patients and in the same patient during life.

    OBJECTIVE: To identify laboratory markers of disease severity in HAE-C1-INH patients.

    METHODS: We studied 162 patients with differently severe HAE-C1-INH during remission, 31 HAE-C1-INH patients during attacks, and 81 normal controls, evaluating complement parameters, spontaneous plasma kallikrein activity, the capacity of plasma to inhibit exogenous kallikrein activity, and cleavage of high-molecular-weight kininogen (HK). Sixty-five HAE-C1-INH patients were screened for mutations in the C1-INH gene.

    RESULTS: As expected, plasma C1-INH levels and activity and C4 levels were low in the HAE-C1-INH patients. Spontaneous plasma kallikrein activity in patients in remission was higher than in controls (P = 0.001) and increased during acute attacks (P = 0.01), whereas the capacity of inhibiting kallikrein activity was lower in patients in remission than in controls (P = 0.001) and further reduced during attacks (P = 0.001). HAE-C1-INH patients in remission had higher levels of cleaved HK than controls (P = 0.001), and these further increased during acute attacks (P = 0.001). Cleaved HK levels were higher in highly symptomatic HAE-C1-INH patients than in those with less frequent attacks (P = 0.001). Thirty-five different mutations in the C1-INH gene were equally distributed in patients with different attack frequencies.

    CONCLUSIONS: Measuring plasma levels of cleaved HK may be a sensitive mean of assessing disease severity in HAE-C1-INH patients.Copyright © 2014 John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/cea.12293/full

    Home treatment of attacks with conestat alfa in hereditary angioedema due to C1-inhibitor deficiency

    Farkas H, Csuka D, Veszeli N, Zotter Z, Szabo E, Varga L. 5/2014 Allergy and Asthma Proceedings

    Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1-INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17-4.50 hours) hours and resolved completely within 9.00 (1.67-58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R = 0.3212; p = 0.0096) and the time to complete resolution of the symptoms (R = 0.4774; p < 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks.

    Available from: http://dx.doi.org/10.2500/aap.2014.35.3743

    Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study

    Campos RA, Valle SO, Franca AT, Cordeiro E, Serpa FS, Mello YF, et al. /2014 Sao Paulo Medical Journal

    CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE) with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil.

    DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients.

    METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored.

    RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age). The symptoms were: subcutaneous edema (22/24); abdominal pain (15/24) and upper airway obstruction (10/24). The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%); 10-20 (5/24; 20.8%); 20-30 (8/24; 33.4%); 30-60 (5/24; 20.8%); and 2 hours (1/24; 4.3%). The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6.

    CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients.

    Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802014000500261

    Long-term prophylaxis with C1-inhibitor concentrate in patients with hereditary angioedema

    Pedrosa M, Lobera T, Panizo C, Jurado J, Caballero T. 01/2014 The Journal of Investigational Allergology and Clinical Immunology (J.Investig.Allergol.Clin.Immunol.)

    2014;24(4):271-273

    Available from: http://www.jiaci.org/issues/vol24issue4/vol24issue04-9.htm (free)

    Open-label, multicenter study of self-administered icatibant for attacks of hereditary angioedema

    Aberer W, Maurer M, Reshef A, Longhurst H, Kivity S, Bygum A 03/2014 Wiley

    BACKGROUND: Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration.

    METHODS: In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naive patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy.

    RESULTS: A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naive) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant.

    CONCLUSIONS: With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice.

    Mar;69(3):305-314

    Online access: http://onlinelibrary.wiley.com/doi/10.1111/all.12303/full (small fee)

    Oral medicine case book 64: Some aspects of the pathophysiology of angioedema with special reference to the upper aerodigestive tract. [Review]

    Bouckaert M, Wood NH, Khammissa R, Lemmer J, Feller L. 10/2014 SADJ: journal of the South African Dental Association = tydskrif van die Suid-Afrikaanse Tandheelkundige Vereniging

    Angioedema refers to a localized oedematous swelling of subcutaneous or submucosal tissues, caused by dilatation and increased permeability of blood vessels, usually mediated either by histamine or by bradykinin. Deficiency or loss of functional activity of the complement component C1 esterase inhibitor (C1-INH) affects multiple systems, including the kallikrein-kinin, complement, coagulation and fibrinolytic pathways, and in the context of angioedema, the result is increased production and release of bradykinin and other vasoactive substances such as C3a. Owing to impairment of C1-INH, factors Xlla and kallikrein, by a positive feedback mechanism, bring about persistent activation of the kallikrein-kinin pathway with amplification of production of bradykinin, resulting in angioedema. Histamine can cause histaminergic angioedema. As the name implies, this oedema is caused by degranulation of mast cells/basophils as a result of an IgE-dependant allergic reaction to extracts of food, drugs, infectious agents, or to physical stimulation; or as the result of direct degranulation of mast cells/basophils independently of IgE, caused by releasing agents such as opiates, antibiotics or radiocontrast media. As dental, oral and maxillofacial operative procedures may trigger the development of angioederria in susceptible individuals, the dental practitioner should be familiar with its signs and symptoms, its pathophysiology and with the firstline treatment of this disorder.

    Available from: http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S0011-85162014000900011

     

    Pasteurized and nanofiltered, plasma-derived C1 esterase inhibitor concentrate for the treatment of hereditary angioedema

    Bork K. 5/2014 Immunotherapy

    Hereditary angioedema (HAE) is a relatively rare autosomal dominant disorder that is typically characterized by recurrent episodes of edema in various body locations. It is most commonly caused by an inherited deficiency of functionally active C1 esterase inhibitor (C1-INH). Replacement therapy with a human plasma-derived C1-INH concentrate is recommended for the treatment and prophylaxis of acute attacks of HAE due to C1-INH deficiency (HAE-C1-INH). This article will discuss the current therapies available for the treatment of HAE-C1-INH, latest treatment guidelines, results of several studies demonstrating the efficacy and safety of the plasma-derived, pasteurized and nanofiltered C1-INH concentrate Berinert() (CSL Behring GmBH, Marburg, Germany), and future perspectives for the treatment and management of HAE-C1-INH.

    Available from: http://www.futuremedicine.com/doi/pdf/10.2217/imt.14.33

    Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study

    Martinez-Saguer I, Cicardi M, Suffritti C, Rusicke E, Aygoren-Pursun E, Stoll H, et al. 06/2014 Transfusion

    BACKGROUND: Hereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.

    STUDY DESIGN AND METHODS: This was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured.

    RESULTS: The mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p=0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild.

    CONCLUSION: With a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated. 2013 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

    2014 Jun;54(6):1552-1561

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/trf.12501/full (free)

    Phenotype standardization of angioedema in the head and neck region caused by agents acting on the angiotensin system

    Wadelius M, Marshall SE, Islander G, Nordang L, Karawajczyk M, Yue QY, et al. 10/2014 Clinical Pharmacology and Therapeutics

    Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172548/

    Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model

    Tradtrantip L, Asavapanumas N, Phuan PW, Verkman AS /2014 PloS one

    Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ~10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.

    Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106824

    Quality of life in patients with hereditary angioedema receiving therapy for routine prevention of attacks

    Lumry WR, Miller DP, Newcomer S, Fitts D, Dayno J. 9/2014 Allergy and Asthma Proceedings

    Patients with hereditary angioedema (HAE) have impaired health-related quality of life (HRQoL), but the effect of preventative treatment strategies on HRQoL has not been evaluated. This study was designed to evaluate the effect of routine prevention therapy with nanofiltered C1 inhibitor (C1 INH-nf; human) on the HRQoL of patients with HAE. Thiry-six-item Short Form (SF-36) Version 1.0 questionnaires were administered at the beginning and end of two 12-week treatment periods in this multicenter, randomized, placebo-controlled, crossover study. Patients (n = 22) received intravenous injections of 1000 U of C1 INH-nf or placebo every 3-4 days for 12 weeks and then crossed over to the other treatment arm for a second 12-week period. Patients could receive open-label C1 INH-nf (1000 U) for the acute treatment of angioedema attacks in either arm of the study. Sixteen patients had evaluable SF-36 data. Mean physical component summary scores (PCSs) were 36.41 at baseline, 37.06 at the end of the placebo period, and 43.92 at the end of the C1 INH-nf period. Mean mental component summary scores (MCSs) were 49.90, 44.98, and 54.00, respectively. Least square mean differences (95% confidence intervals) between C1 INH-nf and placebo in norm-based SF-36 scores at the end of each treatment period were 6.55 (1.48, 11.62; p = 0.015) for PCS and 8.70 (1.67, 15.72; p = 0.019) for MCS. In a clinical trial setting, patients with HAE had significantly better HRQoL after 12 weeks of C1 INH-nf for routine prevention compared with acute treatment of individual angioedema attacks in the absence of routine prevention while on placebo. This study was a part of the clinical trial NCT01005888 registered in www.clinicaltrials.gov.

    Available from: http://docserver.ingentaconnect.com/deliver/connect/ocean/10885412/v35n5/s6.html?expires=1449692787&id=84344691&titleid=6151&accname=Guest+User&checksum=00CF674625C6507A1A240BB169ED972C

    Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial

    Riedl MA, Bernstein JA, Li H, Reshef A, Lumry W, Moldovan D, et al. 02/2014 Ann.Allergy Asthma Immunol.

    BACKGROUND: Hereditary angioedema (HAE), caused by C1 inhibitor (C1INH) deficiency or dysfunction, is characterized by recurrent attacks of tissue swelling affecting multiple anatomic locations. Recombinant human C1INH (rhC1INH) has been shown effective for acute treatment of HAE attacks.

    OBJECTIVE: To evaluate the efficacy and safety of rhC1INH (50 IU/kg to maximum 4,200 IU/treatment) vs placebo in a larger HAE population.

    METHODS: Seventy-five patients experiencing peripheral, abdominal, facial, and/or oropharyngeal laryngeal attacks were randomized (3:2) to rhC1INH (n = 44) or placebo (saline; n = 31). Efficacy was assessed by patient responses on a Treatment Effect Questionnaire (TEQ) and visual analog scale (VAS). Safety also was evaluated.

    RESULTS: Median (95% confidence interval) time to beginning of symptom relief at the primary attack location was 90 minutes (61-150) in rhC1INH-treated patients vs 152 minutes (93, not estimable) in placebo-treated patients (P = .031) based on the TEQ and 75 minutes (60-105) vs 303 minutes (81-720, P = .003) based on a VAS decrease of at least 20 mm. Median time to minimal symptoms was 303 minutes (240-720) in rhC1INH-treated patients vs 483 minutes (300-1,440) in placebo-treated patients based on the TEQ (P = .078) and 240 minutes (177-270) vs 362 minutes (240, not estimable; P = .005), based on an overall VAS less than 20 mm. Overall, rhC1INH was safe and well tolerated; no thromboembolic events, anaphylaxis, or neutralizing antibodies were observed.

    CONCLUSION: Relief of symptoms of HAE attacks was achieved faster with rhC1INH compared with placebo as assessed by the TEQ and VAS, with a positive safety profile. Results are consistent with previous studies showing efficacy and safety of rhC1INH in patients with HAE. Copyright 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    2014 Feb;112(2):163-169.e1

    Available from: http://www.annallergy.org/article/S1081-1206%2813%2900925-3/fulltext (small fee)

    Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial

    Malbran A, Riedl M, Ritchie B, Smith WB, Yang W, Banerji A, et al. 08/2014 Clinical & Experimental Immunology (Clin.Exp.Immunol.)

    Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with >5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 10-20h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 03-12h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 882% of attacks; rescue medication was required in 53% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks. 2014 British Society for Immunology.

    2014 Aug;177(2):544-553

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/cei.12358/full (small fee)

    The effect of weight on the efficacy and safety of C1 esterase inhibitor concentrate for the treatment of acute hereditary angioedema.[Erratum appears in Clin Ther. 2014 Jun 1;36(6):992]

    Bernstein JA, Machnig T, Keinecke HO, Whelan GJ, Craig TJ 4/2014 Clinical therapeutics

    BACKGROUND: Despite the worldwide obesity epidemic, there have been very few studies investigating the influence of body weight on treatment dosing and outcomes in patients with hereditary angioedema (HAE).

    OBJECTIVE: The purpose of this analysis was to determine whether the standard weight-based dosing recommendation of C1 esterase inhibitor (C1-INH) concentrate (20 IU/kg) is adequate in HAE patients with a high body mass index (BMI).

    METHODS: Data from patients treated for HAE attacks with 20 IU/kg of C1-INH concentrate were retrospectively analyzed from the open-label IMPACT2 study (International Multicenter Prospective Angioedema C1-INH Trial). Patients were categorized according to BMI as being normal body weight, overweight, or obese. Efficacy end points were time to onset of symptom relief and time to complete resolution of symptoms. The safety profile was evaluated according to adverse events occurring within 7 to 9 days of treatment.

    RESULTS: Of 57 patients, 24 (42%) were of normal body weight, 20 (35%) were overweight, and 13 (23%) were obese. Median (95% CI) time to onset of symptom relief was 0.37 hour (0.29-0.57) in normal-weight patients, 0.48 hour (0.39-0.53) in overweight patients, and 0.58 hour (0.41-0.94) in obese patients. Median time (95% CI) to complete resolution of symptoms was 15.2 hours (9.3-23.2) in normal-weight patients, 22.6 hours (11.3-44.6) in overweight patients, and 11.0 hours (5.6-23.6) in obese patients (differences not significant). There were no relevant differences in the incidence of adverse events in normal-weight patients (54%), overweight patients (30%), and obese patients (54%).

    CONCLUSIONS: Treatment of HAE attacks with weight-based doses of C1-INH concentrate provided reliable treatment response, regardless of body weight, in these patients with HAE.
    Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

    Available from: https://www.clinicaltherapeutics.com/article/S0149-2918(14)00074-5/fulltext

    The thrombogenicity of C1 esterase inhibitor (human): review of the evidence

    Crowther M, Bauer KA, Kaplan AP. 11/2014 Allergy and Asthma Proceedings

    Thromboembolic events associated with human plasma-derived C1 esterase inhibitor (C1-INH) use in patients with hereditary angioedema (HAE) have been reported in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database. The purpose of this article is to review and assess the strength of available evidence regarding the thrombogenicity of human plasma-derived C1-INH. A PubMed search was conducted of English language articles from January 1990 to December 2013 reporting the thrombogenicity of C1-INH. Original research articles were selected if the following criteria were met: (1) C1-INH was the focus of the study and (2) the authors addressed the pro- or antithrombotic potential of C1-INH. Additional articles on the clinical use of C1-INH in disease states other than HAE were obtained using reference lists of selected articles. Pivotal studies and prescribing information for C1-INH products were also reviewed. Limited animal and clinical data suggest that C1-INH, particularly at high doses of up to 500 U/kg (compared with the U.S. FDA-approved 20-U/kg dose), may be prothrombotic. In contrast, C1-INH has been used in some patients with myocardial infarction, ischemic stroke, sepsis, and capillary leak syndrome at off-label supratherapeutic doses (up to 100 U/kg) without evidence of a thrombogenic effect. Based on our review, thromboembolic events reported with C1-INH use are rare and patients with HAE who experienced such events often have underlying thromboembolic risk factors.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2014/00000035/00000006/art00004

    Training hereditary angioedema patients to self-administer intravenous C1 esterase inhibitor concentrate

    Shapiro RS, Zacek L 7/2014 Journal of infusion nursing : the official publication of the Infusion Nurses Society

    Hereditary angioedema (HAE) is a rare disorder that causes periodic attacks of sometimes painful swelling that may affect any organ system. HAE results in significant morbidity and diminished quality of life and requires patients to seek urgent medical care. HAE can be treated with C1 esterase inhibitor concentrate (C1-INH), icatibant, and ecallantide. Recent consensus guidelines recommend that all HAE patients be considered for training in self-administration of therapy to treat acute attacks or to prevent attacks. Many patients have safely and successfully self-administered intravenous infusions of C1-INH, resulting in rapid treatment, shortened attacks, and improved quality of life. With proper patient selection and adequate guidance and follow-up, self-administered C1-INH therapy is a viable and favorable option to treat HAE, particularly in patients with a moderate to high frequency of attacks.

    Available from:

    https://journals.lww.com/journalofinfusionnursing/Abstract/2014/07000/Training_Hereditary_Angioedema_Patients_to.10.aspx

    Tranexamic acid as maintenance treatment for non-histaminergic angioedema: analysis of efficacy and safety in 37 patients

    Wintenberger C, Boccon-Gibod I, Launay D, Fain O, Kanny G, Jeandel PY, et al. 10/2014 Clinical and Experimental Immunology

    Angioedema (AE) is a clinical syndrome characterized by localised swelling lasting several hours. The swelling is often recurring and can be lethal if it is located in the laryngeal region. Much progress has been made recently in the treatment of acute episodes, but no consensus has been reached on maintenance treatment. We have performed a national retrospective observational study to assess the use of tranexamic acid (TA) as maintenance treatment for non-histaminergic AE [hereditary AE (HAE) or idiopathic non-histaminergic AE]. Records for 64 cases were collected from 1 October 2012 to 31 August 2013; 37 of these were included (12 HAE with C1-inhibitor deficiency, six with HAE with normal C1-inhibitor and 19 idiopathic non-histaminergic AE). When treated with TA over six months, the number of attacks was reduced by 75% in 17 patients, 10 patients showed a lower level of reduction and 10 had the same number of attacks. In no instances were symptoms increased. No thromboembolic events were observed, and the main side effects were digestive in nature. Thus, TA, which is well tolerated and inexpensive, appears to be an effective maintenance treatment for some patients with HAE or idiopathic non-histaminergic AE.Copyright © 2014 British Society for Immunology.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/cei.12379/full

    Treatment of hereditary angioedema with icatibant: efficacy in clinical trials versus effectiveness in the real-world setting

    Maurer M, Longhurst HJ, Fabien V, Li HH, Lumry WR. 9/2014 Allergy and Asthma Proceedings

    Icatibant was efficacious and generally well tolerated for type I or II hereditary angioedema (HAE) attacks in adults in the phase III, randomized, placebo-controlled For Angioedema Subcutaneous Treatment (FAST)-3 trial. The Icatibant Outcome Survey (IOS) is an international, observational study assessing icatibant treatment of HAE attacks. We conducted a posthoc analysis to compare for the first time the treatment of HAE type I or II attacks in patients prescribed icatibant in real-world (IOS) versus controlled trial settings (FAST-3). In FAST-3, patients received icatibant administered by health care professionals (HCPs). In IOS, patients self-administered icatibant or were treated by HCPs. Median time to treatment, time to resolution (almost complete resolution [FAST-3] or complete resolution [IOS]), and attack duration in patients who were treated by an HCP were compared between IOS and FAST-3. Descriptive statistical methods compared nonlaryngeal attacks treated less than 12 hours from attack onset. Analysis included 102 patients (376 attacks) from IOS and 43 patients (43 attacks) from FAST-3 (controlled phase). All endpoints were significantly longer for patients in FAST-3 (HCP administration) versus IOS (HCP administration) (p < .001; all comparisons). For FAST-3 (HCP administered) versus IOS (HCP administered), median time from attack onset to treatment was 6.5 versus 2.0 hours, median time to symptom resolution was 8.0 versus 3.5 hours, and median attack duration was 16.9 versus 7.3 hours, respectively. For combined HCP and self-administration in IOS, these endpoints were 1.6, 4.4, and 7.8 hours, respectively. This posthoc analysis showed for the first time that type I and II HAE attacks were treated earlier with icatibant in a real-world versus a phase III setting, with a shortened time to symptom resolution and attack duration. ClinicalTrials.gov NCT00912093 (FAST-3); NCT01034969 (IOS).

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2014/00000035/00000005/art00007

    Treatment of hereditary angioedema: a review (CME)

    Bhardwaj N, Craig TJ. 11/2014 Transfusion

    Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety. Copyright © 2014 AABB.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/trf.12674/full

    Urticaria and angioedema

    Spickett G. 01/2014 Royal College of Physicians of Edinburgh (J.R.Coll.Physicians.Edinb.)

    Urticaria, also known as hives, and angioedema, where the swelling occurs below the skin instead of on the skin, are extremely common but there is a misconception that the most likely cause is an allergic reaction. Chronic urticaria in particular is rarely due to allergy. Equally for angioedema, many will consider the exceptionally rare hereditary angioedema (HAE), but in fact other medical causes are the most likely, in particular the use of angiotensin-converting enzyme inhibitor (ACE-I) drugs. Approximately 3-5% of patients receiving ACE-I will develop angioedema at some time in the course of their treatment.1 Stress is a major contributor to both chronic urticaria and recurrent angioedema. Treatment needs to focus on the use of long-acting, non-sedating, antihistamines. Corticosteroids may be used acutely but not long term.

    2014;44(1):50-54

    Available from: http://www.rcpe.ac.uk/sites/default/files/spickett.pdf (free)

    Use of recombinant C1 inhibitor in patients with resistant or frequent attacks of hereditary or acquired angioedema

    Manson AL, Dempster J, Grigoriadou S, Buckland MS, Longhurst HJ. 1/2014 European Journal of Dermatology

    BACKGROUND: Conestat alfa (Ruconest, rhC1INH) is the first recombinant human C1 inhibitor protein (C1INH) for the treatment of acute attacks of hereditary angioedema (HAE).

    OBJECTIVE: To assess clinical experience of the first 11 adult patients who received rhC1INH in clinical practice in the UK.

    METHODS: Eleven patients (nine HAE type 1, one HAE type 2 and one acquired angioedema with C1 inhibitor deficiency) received between one and six, mostly self-administered, doses of rhC1INH for acute HAE attacks. They were asked to record their time to first response and complete resolution following the treatment. This cohort included our most severely affected and difficult to treat patients.

    RESULTS: In most cases, time to first improvement following rhC1INH and complete resolution was recorded as comparable to their typical response to pdC1INH, although 4/11 patients reported that the time to first improvement was much quicker than their average pdC1INH response. Five of the 11 patients continued with rhC1INH as their preferred rescue treatment. Of those who chose not to continue the treatment, four reported a recurrence or early return of symptoms with rhC1INH.

    CONCLUSION: In our experience, rhC1INH is a beneficial treatment for patients with preference for a C1INH that is not plasma derived and it is suitable for home treatment. In some cases it demonstrates cost saving, especially for heavier patients who require higher doses. In some patients rhC1INH may result in faster resolution of symptoms. It may be associated with an early return of symptoms in patients with exceptionally frequent attacks.

    Available from: http://link.springer.com/article/10.1684%2Fejd.2013.2252

    Analysis of characteristics associated with reinjection of icatibant: Results from the icatibant outcome survey

    Longhurst HJ, Aberer W, Bouillet L, Caballero T, Fabien V, Zanichelli A, et al. 9/2015 Allergy and Asthma Proceedings

    PURPOSE: Phase 3 icatibant trials showed that most hereditary angioedema (HAE) (C1 inhibitor deficiency) acute attacks were treated successfully with one injection of icatibant, a selective bradykinin B2 receptor antagonist. We conducted a post hoc analysis of icatibant reinjection for HAE type I and II attacks in a real-world setting by using data from the Icatibant Outcome Survey, an ongoing observational study that monitors the safety and effectiveness of icatibant treatment.

    METHODS: Descriptive retrospective analyses of icatibant reinjection were performed on Icatibant Outcome Survey data (February 2008 to December 2012). New attacks were defined as the onset of new symptoms after full resolution of the previous attack. Potential associations between the patient and attack characteristics and reinjection were explored by using logistic regression analysis.

    RESULTS: Icatibant was administered for 652 attacks in 170 patients with HAE type I or II. Most attacks (89.1%) were treated with a single icatibant injection. For attacks that required two or three injections, the second injection was given a median of 11.0 hours after the first injection, with 90.4% of second injections administered >6 hours after the first injection. Time to resolution and attack duration were significantly longer for two or three injections versus one icatibant injection (p < 0.0001 and p < 0.05, respectively). Multivariate logistic regression analysis identified sex, attack severity, and laryngeal attacks as significantly correlated with reinjection (all p < 0.05). These factors did not remain predictors for reinjection when two outlier patients with distinct patterns of icatibant use were excluded.

    CONCLUSIONS: In this real-world setting, most HAE attacks resolved with one icatibant injection. There was no distinct profile for patients or attacks that required reinjection when outliers with substantially different patterns of use were excluded. Because new attacks were not distinguished from the recurrence of symptoms, reinjection rates may be slightly higher than shown here. Clinical trial identifier: NCT01034969.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2015/00000036/00000005/art00016

    Angiotensin-converting enzyme inhibitor-induced angioedema and hereditary angioedema: a comparison study of attack severity

    Javaud N, Charpentier S, Lapostolle F, Lekouara H, Boubaya M, Lenoir G, et al. /2015 Internal Medicine

    OBJECTIVE: There appears to be differences in the clinical presentation of hereditary angioedema (HAE) and angiotensin-converting enzyme inhibitor-induced (ACE-I) angioedema (AE). The aim of this study was to compare the clinical characteristics of these two AE forms. Methods We conducted a retrospective study of consecutive patients with HAE or ACE-I AE. The attack characteristics experienced by the patients were compared by a logistic regression analysis using generalized estimating equations. Results A total of 56 patients were included in this study (ACE-I AE, n=25; HAE, n=31). A total of 534 attacks were documented. Severe attacks were more common in the patients who had an acute episode of ACE-I AE than HAE. Swelling of the tongue, lips and larynx were significantly associated with ACE-I AE [OR: 8.70 (95% CI, 1.04-73.70), OR: 20.4 (95% CI, 4.9-84.2) and OR: 7.50 (95% CI, 1.20-48.30), respectively]. Conclusion Swelling of the tongue, lips and larynx are significantly more frequent in drug-induced AE than HAE.

    Available from: https://www.jstage.jst.go.jp/article/internalmedicine/54/20/54_54.4181/_article

    Applying complement therapeutics to rare diseases

    Reis ES, Mastellos DC, Yancopoulou D, Risitano AM, Ricklin D, Lambris JD. 12/2015 Clinical Immunology

    Around 350 million people worldwide suffer from rare diseases. These may have a genetic, infectious, or autoimmune basis, and several include an inflammatory component. Launching of effective treatments can be very challenging when there is a low disease prevalence and limited scientific insights into the disease mechanisms. As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation. In view of the clinical experience acquired with drugs licensed for the treatment of rare diseases such as hereditary angioedema and paroxysmal nocturnal hemoglobinuria, growing evidence supports the safety and efficacy of complement therapeutics in restoring immune balance and preventing aggravation of clinical outcomes. This review provides an overview of the candidates currently in the pharmaceutical pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1521661615300267 (small fee)

    Characterization of anaphylaxis after ecallantide treatment of hereditary angioedema attacks

    Craig TJ, Li HH, Riedl M, Bernstein JA, Lumry WR, MacGinnitie AJ, et al. 3/2015 The Journal of Allergy and Clinical Immunology: In Practice

    BACKGROUND: Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis.

    OBJECTIVE: The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the ecallantide clinical trials database.

    METHODS: Potential cases of hypersensitivity reactions in the ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined.

    RESULTS: Among patients who received subcutaneous ecallantide (n = 230 patients; 1045 doses of 30 mg ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions.

    CONCLUSION: Anaphylaxis episodes after subcutaneous ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-ecallantide or anti-P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S2213219814003912

    Characterization of patients with angioedema without wheals: the importance of F12 gene screening2015

    Firinu D, Bafunno V, Vecchione G, Barca MP, Manconi PE, Santacroce R, et al. 4/2015 Clinical Immunology

    Sporadic and familiar forms of non-histaminergic angioedema and normal C1 inhibitor encompass a group of disorders possibly caused by bradikinin. We aimed to study the subgroups of hereditary angioedema with FXII mutation (FXII-HAE), unknown genetic defect (U-HAE) and idiopathic non-histaminergic acquired angioedema (InH-AAE). We screened the F12 locus in our cohort and delineated the clinical, laboratory and genetic features. Four families carried the p.Thr309Lys mutation in F12 gene. Haplotyping confirmed the hypothesis of a common founder. Six families were affected by U-HAE and 13 patients by sporadic InH-AAE. C4 levels were significantly lower in FXII-HAE than in InH-AAE. In the FXII-HAE group, none had attacks exclusively in high estrogenic states; acute attacks were treated with icatibant. Prophylaxis with tranexamic acid reduced the attack frequency in most patients. Our study provides new data on the diagnosis, clinical features and treatment of non-histaminergic angioedema, underlying the role of the screening for F12 mutations. Copyright © 2015 Elsevier Inc. All rights reserved.

    Available from: http://europepmc.org/abstract/med/25744496

     

    Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan

    Ohsawa I, Honda D, Nagamachi S, Hisada A, Shimamoto M, Inoshita H, et al. 6/2015 Annals of Allergy, Asthma & Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening condition that results from mutations in the C1 inhibitor (C1-INH). Awareness of HAE among physicians in Japan is increasing, but real-world data are lacking.

    OBJECTIVE: To explore the clinical manifestations, diagnosis, quality of life (QOL), and treatment of Japanese patients with HAE.

    METHODS: A 14-point survey was developed and sent to 387 physicians in Japan (March to May 2014) to gather clinical data on their HAE patients’ family history, severity and frequency of attacks, QOL, and therapy use.

    RESULTS: Data on 171 HAE patients were collected from 94 physicians (24.3% response rate). Of the patients, 76.6% had a family history of angioedema (AE), and 11.7% had experienced a death in the family due to an AE attack. HAE type I occurred in 99 patients (57.9%), HAE type II occurred in 9 patients (5.3%), HAE with normal C1-INH occurred in 3 patients (1.8%), and an additional 60 patients were unclassified. Mean time from initial symptoms to diagnosis was 13.8 years. Attacks that required airway management and abdominal surgery with uncertain diagnosis were observed in 9.5% and 2.9% of patients, respectively. In the past year, 21.0% of patients presented with more than 10 attacks, 21.1% were admitted to the hospital for more than 1 day, and 28.7% were absent from work or school. On-demand C1-INH concentrate and prophylactic tranexamic acid were used in approximately half of the patients (47.4% and 39.2%, respectively).

    CONCLUSION: HAE is a severe condition characterized by recurrent AE attacks. In Japan, delayed patient diagnosis and limited use of HAE-specific therapies exacerbate the burden on HAE patients.Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(15)00161-1/fulltext (small fee)

    Clinical Pattern and Acute and Long-term Management of Hereditary Angioedema Due to C1-Esterase Inhibitor Deficiency

    Gomez-Traseira C, Perez-Fernandez E, Lopez-Serrano MC, Garcia-Ara MC, Pedrosa M, Lopez-Trascasa M, et al. 5/2015 Journal of Investigational Allergology and Clinical Immunology

    BACKGROUND: Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease.

    OBJECTIVES: To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice.

    METHODS: An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009).

    RESULTS: We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%.

    CONCLUSION: Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often.

    Available from: http://www.jiaci.org/summary/vol25-issue5-num1261

    Comparison of chromogenic and ELISA functional C1 inhibitor tests in diagnosing hereditary angioedema

    Li HH, Busse P, Lumry WR, Frazer-Abel A, Levy H, Steele T, et al. 3/2015 The Journal of Allergy and Clinical Immunology: In Practice

    INTRODUCTION: Measuring functional C1 inhibitor (C1 INH) with chromogenic or ELISA methods can confirm a diagnosis of hereditary angioedema (HAE) due to C1 INH deficiency. Previous studies found differences in the agreement of these assays.

    OBJECTIVE: To evaluate the agreement between chromogenic or ELISA methods in the context of an observational study.

    METHODS: Patients with previously confirmed HAE underwent functional C1 INH testing. These patients contacted first-degree relatives (parents, siblings, or offspring) not previously evaluated for HAE, who underwent a panel of complement testing, including for functional C1 INH.

    RESULTS: Overall, 31 patients with HAE and 46 untested relatives enrolled. Of 46 relatives, 14 (30.4%) were newly diagnosed with HAE based on their laboratory results. Among the 31 patients previously confirmed with HAE, all had low functional C1 INH according to the chromogenic method, whereas 22 (71.0%) had low, 7 (22.6%) had equivocal, and 2 (6.5%) had normal functional C1 INH according to the ELISA method. In the 14 newly diagnosed relatives, all had low functional C1 INH according to the chromogenic method, whereas 11 (78.5%) had low and 3 (21.4%) had equivocal results according to the ELISA method.

    CONCLUSION: Despite the apparent discordance in the ELISA and chromogenic assays in a small number of patients, both were useful in measuring functional C1 INH. To establish the diagnosis of HAE due to C1 INH deficiency, functional C1 INH results should be interpreted in combination with family and clinical history, and with other complement tests.Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S2213219814003407 (small fee)

    Critical appraisal of androgen use in hereditary angioedema: a systematic review

    Riedl MA. 4/2015 Annals of Allergy, Asthma, and Immunology

    OBJECTIVE: To provide an objective basis for evaluating the risk-benefit ratio of long-term androgen use in patients with hereditary angioedema (HAE).

    DATA SOURCES: PubMed was searched with no time limitations using the keywords hereditary angioedema or angio-oedema combined with danazol, stanozolol, and androgen.

    STUDY SELECTION: Qualifying articles were English-language reports of androgen use in patients with HAE, with relevant safety and/or efficacy information. Reports were categorized according to level of evidence (LOE).

    RESULTS: The search process identified 153 citations, 63 of which contained relevant information; 2 additional publications were identified while other citations were being reviewed. Fifteen LOE 2 studies and multiple LOE 4 reports provided efficacy data, confirming a high level of prophylactic efficacy for androgen therapy in HAE, with occasional reports of poor prophylactic response. Common adverse events include weight gain, menstrual irregularities, virilization, headaches, myalgias or cramps, mood changes, and elevations in creatine phosphokinase level, liver function test results, and serum lipid level. The risk of adverse events is often correlated with dose and/or treatment duration. Rare cases of hepatic adenomas and hepatocellular carcinoma associated with long-term androgen use often had no preceding changes in liver function test results.

    CONCLUSION: Androgen therapy may be effective for most patients with HAE; however, potential risks and adverse effects must be carefully considered and discussed with patients when considering options for long-term HAE prophylaxis.Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1081120615000344 (small fee)

    Current characteristics associated with hereditary angioedema attacks and treatment: the home infusion based patient experience

    Tachdjian R, Banerji A, Guyer A, Morphew T. 4/2015 Allergy and Asthma Proceedings

    This article presents a current perspective on the characteristics of hereditary angioedema (HAE) attacks and treatment as captured by a home infusion service. Retrospective data on 158 HAE patients who were enrolled in this acute treatment program were analyzed for factors surrounding an attack. The majority of patients had a high level of disease severity at baseline (88%), with a higher than expected likelihood of having a positive family history (87.8%). The most likely times for patients to call for home treatment were just before and during working hours (6:00 A.M.-5:00 P.M.). Eighty-three percent had more than one alternate mode of medication. Factors associated with a severe attack included an overall severe rating of HAE attacks in the previous year, an abdominal attack alone or a combination of peripheral and abdominal attacks versus a peripheral attack alone, and the use of two doses rather than one for treatment of the current attack. Average time to relief onset was 43.5 minutes. One dose of ecallantide was sufficient to treat the majority of attacks, and a second dose was needed in 23.6% of patients experiencing a severe attack. However, patients who reported both a severe attack rating during the previous year and experiencing only a peripheral current attack were more likely to experience a severe current attack. Acute treatment paradigms for HAE remain diverse. Understanding factors driving these decisions could help alleviate the overall burden of this disease and help overcome some of the challenges faced by the patients and their caretakers and improve their quality of life. Enhanced capture and analysis of prodromal factors in future studies should help us further alleviate the burden of this disease.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2015/00000036/00000002/art00013 (small fee)

    Current medical management of hereditary angioedema: follow-up survey of US physicians

    Riedl MA, Banerji A, Gower R. 3/2015 The Journal of Allergy and Clinical Immunology: In Practice

    BACKGROUND: A physician survey conducted in the United States between October 2009 and February 2010 revealed wide variability in hereditary angioedema (HAE) management.

    OBJECTIVE: A follow-up survey was conducted to assess the impact of newly available treatment options and investigate changes in HAE care patterns.

    METHODS: Between March and June 2013, 6570 physicians were contacted, of whom, 245 HAE-treating physicians responded. Participants completed a 46-question online survey that was closely patterned after the initial survey. Although most data were analyzed descriptively, selected questions underwent statistical analysis to evaluate differences in treatment patterns between the 2 surveys.

    RESULTS: Compared with the prior survey, this follow-up survey found that the proportion of physicians who reported danazol as the preferred long-term prophylaxis agent declined from 56% to 23% (P < .00005); conversely, C1-esterase inhibitor increased in this category (20% to 57%; P < .00005). The percentage of attacks self-treated at home increased from 8% to 27% (P < .00005). Decreases were observed in emergency department visits (61% to 54%; P = not significant) and hospitalizations (13% to 3%; P = .0001) for HAE attacks. The percentage of patients perceived by physicians to be very satisfied with HAE treatment increased from 13% to 40% (P < .00005). In 2013, convenience was reported more frequently as an important patient factor that drove long-term prophylaxis choice (27% vs 10%; P < .00005), whereas adverse effects were cited less frequently (16% vs 42%; P < .00005); in both surveys, cost and/or insurance coverage was the greatest driver in this category (43% and 46%).

    CONCLUSION: Analysis of these findings suggests that the change in HAE treatment has increased self-treatment at home, decreased emergency department visits and/or hospitalizations, and provided greater patient satisfaction.Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S2213219814004012 (small fee)

    Development and content validity testing of a patient-reported outcomes questionnaire for the assessment of hereditary angioedema in observational studies

    Bonner N, Abetz-Webb L, Renault L, Caballero T, Longhurst H, Maurer M, et al. /2015 Health and Quality of Life Outcomes

    BACKGROUND: Hereditary Angioedema (HAE), a rare genetic disease, manifests as intermittent, painful attacks of angioedema. Attacks vary in frequency and severity and include skin, abdominal and life-threatening laryngeal swellings. This study aimed to develop a patient reported outcome (PRO) tool for the assessment of HAE attacks, including their management and impact on patients’ lives, for use in clinical studies, or by physicians in general practice.

    METHODS: The results of open-ended face to face concept elicitation interviews with HAE patients in Argentina (n=10) and the US (n=33) were used to develop the first draft questionnaire of the HAE patient reported outcomes questionnaire (HAE PRO). Subsequently, in-depth cognitive debriefing interviews were performed with HAE patients in the UK (n=10), Brazil (n=10), Germany (n=11) and France (n=12). Following input from eight multinational clinical experts further cognitive interviews were conducted in the US (n=12) and Germany (n=12). Patients who experienced abdominal, cutaneous or laryngeal attacks of varying severity levels were included in all rounds of interviews. Across the rounds of interviews patients discussed their HAE attack symptoms, impacts and treatments. Cognitive debriefing interviews explored patient understanding and relevance of questionnaire items. All interviews were conducted face to face following a pre-defined semi-structured interview guide in the patient’s native language.

    RESULTS: Patients reported a variety of HAE symptoms, attack triggers, warning signs, attack impacts and treatment options which were used to develop the HAE PRO. The HAE PRO was revised and refined following input from patients and clinical experts. The final 18-item HAE PRO provides an assessment of the HAE attack experience including symptoms, impacts, treatment requirements, healthcare resource use and loss of productivity caused by HAE attacks.

    CONCLUSIONS: Patient and expert input has contributed to the development of a content valid questionnaire that assesses concepts important to HAE patients globally. HAE patients across cultures consider the HAE PRO a relevant and appropriate assessment of HAE attacks and treatment.

    Available from: http://hqlo.biomedcentral.com/articles/10.1186/s12955-015-0292-7

    Diagnostic and therapeutic management of hereditary angioedema due to C1-inhibitor deficiency: the Italian experience

    Cancian M, Italian network for C1-INH-HAE (ITACA) 8/2015 Current Opinion in Allergy & Clinical Immunology

    PURPOSE OF REVIEW: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease, with a reported prevalence of about 1 : 50 000. C1-INH-HAE causes disabling symptoms, which may be life-threatening if swelling affects upper airways. Diagnostic procedures are now well established and the role of bradykinin as the main mediator of plasma outflow eliciting angioedema formation has been clearly elucidated.

    RECENT FINDINGS: Increased understanding of the pathogenesis of C1-INH-HAE allowed in recent years the development of new drugs targeted to inhibit bradykinin synthesis (Ecallantide) or activity (Icatibant). At the same time, a recombinant C1-INH concentrate (Ruconest) was produced from the milk of transgenic rabbits and two plasma-derived C1-INHs (Berinert, Cinryze) underwent controlled trials to obtain marketing authorization. In 2012, an Italian network for C1-INH-HAE (ITACA) was established by physicians of 17 HAE reference centres to collect data from Italian patients and to homogenize and improve the diagnostic and therapeutic approach to the disease.

    SUMMARY: Although there is a widespread agreement on therapeutic goals and treatment of C1-INH-HAE acute attacks, different approaches to prophylaxis are still present among HAE experts. The clinical experience of ITACA on a large population of C1-INH-HAE patients followed for several years may help in identifying the most effective strategies for the management of the disease.

    Available from: http://journals.lww.com/co-allergy/pages/articleviewer.aspx?year=2015&issue=08000&article=00018&type=abstract (small fee)

    Distinct conditions support a novel classification for bradykinin-mediated angio-oedema

    Dessart P, Defendi F, Humeau H, Nicolie B, Sarre M, Charignon D, et al. 4/2015 Dermatology

    BACKGROUND: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO.

    OBJECTIVE: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism).

    METHODS: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. RESULTS: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation.

    CONCLUSION: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK.

    Available from: https://www.karger.com/Article/Purchase/371814 (small fee)

    Efficacy of C1 esterase inhibitor concentrate in treatment of cutaneous attacks of hereditary angioedema

    Bork K, Craig TJ, Bernstein JA, Feuersenger H, Machnig T, Staubach P. 6/2015 Allergy and Asthma Proceedings

    BACKGROUND: Although treatment with C1 esterase inhibitor (C1-INH) concentrate is well established for hereditary angioedema (HAE) attacks in general, data that assess its efficacy for cutaneous attack treatment are sparse.

    OBJECTIVE: To assess efficacy of plasma-derived, nanofiltered C1-INH concentrate for cutaneous attack treatment by comparing treated attacks from the uncontrolled I.M.P.A.C.T.2 study with historical data for untreated attacks.

    METHODS: Cutaneous attack data from patients with HAE who were treated for cutaneous edema with 20 IU/kg body weight C1-INH concentrate in the uncontrolled I.M.P.A.C.T.2 study (38 patients) were compared with data from untreated patients from an historical data base (46 patients) and included subset analyses for facial edema (treated group, 21 patients; untreated group, 33 patients) and peripheral edema (30 patients in each group). Average attack duration (AAD) per patient was the efficacy end point used to compare treated and untreated patients. Differences were assessed with a Wilcoxon test (primary analysis) and a log-rank test; AAD per patient was analyzed descriptively and graphically with Kaplan-Meier curves.

    RESULTS: The AAD per patient of all cutaneous attacks or facial and peripheral cutaneous attack subsets was significantly faster with C1-INH treatment than without treatment (Wilcoxon and log-rank tests, both p < 0.0001 for all comparisons). Mean AADs per patient for all, facial, and peripheral attacks were 2.04, 1.45, and 2.16 days, respectively, in the C1-INH-treated group, and were 3.74, 4.45, and 2.98 days, respectively, in the untreated group. Kaplan-Meier curves corroborated the observed group differences.

    CONCLUSION: Treatment of cutaneous HAE attacks (all attacks or facial and peripheral attack subsets) with 20 IU/kg C1-INH concentrate provided faster attack resolution compared with no treatment.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405603/

    Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency

    Zanichelli A, Mansi M, Azin GM, Wu MA, Periti G, Casazza G. et al. 12/2015 Allergy

    BACKGROUND: Angioedema due to hereditary deficiency of C1 inhibitor causes temporarily disability. Guidelines recommend early on-demand treatment of attacks to reduce morbidity. In this prospective observational study, we evaluated the efficacy of on-demand approach.

    METHODS: From January 2009 to August 2014, data on attacks and treatments were collected from 227 patients from our centre in Milan.

    RESULTS: A total of 4244 attacks were reported; 50% were treated with approved therapies (pdC1-INH or icatibant), 15% were with tranexamic acid, and 35% were not treated. Attack locations were peripheral cutaneous (46%), abdominal (34%), multiple (12%), facial (5%) and laryngeal (3%). Attack severities were moderate (48%), mild (28%) and severe (24%). Median attack duration (data available for 2393 attacks) with approved therapies was 10 h, significantly shorter than without treatment (45 h) or with tranexamic acid (38 h). Most of the treatments were self-administered: 93% with icatibant and 59% with pd-C1-INH. Median attack duration with icatibant was 8 and 11.5 h with pd-C1 INH. Median time from onset of symptoms to drug administration was 1 h with icatibant and 2 h with pd-C1INH and median time from drug administration to complete resolution was 5.5 and 8 h, respectively. Second treatment was required in 12.7% of icatibant-treated attacks and in 1.9% of pdC1-INH-treated attacks.

    CONCLUSION: This study provides evidence that on-demand treatment is effective in reducing disease-related morbidity. The use of on-demand treatment in Italy has increased up to 50% of attacks in the last years, reflecting a better adherence to international guidelines.
    Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/all.12731

    Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk

    Reshef A, Zanichelli A, Longhurst H, Relan A, Hack CE. 5/2015 Allergy

    BACKGROUND: Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE.

    METHODS: Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment.

    RESULTS: Plasma D-dimer levels were elevated in 80% of the patients (median [25th-75th percentiles]: 2149 [480-5105] mug/l; normal <250 mug/l) and were higher in patients with submucosal (abdominal, oropharyngeal-laryngeal) attacks (3095 [890-10000] mug/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] mug/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475-4568] mug/l rhC1INH; 2259 [586-7533] mug/l saline) and 2 h postinfusion (2389 [760-4974] mug/l rhC1INH; 2550 [310-8410] mug/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232-3240] mug/l rhC1INH; 418 [246-2318] mug/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls.

    CONCLUSION: Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.Copyright © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12587/full

    Epidemiology of angioedema without wheals in an allergy and immunology center

    Malbran E, Fernandez Romero D, Juri MC, Larrauri BJ, Malbran A. 5/2015 Medicina

    We describe the diagnostic epidemiology, the clinical course, the family history and the response to treatment of patients with angioedema without wheals (AWW) at an Allergy and Immunology Clinical Center. We reviewed the case records of all patients at our office from January 1997 to April 2013. We recorded sex, age, age at onset of symptoms, family history of angioedema, number of visits to the office, type of angioedema, and response to treatment from those patients with angioedema without wheals. We classified angioedema according to its pathophysiology. We also describe those patients with angioedema mimics. From a total of 17,823 new patients, 303 had a presumptive diagnosis of angioedema without wheals. Twenty-three patients had an angioedema mimic. Forty percent were male and 60% were female. Average age at first visit was 40.6. Average number of visits was 2.4. Fifty-seven patients referred a family history. We attributed idiopathic angioedema to 55.7% of patients, 24.3% were drug related, 15.7% were due to C1 inhibitor deficiency, 2.1% were drug related+idiopathic angioedema, 1.4% were type III and 0.7% had exercise-induced angioedema. Ninety six percent of 53 evaluable idiopathic angioedema patients referred a benefit with anti-histamine therapy. AWW was a rare cause of consultation. Most of our patients had anti H1 responsive idiopathic angioedema and none had allergic angioedema. Women cases prevailed over men’s. Family history and average age of onset of symptoms were different among the different types of angioedema.

    Available from: www.medicinabuenosaires.com/PMID/26502460.pdf

    Facilitating home-based treatment of hereditary angioedema

    Bernstein JA, Riedl M, Zacek L, Shapiro RS. 3/2015 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients’ quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient’s primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2015/00000036/00000002/art00005

    Factors associated with hospital admission in hereditary angioedema attacks: a multicenter prospective study

    Javaud N, Gompel A, Bouillet L, Boccon-Gibod I, Cantin D, Smaiti N, et al. 6/2015 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Acute attacks of hereditary angioedema are characterized by recurrent localized edema. These attacks can be life threatening and are associated with substantial morbidity and mortality.

    OBJECTIVE: To determine factors associated with hospital admission of patients with an acute attack of hereditary angioedema presenting at the emergency department.

    METHODS: This was a multicenter prospective observational study of consecutive patients (January 2011 through December 2013) experiencing an acute hereditary angioedema attack and presenting at the emergency department at 1 of 4 French reference centers for bradykinin-mediated angioedema. Attacks requiring hospital admission were compared with those not requiring admission.

    RESULTS: Of 57 attacks in 29 patients, 17 (30%) led to hospital admission. In multivariate analysis, laryngeal and facial involvements were associated with hospital admission (odds ratio 18.6, 95% confidence interval 3.9-88; odds ratio 7.7, 95% confidence interval 1.4-43.4, respectively). Self-injection of icatibant at home was associated with non-admission (odds ratio 0.06, 95% confidence interval 0.01-0.61). The course was favorable in all 57 cases. No upper airway management was required.

    CONCLUSION: Most patients attended the emergency department because they were running out of medication and did not know that emergency treatment could be self-administered. Risk factors associated with hospital admission were laryngeal and facial involvement, whereas self-injection of icatibant was associated with a return home.Copyright © 2015. Published by Elsevier Inc.

    Available from: http://www.annallergy.org/article/S1081-1206(15)00236-7/fulltext

    Health-related quality of life in Danish patients with hereditary angioedema

    Aabom A, Andersen KE, Perez-Fernandez E, Caballero T, Bygum A. 2/2015 Acta Dermato Venereologica

    Available from: http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1835&html=1

    Hereditary angioedema and lupus: A French retrospective study and literature review

    Gallais Serezal I, Bouillet L, Dhote R, Gayet S, Jeandel PY, Blanchard-Delaunay C, et al. 6/2015 Autoimmunity Reviews

    Hereditary angioedema (HAE) is a rare genetic disorder that is primarily caused by a defect in the C1 inhibitor (C1-INH). The recurrent symptoms are subcutaneous edema and abdominal pain. Laryngeal edema, which can also occur, is life threatening if it goes untreated. HAE can be associated with some inflammatory and autoimmune disorders, particularly lupus. The aim of this study was to describe cases of lupus among HAE patients in France and to perform a literature review of lupus and HAE studies. Case detection and data collection (a standardized form) were performed, thanks to the French Reference Center for Kinin-related angioedema. Data were collected from 6 patients with type 1 HAE and lupus in France; no cases of systemic lupus erythematosus were reported. In the literature review, 32 cases of lupus combined with HAE were identified, including 26 female patients. The median patient age at the time of first reported HAE symptoms and at diagnosis were 17.5 years (range, 9-41 years) and 19 years (range, 9-64 years), respectively for our 6 patients and 14 years (range, 3-30 years) and 17 years (range, 7-48 years), respectively, for the literature review. The clinical manifestations of HAE were mainly abdominal pain (83% in our patients vs 47% in the literature) and edema of the limbs (83% vs 38%). The C4 levels were low (for 100% of our cases vs 93% in the literature). Eighteen patients in the literature demonstrated HAE symptoms prior to the lupus onset vs 5 for our patients. The mean patient age at lupus onset was 20 years (range, 13-76 years) for our patients and 19.5 years (range, 1-78 years) in the literature, respectively. In the literature, 81% of the patients had skin manifestations, 25% had renal involvement and 28% received systemic steroids to treat lupus. Treatment with danazol did not modify the clinical expression of lupus. The association between lupus and HAE is a rare but not unanticipated event. Patients are often symptomatic for HAE before developing lupus. Lupus cases associated with HAE share some characteristics of lupus cases related to other complement deficiencies, such as the absence of severity and the predominance of cutaneous symptoms.Copyright © 2015 Elsevier B.V. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S1568997215000348 (small fee)

    Hereditary angioedema with a focus on the child

    Bennett G, Craig T. 1/2015 Allergy and Asthma Proceedings

    Hereditary angioedema (HAE) is a rare disease that causes recurrent mucosal and cutaneous swelling. Skin swelling, abdominal pain, and airway swelling cause significant morbidity and potential mortality. Symptoms often appear early in life and accelerate around puberty. Despite this, there is a paucity of both data and treatment options for HAE in children in the United States. Our objective was to summarize the published data and perform a retrospective chart review on children with HAE to improve care of the child with the disease. A retrospective chart review study was performed after Institutional Review Board approval. A search of electronic medical records from 2001 to 2011 was performed for children aged 1 to 18 years with a confirmed diagnosis of HAE. Demographic patient information was obtained and analyzed. Twenty-five pediatric patients were identified with the diagnosis of HAE: 13 female and 12 male. The median age at diagnosis was seven years. The most common initial presenting symptom was swelling of the upper extremity, followed by abdominal pain, swelling of the face and/or lower extremity, and scrotal swelling. Three patients reported no previous symptoms and were diagnosed due to family history of HAE and positive laboratory testing. The majority of patients (84%) reported a family history of HAE. Accurate and timely diagnosis of HAE is imperative for children to prevent further morbidity and mortality associated with the disease.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2015/00000036/00000001/art00013

    Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations

    Bork K, Wulff K, Witzke G, Hardt J. 8/2015 Allergy

    BACKGROUND: Hereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown.

    METHODS: Sixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied.

    RESULTS: Both HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1 : 68 in HAE-FXII and 1 : 6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35 : 14 for HAE-FXII and 109 : 12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3 years in patients with HAE-FXII and 29.6 years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased.

    CONCLUSIONS: HAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/all.12648/full

    Home Therapy with Plasma-Derived C1 Inhibitor: A Strategy to Improve Clinical Outcomes and Costs in Hereditary Angioedema

    Petraroli A, Squeglia V, Di Paola N, Barbarino A, Bova M, Spano R, et al. 6/2015 International Archives of Allergy and Immunology

    BACKGROUND: Attacks of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) are commonly treated in the emergency department. Self-administration is emerging as an effective treatment option. In this study, we assessed the impact of home therapy with plasma-derived C1 esterase inhibitor (pdC1-INH) concentrate on treatment outcomes and costs.

    METHODS: This is an observational study in C1-INH-HAE patients who switched to home therapy with pdC1-INH (Berinert) after learning intravenous self-infusion in a training course at a center in Southern Italy. Before starting home therapy and after the first year of home therapy, patients were interviewed about their treatment and outcomes during the prior 12 months. Annual costs were analyzed by cost minimization from the Italian health care payer perspective and the societal perspective. Outcomes and costs before and after the switch to home therapy were compared.

    RESULTS: The training course was attended by 36 participants, 17 (47.2%) of whom decided to switch to home therapy. This therapy was associated with a significant decrease in the mean annual number of hospitalizations (16.8 vs. 2.1, p = 0.003) and missed work/school days (20.3 vs. 7.1, p = 0.037) compared to conventional treatment. The times from symptom onset to treatment administration and from treatment administration to symptom improvement/resolution were not significantly different between the two strategies. The mean annual per-patient costs decreased with home therapy from EUR 30,010.57 to EUR 26,621.16 (11.3% saving) and from EUR 29,309.34 to EUR 26,522.04 (9.5% saving) from the societal and payer perspective, respectively.

    CONCLUSIONS: Home therapy with pdC1-INH is a feasible strategy for the management of C1-INH-HAE and may result in cost savings.

    Available from: https://www.karger.com/Article/Abstract/381341

    Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3

    Lumry WR, Farkas H, Moldovan D, Toubi E, Baptista J, Craig T, et al. /2015 International Archives of Allergy and Immunology

    BACKGROUND: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093).

    METHODS: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale).

    RESULTS: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant.

    CONCLUSIONS: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.Copyright © 2015 S. Karger AG, Basel.

    Available from: http://www.karger.com/Article/Purchase/441060 (small fee)

    Icatibant in angiotensin-converting enzyme (ACE) inhibitor-associated angioedema

    Fok JS, Katelaris CH, Brown AF, Smith WB. 8/2015 Internal Medicine Journal

    BACKGROUND: Angioedema occurs in up to 2% of those taking angiotensin-converting enzyme (ACE) inhibitors. Upper airway angioedema may potentially require endotracheal intubation or cricothyrotomy, and is usually unresponsive to adrenaline. The bradykinin receptor antagonist icatibant is proven to be effective in the treatment of acute attacks of hereditary angioedema, and has also been reported effective in the treatment of angioedema associated with ACE inhibitors. AIM: To describe the use of icatibant for ACE inhibitor-associated airway angioedema.

    METHODS: We treated 13 consecutive emergency department (ED) patients, who had not improved with adrenaline and/or corticosteroids, with icatibant 30mg subcutaneously for ACE inhibitor-associated upper respiratory tract angioedema according to an agreed protocol.

    RESULTS: Four patients were intubated in the ED either before or after receiving icatibant; three of these were extubated within 24h of treatment. Eight patients received early icatibant and did not require intubation. The time from onset of airway angioedema to ED presentation ranged from 1h to 3 days (median 4h); from ED presentation to receiving icatibant, from 30 minutes to 3 days (median 3h); and to onset of symptom improvement after icatibant, 15 minutes to 7h (median 2h). One patient received a second dose of icatibant.

    CONCLUSION: All patients improved after receiving icatibant, consistent with its bradykinin receptor blocking mechanism. Icatibant rapidly reversed symptoms, and appeared to avert the need for intubation or expedite extubation. Timely use of icatibant in ACE inhibitor-associated angioedema may avert the need for invasive airway procedures and intensive care unit admission.Copyright © 2015 Royal Australasian College of Physicians.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/imj.12799/full (small fee)

    Patients perception of self-administrated medication in the treatment of hereditary angioedema. Annals of Allergy, Asthma, & Immunology

    Wang A, Fouche A, Craig TJ. 8/2015 Annals of Allergy, Asthma, and Immunology

    BACKGROUND: Early therapy of hereditary angioedema (HAE) decreases morbidity, improves outcomes, decreases absenteeism, and possibly decreases mortality. This can be accomplished best with self-therapy. Previously, the authors examined barriers to self-therapy from the perspective of the nurse and the physician, but data are lacking on what patients perceive as major barriers to self-administered therapy for HAE.

    OBJECTIVE: To identify those barriers in a prospective fashion by patient interview.

    METHODS: After approval from the institutional review board, a telephone survey was performed of patients with HAE from a database of patients who were recently seen in the clinic. The survey focused on anxiety, depression, stress, concerns regarding method of administration, the ability to inject themselves, and what they perceived as barriers to providing self-care.

    RESULTS: Ninety-two patients were contacted and 59 agreed to participate. With 69% of those patients currently undergoing self-administered treatment, the results showed minimal depression and anxiety, a high satisfaction with treatment, and significant compliance with treatment. Most of those not yet on self-administered therapy wanted to start despite being satisfied with the care received in the emergency department. They also believed care at home would be optimal. The main concern of the 2 groups was not being able to treat themselves in the event of an HAE attack.

    CONCLUSION: From these data, it is obvious that most patients are willing to self-treat. This suggests that physicians should encourage self-treatment of HAE to improve outcomes and quality of life of patients with HAE.Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206%2815%2900390-7/abstract

    Pharmacokinetics of single and repeat doses of icatibant

    Leach JK, Spencer K, Mascelli M, McCauley TG 3/2015 Clinical pharmacology in drug development

    PURPOSE: Icatibant is a bradykinin-2 receptor antagonist approved to treat acute hereditary angioedema attacks in adults. To-date, no thorough investigation of the clinical pharmacokinetic (PK) parameters of icatibant and its primary metabolites has been reported. Here we present the PK results of two phase I clinical studies of icatibant in healthy human volunteers.

    METHODS: Single- and multiple-dose plasma pharmacokinetics of icatibant were characterized in healthy volunteers. Icatibant concentration-time profiles and PK parameters were derived after a single 30- or 90-mg dose or three 30-mg doses given at 6-hour intervals.

    RESULTS: Maximal plasma concentrations for the 30-mg (979+/-262ng/mL) and 90-mg doses (2,719+/-666ng/mL) were achieved at <1hour postdose. The total plasma icatibant exposure for the 30- and 90-mg doses was 2,191+/-565 and 6,736+/-1,230h.ng/mL, respectively, with elimination half-life values of 1.48+/-0.35 and 2.00+/-0.57hours, respectively.

    CONCLUSIONS: Single 30- and 90-mg subcutaneous administration of icatibant exhibited dose-proportional PK with no appreciable accumulation upon repeated 30-mg doses administered at 6-hour intervals.
    Copyright © 2014, The American College of Clinical Pharmacology.

    Available from: https://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/cpdd.138

    Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate

    Zuraw BL, Cicardi M, Longhurst HJ, Bernstein JA, Li HH, Magerl M, et al. 10/2015 Allergy

    BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long-term prophylaxis with twice-weekly intravenous injections of plasma-derived C1-inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE.

    METHODS: This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity.

    RESULTS: After SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event.

    CONCLUSIONS: Subcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.Copyright © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.

    Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755045/

    Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review

    Craig TJ, Schneider LC, MacGinnitie AJ. 9/2015 Pediatric Allergy and Immunology

    Presently, medications approved for children with Hereditary Angioedema (HAE) are extremely limited. This is especially the case for children under 12 years of age. For this reason we reviewed and summarized the data on treatment of children with HAE. Available data indicate that plasma derived C1-inhibitor is a safe, effective treatment option for HAE in pediatric patients, including those below 12 years of age. Other therapies are also appear safe for the under 12 year of age, but less data are available. Importantly, home-based treatment of HAE in this age group appears to be safe and effective and can improve quality of life. These findings support current HAE consensus guidelines which strongly recommend the use of plasma derived C1-inhibitor as a first-line treatment in children and encourage home and self-treatment. Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/pai.12425/full

    Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients

    Mansi M, Zanichelli A, Coerezza A, Suffritti C, Wu MA, Vacchini R, et al. 5/2015 Journal of Internal Medicine

    BACKGROUND: The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance.

    METHODS: In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor.

    RESULTS: According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment.

    CONCLUSION: Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.Copyright © 2014 The Association for the Publication of the Journal of Internal Medicine.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/joim.12304/full

    Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE)

    Sabharwal G, Craig T. 3/2015 Expert Review of Clinical Immunology

    The lack of C1 inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma kallikrein inhibitor (ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile.

    Available from: http://www.tandfonline.com/doi/full/10.1586/1744666X.2015.1012502 (small fee)

    Recombinant human C1 esterase inhibitor in the management of hereditary angioedema. [Review]

    Riedl M 7/2015 Clinical drug investigation

    Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488495/

    Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks

    Li HH, Moldovan D, Bernstein JA, Reshef A, Porebski G, Stobiecki M, et al. 6/2015 The Journal of Allergy and Clinical Immunology: In Practice

    BACKGROUND: Hereditary angioedema (HAE) caused by a deficiency in functional C1 esterase inhibitor (C1INH) is characterized by recurrent episodes of cutaneous and/or mucosal/submucosal tissue swelling affecting multiple anatomic locations. Previous studies demonstrated efficacy of recombinant human C1INH (rhC1INH) for acute HAE attacks.

    OBJECTIVE: This study evaluated the efficacy and safety of rhC1INH (50 IU/kg) for the treatment of multiple HAE attacks in an open-label extension study.

    METHODS: Time to onset of symptom relief and time to minimal symptoms were assessed using a Treatment Effect Questionnaire (TEQ), a visual analog scale, and a 6-point ordinal scale Investigator Score.

    RESULTS: Forty-four patients received rhC1INH, and a single dose was administered for 215 of 224 (96%) attacks. Median time to beginning of symptom relief based on TEQ for the first 5 attacks was 75.0 (95% CI, 69-89) minutes, ranging from 62.5 (95% CI, 48-90) to 134.0 (95% CI, 32-119) minutes. Median time to minimal symptoms using TEQ for the first 3 attacks was 303.0 (95% CI, 211-367) minutes. rhC1INH was well tolerated. There were no discontinuations due to adverse events. No thrombotic or anaphylactic events were reported, and repeat rhC1INH treatments were not associated with neutralizing anti-C1INH antibodies.

    CONCLUSIONS: A single 50-IU/kg dose rhC1INH was effective for improving symptoms of an HAE attack with sustained efficacy for treatment of subsequent attacks. rhC1INH had a positive safety profile throughout the study. This study supports repeated use of rhC1INH over time in patients with HAE attacks.Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S2213219815000094

    Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency

    Moldovan D, Bernstein JA, Cicardi M. 7/2015 Immunotherapy

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest() (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

    Available from: http://www.futuremedicine.com/doi/full/10.2217/imt.15.44

    Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema

    Lumry W, Soteres D, Gower R, Jacobson KW, Li HH, Chen H, et al. 11/2015 Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

    BACKGROUND: Human plasma-derived nanofiltered C1 esterase inhibitor (C1 INH-nf) is used to treat acute angioedema attacks in patients with hereditary angioedema (HAE), but data regarding use in children are sparse.

    METHODS: Patients 2 to <12 years of age, body weight >=10 kg, with a diagnosis of HAE type I or II, were recruited for a multicenter open-label trial. Patients were recruited into 2 weight categories (10-25 kg, >25 kg). Each weight category included 2 dosing levels: C1 INH-nf (500 units [U], 1000 U) and C1 INH-nf (1000 U, 1500 U), respectively. Patients experiencing an angioedema attack were given a single intravenous dose. Primary efficacy end-point was the onset of unequivocal relief of the defining symptom within 4 h following initiation of C1 INH-nf treatment.

    RESULTS: Nine children were treated: 3 (10-25 kg) received 500 U; 3 (>25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. The lower weight/higher dose category (10-25 kg, 1000 U) was not successfully enrolled. All patients completed the study. Most angioedema attacks (n = 5) were abdominal. All patients met the primary end-point; median time to unequivocal symptom relief was 0.5 (range: 0.25-2.5) h. Doses of C1 INH-nf ranged from 20.8 to 51.9 U/kg.

    CONCLUSIONS: Treatment of a single angioedema attack with C1 INH-nf doses of 500 U (in patients 10-25 kg), 1000 U, and 1500 U (in patients >25 kg) were well tolerated. Doses of C1 INH-nf <1000 U may be appropriate in some pediatric patients.
    Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/pai.12444

    Safety of C1-esterase inhibitor in acute and prophylactic therapy of hereditary angioedema: findings from the ongoing international Berinert patient registry

    Busse P, Bygum A, Edelman J, Lumry W, Machnig T, Martinez-Saguer I, et al. 3/2015 The Journal of Allergy and Clinical Immunology: In Practice

    BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products, typically with off-label use or at supratherapeutic doses.

    OBJECTIVES: Active surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events.

    METHODS: A registry was initiated in April 2010 at 27 US and 4 EU sites to obtain both prospective and retrospective safety and usage data on subjects who were administered C1-INH (Berinert).

    RESULTS: As of May 10, 2013, data were available for 135 subjects and 3196 infusions. By subject, 67.4% were using C1-INH as on-demand therapy and 23.0% as both on-demand therapy and prophylactic administration. Approximately half of the infusions (49.5%) were administered for prophylaxis and >90% were given by the patient or a caregiver in the home setting. A total of 299 adverse events were reported, for an overall rate of 0.09 events per infusion with only 6 considered related to C1-INH. Two thromboembolic events were reported, both in patients with prothrombotic risk factors.

    CONCLUSION: This large pool of real-world clinical usage data in HAE further supports the extensive safety profile of 2 Berinert formulations when used on demand and/or for prophylaxis in both home and health care settings. No evidence was found to suggest that Berinert is an independent, causative risk factor for thromboembolic events.Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.sciencedirect.com/science/article/pii/S2213219814003961 (small fee)

    Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe

    Turley AJ, Gathmann B, Bangs C, Bradbury M, Seneviratne S, Gonzalez-Granado LI, et al. 2/2015 Journal of Clinical Immunology

    INTRODUCTION: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management.

    METHODS: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software.

    RESULTS: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p<0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects.

    CONCLUSION: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.

    Available from: http://link.springer.com/article/10.1007%2Fs10875-015-0137-5 (small fee)

    The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

    Hansen CB, Csuka D, Munthe-Fog L, Varga L, Farkas H, Hansen KM, et al. 10/2015 The Journal of Immunology

    C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE. Copyright © 2015 by The American Association of Immunologists, Inc.

    Available from: http://www.jimmunol.org/content/195/8/3596.long (small fee)

    Treatment of angiotensin receptor blocker-induced angioedema: A case series

    Strassen U, Bas M, Hoffmann TK, Knopf A, Greve J. 7/2015 Laryngoscope

    BACKGROUND: Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist.

    METHODS: We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n = 3) or prednisolone-21-hydrogen succinate/clemastine (n = 5). Both patient groups were compared with an untreated patient cohort (n = 3). All patients were previously diagnosed with essential hypertonia.

    RESULTS: Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema.

    CONCLUSIONS: Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker-induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway.Copyright © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

    Available from: https://www.karger.com/Article/FullText/381341

    Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals

    Hernandez Fernandez de Rojas D, Ibanez E, Longhurst H, Maurer M, Fabien V, Aberer W, et al. 7/2015 International Archives of Allergy and Immunology

    BACKGROUND: Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of acute hereditary angio-oedema (HAE) attacks in adults, can be administered by health care professionals (HCPs) or self-administered. This analysis compared characteristics and outcomes of acute HAE attacks treated with self-administered and HCP-administered icatibant in a real-world setting.

    METHODS: The Icatibant Outcome Survey (Shire, Zug, Switzerland; NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (February 2008 to December 2012).

    RESULTS: Icatibant was used in 652 attacks in 170 patients with HAE type I/II. Most icatibant injections were self-administered (431/652, 68.5%). The proportion of self-treated attacks increased over time (40.3% in 2009 vs. 89.7% in 2012). The median time to administration was significantly shorter in self- versus HCP-treated attacks (1.5 vs. 2.4 h; p = 0.016). Earlier treatment (<2 h after onset) was significantly associated with a shorter median time to resolution (2.5 vs. 5.0 h; p = 0.032) and attack duration (3.0 vs. 14.0 h; p < 0.0001), regardless of administration method. Patients self-administered icatibant for attacks of all severities; overall, 34.7% of severe and 30.2% of very severe attacks were HCP treated. Logistic regression analysis did not find use of long-term prophylaxis, attack location or gender to be predictive for self-administration.

    CONCLUSIONS: The proportion of HAE attacks treated with self-administered icatibant increased over time. Patients successfully self-administered icatibant for a wide variety of HAE attacks, demonstrating that icatibant is generally well tolerated and effective for self-administration. Self-administration of icatibant provides a complementary option to HCP administration, enabling optimization of patient care.Copyright © 2015 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/FullText/430864

    Year in review: urticaria and angioedema

    Hsieh FH. 3/2015 Annals of Allergy, Asthma, and Immunology

    Available from: http://www.annallergy.org/article/S1081-1206%2814%2900872-2/abstract

    A decade of change: Recent developments in pharmacotherapy of hereditary angioedema (HAE)

    Bork K. 10/2016 Clinical Reviews in Allergy and Immunology

    Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare but medically significant disease that can be associated with considerable morbidity and mortality. Research into the pathogenesis of HAE-C1-INH has expanded greatly in the last six decades and has led to new clinical trials with novel therapeutic agents and treatment strategies. Mechanisms of pharmacotherapy include (a) supplementing C1-INH, the missing serine-protease inhibitor in HAE; (b) inhibiting the activation of the contact system and the uncontrolled release of proteases in the kallikrein-kinin system, by blocking the production/function of its components; (c) inhibiting the fibrinolytic system by blocking the production/function of its components; and (d) inhibiting the function of bradykinin at the endothelial level. Strategies for managing HAE-C1-INH are aimed at treating acute attacks, or preventing attacks, through the use of prophylactic treatment. Available agents for treating acute attacks include plasma-derived C1-INH concentrates, a recombinant C1-INH, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor. Long-term prophylactic treatments include attenuated androgens, plasma-derived C1-INH concentrates, and anti-fibrinolytics. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are already approved for self-administration at home. The number of management options for HAE-C1-INH has increased considerably within the past decade, thus helping to alleviate the burden of this rare disease.

    Available from: http://link.springer.com/article/10.1007%2Fs12016-016-8544-9

    A recombinant C1 esterase inhibitor (Ruconest) for hereditary angioedema

    Anonymous 3/2016 The Medical Letter on Drugs and Therapeutics

    Available from : secure.medicalletter.org/TML-article-1491d

    ACE-I angioedema: Accurate clinical diagnosis may prevent epinephrine-induced harm

    Curtis RM, Felder S, Borici-Mazi R, Ball I. 5/2016 The Western Journal of Emergency Medicine

    INTRODUCTION: Upper airway angioedema is a life-threatening emergency department (ED) presentation with increasing incidence. Angiotensin-converting enzyme inhibitor induced angioedema (AAE) is a non-mast cell mediated etiology of angioedema. Accurate diagnosis by clinical examination can optimize patient management and reduce morbidity from inappropriate treatment with epinephrine. The aim of this study is to describe the incidence of angioedema subtypes and the management of AAE. We evaluate the appropriateness of treatments and highlight preventable iatrogenic morbidity.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899059/

    Allergenicity and safety of recombinant human C1 esterase inhibitor in patients with allergy to rabbit or cow’s milk

    van den Elzen MT, van Os-Medendorp H, Rockmann-Helmbach H, van Hoffen E, Lebens AF, van Doorn H, Klemans RJ, Bruijnzeel-Koomen CA, Hack CE, Kaufman L, Relan A, Knulst AC. 8/2016 The Journal of Allergy and Clinical Immunology

    BACKGROUND: Recombinant human C1 inhibitor (rhC1INH) for on-demand treatment of hereditary angioedema is purified from milk of transgenic rabbits. It contains low amounts (<0.002%) of host-related impurities, which could trigger hypersensitivity reactions in patients with rabbit allergy (RA) and/or cow’s milk allergy (CMA).

    OBJECTIVE: This study is an assessment of allergenicity and safety of rhC1INH in patients with RA and/or CMA.

    METHODS: Patients with CMA and/or RA underwent skin prick test (SPT), intracutaneous test (ICT), and, when results for both were negative, subcutaneous (SC) challenge with up to 2100U (14 mL) rhC1INH. The negative predictive value of the skin test protocol was calculated, defined as the ratio of patients without systemic symptoms of hypersensitivity following SC challenge, over the number of patients having tested negative for both the SPT and the ICT. Adverse events after exposure to rhC1INH were recorded.

    RESULTS: Twenty-six patients with RA and/or CMA were enrolled. Twenty-four had negative SPT and ICT results for rhC1INH, whereas 2 had negative SPT result but positive ICT result to rhC1INH (only the highest concentration). Twenty-two patients with negative SPT and ICT results underwent SC challenge. None developed allergic symptoms. Local treatment-emergent adverse events occurred in 7 patients (32%) after SC challenge. In 5 these were considered drug related. All were mild.

    CONCLUSIONS: None of the patients with negative SPT and ICT results for rhC1INH had allergic symptoms during rhC1INH challenge. The negative predictive value of the combination of SPT and ICT for the outcome of the SC challenge was 100% (95% CI, 84.6%-100%). SC administration of rhC1INH was well tolerated.
    Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.jacionline.org/article/S0091-6749(16)30280-9/fulltext

    Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor

    Farkas H, Varga L, Moldovan D, Obtulowicz K, Shirov T, Machnig T, Feuersenger H, Edelman J, Williams-Herman D, Rojavin M. 11/2016 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Limited data are available regarding C1 inhibitor (C1-INH) administration and anti-C1-INH antibodies.

    OBJECTIVE: To assess the incidence of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH) in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) and the comparative efficacy of pnfC1-INH in patients with and without antibodies.

    METHODS: In this multicenter, open-label study, patients with C1-INH-HAE (>=12 years of age) were given 20 IU/kg of pnfC1-INH per HAE attack that required treatment and followed up for 9 months. Blood samples were taken at baseline (day of first attack) and months 3, 6, and 9 and analyzed for inhibitory anti-C1-INH antibody (iC1-INH-Ab) and noninhibitory anti-C1-INH antibodies (niC1-INH-Abs).

    RESULTS: The study included 46 patients (69.6% female; mean age, 38.9 years; all white) who received 221 on-site pnfC1-INH infusions; most patients received 6 or fewer infusions. No patient tested positive (titer >=1:50) for iC1-INH-Ab at any time during the study. Thirteen patients (28.2%) had detectable niC1-INH-Abs in 1 or more samples. Nine patients (19.6%) had detectable niC1-INH-Abs at baseline; 3 of these had no detectable antibodies after baseline. Of 10 patients (21.7%) with 1 or more detectable result for niC1-INH-Abs after baseline, 6 had detectable niC1-INH-Abs at baseline. Mean times to symptom relief onset and complete symptom resolution per patient were similar for those with or without anti-niC1-INH-Abs.

    CONCLUSION: Administration of pnfC1-INH was not associated with iC1-INH-Ab formation in this population. Noninhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no effect on pnfC1-INH efficacy.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01467947.
    Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(16)30580-4/fulltext

    Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1-inhibitor deficiency

    Zotter Z, Veszeli N, Kohalmi KV, Varga L, Imreh E, Kovacs G, Nallbani M, Farkas H. 12/2016 Allergy

    Urinary tract infections are considered among the most common infectious disorders in humans. Various infections may have a role in inducing HAE attacks. Our study intended to evaluate bacteriuria in the urinalysis of patients with C1-INH-HAE. Urine specimens contributed by 139 patients with C1-INH-HAE at the annual control visits were studied retrospectively for microorganisms. We analyzed the presence of bacteriuria in relation to the clinical symptoms. Taking into account three randomly selected urine specimens, we found that the cumulative number of edematous attacks was higher in patients with bacteriuria than in those without (P = 0.019, P = 0.022, P = 0.014). Considering the same patients, attack number was significantly higher (14.51 vs 8.63) in patients with bacteriuria than in those without (P < 0.0001). In patients with bacteriuria, we found a higher incidence of edema formation during the year before evaluation, which may suggest the triggering role of bacteriuria in the occurrence of edematous episodes.
    Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/all.13034/full

    Bradykinin-mediated angioedema

    Obtulowicz K. 1/2016 Polskie Archiwum Medycyny Wewnetrznej

    Angioedema and urticaria often constitute a challenge in daily clinical practice. They may either co- -occur or present as independent conditions. They are characterized by a complex pathomechanism, and their symptoms may be triggered by diverse factors. These differences are crucial for developing a successful treatment regimen. Both conditions may have an allergic origin (immunoglobulin [Ig] E and non-IgE-related), usually induced by histamine, or a nonallergic one, such as bradykinin-mediated angioedema in patients with C1 inhibitor (C1-INH) deficiency or angioedema induced by certain drugs (eg, angiotensin-converting enzyme inhibitors). Currently, we distinguish 5 types of nonallergic angioedema: hereditary angioedema (HAE) due to C1-INH deficiency, acquired angioedema (AAE), and angioedema induced by the renin-angiotensin-aldosterone system, all of which are mediated by bradykinin, as well as pseudoallergic angioedema and idiopathic angioedema. Bradykinin-mediated angioedema (eg, laryngeal angioedema) may be life-threatening because of resistance to corticosteroids and antihistamine drugs. C1-INH concentrates are the drugs of choice in the treatment of HAE and AAE. In recent years, some new drugs have been introduced in the treatment of bradykinin-mediated angioedema, such as bradykinin B2-receptor antagonist, icatibant, and kallikrein inhibitor, ecallantide, which allow to improve treatment outcomes.

    Available from: http://pamw.pl/en/issue/article/26842379

    Bradykinin-mediated angioedema: Factors associated with admission to an intensive care unit, a multicenter study

    Javaud N, Floccard B, Gontier F, Lapostolle F, Boccon-Gibod I, Martin L, Amarger S, Boumedienne A, Boubaya M, Asfar P, Coppere B, Ollivier Y, Bouillet L, Adnet F, Fain O. 6/2016 European Journal of Emergency Medicine: Official Journal of the European Society for Emergency Medicine

    OBJECTIVE: Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life-threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU.

    PATIENTS AND METHODS: We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission.

    RESULTS: Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4+/-5 days). One death was observed by asphyxiation because of laryngeal swelling.

    CONCLUSION: Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe.

    Available from: https://journals.lww.com/euro-emergencymed/Abstract/2016/06000/Bradykinin_mediated_angioedema___factors.12.aspx

    Clinical presentation, pathophysiology, diagnosis, and treatment of acquired and hereditary angioedema: Exploring state-of-the-art therapies in RI

    Guo C, Settipane RA. 6/2016 Rhode Island Medical Journal (2013)

    Hereditary and acquired angioedema are potentially life-threatening diseases characterized by spontaneous episodes of subcutaneous and submucosal swelling of face, lips, oral cavity, larynx, and GI tract. Hereditary angioedema (HAE) usually presents within the first and second decades of life, whereas acquired angioedema presents in adults after 40 years of age. These clinical symptoms together with reduced C1 inhibitor levels and/or activity can usually confirm the diagnosis. In recent years, multiple novel therapies for treating hereditary angioedema have emerged including C1 inhibitor concentrates, ecallantide/kallikrein inhibitor, and icatibant/bradykinin receptor antagonist. This article reviews the clinical presentation, diagnosis, treatment, and prophylaxis of HAE. Lastly, this article takes into consideration that, in reality, acute care treatment can often be limited by each hospital’s formulary, included is a review of HAE treatments available at the nine major hospitals in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login].

    Available from:  http://www.rimed.org/rimedicaljournal/2016/06/2016-06-41-cont-guo.pdf

    Complement inhibition for prevention and treatment of antibody-mediated rejection in renal allograft recipients

    Jordan SC, Choi J, Kahwaji J, Vo A. 4/2016 Transplantation Proceedings

    Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo-controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development.

    Copyright © 2016 Elsevier Inc. All rights reserved.

    Available from: http://www.transplantation-proceedings.org/article/S0041-1345(16)00130-5/fulltext

    Complements are not always a good thing: Novel therapies for angioedema

    Bailey AM, Reed BS, Weant KA, Justice SB. 4/2016 Advanced Emergency Nursing Journal

    Hereditary angioedema attacks are rare, but emergency care providers must be aware of the clinical presentation and treatment of these patients because the emergency department remains the most common setting where these patients seek treatment. If providers are not aware of the past medical history of these patients, they are likely to receive standard therapies for respiratory distress and anaphylaxis including antihistamines, corticosteroids, and epinephrine. However, these medications may not work in these patients, given the pathophysiology of their underlying disease. Since 2009, several new therapies have been approved for the treatment of acute hereditary angioedema attacks. This article discusses pathophysiology, clinical presentation, and use of novel therapies for the management of angioedema.

    Available from : http://journals.lww.com/aenjournal/pages/articleviewer.aspx?year=2016&issue=04000&article=00004&type=abstract

    Current treatment options for hereditary angioedema due to C1 inhibitor deficiency

    Wu MA, Zanichelli A, Mansi M, Cicardi M. 1/2016 Expert Opinion on Pharmacotherapy

    INTRODUCTION: Hereditary angioedema (HAE) usually results from C1 inhibitor (C1-INH) deficiency or dysfunction. It is a rare autosomal dominant disorder characterized by localized, non-pitting edema of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus, due to a temporary increase in vascular permeability. Other forms of HAE have been described, but therapies are approved only for HAE with C1-INH deficiency: hence, this review focuses on C1-INH-HAE.

    AREAS COVERED: The aim of this review article is to present current available therapies for treatment of acute attacks as well as for short- and long-term prophylaxis of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). The Authors highlight also critical issues on the management of C1-INH-HAE, which is continuously evolving thanks to evidence from clinical trials, post-marketing experience and ongoing studies.

    EXPERT OPINION: In the last decade, the quality of life of C1-INH-HAE patients has significantly improved due to increased knowledge and awareness of the disease, improved patient support and major progress in pharmacotherapy. Ongoing research will probably provide patients with other new effective therapeutic agents in the near future.

    Available from: http://www.tandfonline.com/doi/full/10.1517/14656566.2016.1104300?needAccess=true

    Dedicated call center (SOS-HAE) for hereditary angioedema attacks: study protocol for a randomised controlled trial

    Javaud N, Fain O, Durand-Zaleski I, Launay D, Bouillet L, Gompel A, Sobel A, Woimant M, Rabetrano H, Petrovic T, Lapostolle F, Boccon-Gibod I, Reuter PG, Bertrand P, Coppere B, Floccard B, Kanny G, Martin L, Vicaut E, Adnet F. 4/2016 Trials

    BACKGROUND: Despite the availability of guidelines for the specific treatment of hereditary angioedema (HAE) attacks, HAE morbidity and mortality rates remain substantial. HAE attacks are a major medical issue requiring specific treatment as well as a considerable socio-economic burden. We report a protocol designed to test whether a dedicated call centre is more effective than usual practice in the management of patients experiencing an HAE attack.

    METHODS/DESIGN: This prospective, cluster-randomised, single-blind, parallel-group, multicentre trial evaluates the morbidity and consequent socio-economic costs of the management of patients experiencing an HAE attack by a dedicated call centre as compared to usual practice. The trial aims to recruit 200 patients. Patients in the intervention arm are provided with an SOS-HAE card with the call centre’s freephone number that they can access in the case of an attack. The centre’s mission is to provide recommended expert advice on early home treatment. The centre can route the call to a local emergency medical service with competency in HAE management or even arrange for the drugs needed for the specific treatment of an HAE attack to be sent to the emergency department of the local hospital. The primary outcome measure is the number of hospital admissions for an HAE attack. Each patient will be followed up every 2 months for 2 years. The study has been approved by the ethics committee (Comite de Protection des Personnes d’Ile de France 10; registration number: 2012-A00044-39; date of approval: 19 January 2012).

    DISCUSSION: The SOS-HAE protocol has been designed to address the handling of attacks experienced by patients with HAE in the home. The proposed trial will determine whether the setting up of a dedicated call centre is more effective than usual practice in terms of reducing morbidity as given by the numbers of hospital admissions. The results are also anticipated to have important implications in terms of socio-economic costs for both healthcare services and patients.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01679912 .

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853856/

    Efficacy of different medical therapies for the treatment of acute laryngeal attacks of hereditary angioedema due to C1-esterase inhibitor deficiency

    Bork K, Bernstein JA, Machnig T, Craig TJ. 4/2016 The Journal of Emergency Medicine

    BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by C1-esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema, which can be life-threatening if they occur in the upper airway. No head-to-head comparisons of different treatment options for acute HAE attacks are available. Because immediate symptom relief is critical for potentially life-threatening laryngeal attacks, it is important to determine the treatment option that provides optimal treatment response.

    OBJECTIVE: Review and compare data from clinical studies that evaluated the efficacy and safety of treatments for laryngeal HAE attacks.

    METHODS: We conducted an indirect comparison of clinical outcomes from prospective studies for treatment of 881 acute laryngeal attacks with plasma-derived C1-INH concentrate (pdC1-INH) at fixed doses (500 or 1000 U) or a body weight-adjusted dose (20 U/kg), recombinant C1-INH concentrate at a fixed dose (2100 U), or a body weight-adjusted dose (50 U/kg), icatibant (30 mg), or ecallantide (30 mg). Comparisons included time to onset of symptom relief and need for re-dosing or emergency procedures.

    RESULTS: The median time to onset of symptom relief ranged between 15 min and approximately 2 h, and was shortest with body weight-adjusted doses of pdC1-INH. The proportion of laryngeal attacks with re-dosing ranged between 0% and 72%. No re-dosing was needed after treatment with a single body weight-adjusted dose of pdC1-INH (48 attacks).

    CONCLUSIONS: Available data suggest that among different HAE treatments, body weight-adjusted pdC1-INH (20 U/kg) provides the most reliable treatment response for treatment of laryngeal HAE attacks.

    Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.jem-journal.com/article/S0736-4679(15)01268-8/fulltext

    Hereditary angio-oedema with C1 inhibitor deficiency: Characteristics and diagnostic delay of Czech patients from one centre

    Hakl R, Kuklinek P, Kadlecova P, Litzman J. 5/2016 Allergologia et Immunopathologia

    BACKGROUND: Hereditary angio-oedema (HAE) is manifested by repeated episodes of localised subcutaneous or sub-mucosal oedema. Symptoms are extremely variable in frequency, localisation, and severity. Atypical or mild clinical symptoms of the disease may lead to erroneous diagnosis, causing diagnostic delay. The goal of this study was to assess how diagnostic delay has changed over 33 years at a single referral centre.

    METHODS: We analysed diagnostic delay and first symptoms of HAE in patients who were diagnosed at an immunology department between 1980 and 2013. Patient’s records were analysed.

    RESULTS: The median diagnostic delay in 77 HAE type 1 and 2 patients was seven (range, 0-42) years. The difference observed in diagnostic delay between probands (18 [0-42] years) and others (1 [0-37] year) was significant (p<0.001). Our data show a significant negative correlation between the length of diagnostic delay and the year of diagnosis in our group of patients (p=0.024). The median age of first symptoms among all HAE patients (N=64) was 17 (1-40) years. The first symptoms of HAE in 64 patients were analysed. Twenty-six patients had abdominal, seventeen peripheral, five facial, two urogenital, and three had laryngeal oedema as the first manifestation of the disease. The last death that was attributed to HAE was in 1977.

    CONCLUSIONS: Our observations demonstrate improved awareness of HAE among physicians, as documented by the significant decrease in diagnostic delay. It is believed that earlier treatment will improve patient quality of life and life expectancy.

    Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

    Available from: http://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hereditary-angio-oedema-with-c1-inhibitor-S0301054615001482

    Hereditary angioedema attacks: local swelling at multiple sites

    Hofman ZL, Relan A, Hack CE. 2/2016 Clinical Reviews in Allergy and Immunology

    Hereditary angioedema (HAE) patients experience recurrent local swelling in various parts of the body including painful swelling of the intestine and life-threatening laryngeal oedema. Most HAE literature is about attacks located in one anatomical site, though it is mentioned that HAE attacks may also involve multiple anatomical sites simultaneously. A detailed description of such multi-location attacks is currently lacking. This study investigated the occurrence, severity and clinical course of HAE attacks with multiple anatomical locations. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. Visual analog scale scores filled out by the patients for various symptoms at various locations and investigator symptoms scores during the attack were analysed. Data of 219 eligible attacks in 119 patients was analysed. Thirty-three patients (28%) had symptoms at multiple locations in anatomically unrelated regions at the same time during their first attack. Up to five simultaneously affected locations were reported. The observation that severe HAE attacks often affect multiple sites in the body suggests that HAE symptoms result from a systemic rather than from a local process as is currently believed.

    Available from: http://link.springer.com/article/10.1007/s12016-014-8463-6

    Hereditary angioedema in swedish adults: Report from the national cohort

    Nordenfelt P, Nilsson M, Bjorkander J, Mallbris L, Lindfors A, Wahlgren CF. 5/2016 Acta Dermato-venereologica

    Hereditary angioedema (HAE) is rare, disabling and sometimes life-threatening. The aim of this study is to describe its prevalence, symptomatology and treatment in Sweden. A total of 146 patients were identified; 110 adults and 36 children with HAE type I (n=136) or II (n=10), giving a minimal HAE prevalence of 1.54/100,000. All patients received a written questionnaire followed by a structured telephone interview. This report focuses on the 102 adults who responded. Females reported 19 attacks in the previous year vs. 9 for males (p<0.01), and females reported 10 days of sick leave vs. 4 days for males (p<0.05). For all treated acute attacks, plasma-derived C1-inhibitor concentrate (pdC1INH) (used in 27% of patients) had a good effect. For maintenance treatment, 43% used attenuated androgens and 8% used pdC1INH, which reduced their attack rate by more than 50%. In conclusion, the minimal HAE prevalence in Sweden was 1.54/100,000. HAE affected females more severely. Attenuated androgens and pdC1INH had a good effect on preventing attacks.

    Available from: https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2274

    Hereditary angioedema with F12 mutation: Clinical features and enzyme polymorphisms in 9 Southwestern Spanish families

    Pinero-Saavedra M, Gonzalez-Quevedo T, Saenz de San Pedro B, Alcaraz C, Bobadilla-Gonzalez P, Fernandez-Vieira L, Hinojosa B, Garcia-Lozano R. 11/2016 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Information on F12 mutation hereditary angioedema (HAE) is still limited, but Spain is now recognized as having one of the highest concentrations of cases in Western Europe.

    OBJECTIVE: To describe unique features of HAE in Spanish carriers of the F12 mutation and investigate a potential role for angiotensin-converting enzyme (ACE) and aminopeptidase-P polymorphisms in disease expression.

    METHODS: This was a prospective observational cohort study of 35 individuals (80% females) from 9 unrelated families carrying the p.Thr309Lys mutation. We analyzed detailed medical records and complement activity (C4, C1q, C1 inhibitor) and screened for mutations in exon 9 of the F12 gene and 2 polymorphisms: XPNPEP2 c-2399A and the ACE insertion/deletion polymorphism.

    RESULTS: The p.Thr309Lys mutation was found in all individuals. Three of the 9 index patients had a clinically negative family history, and 72% of males and 29% of females were asymptomatic. Sixteen females (44% estrogen dependent, 56% estrogen sensitive) were clearly symptomatic. The most common locations of attacks were the abdomen (63%), face (25%), and peripheral structures (6%). Triggers other than hyperestrogenic states included stress and minor trauma or pressure. Short-term treatment with C1-inhibitor concentrate and icatibant and long-term prophylaxis with tranexamic acid were useful. The combination of the I allele and A allele was detected in 17% of patients.

    CONCLUSION: The polymorphisms analyzed were not a major determinant of disease expression in our population. We recommend searching for F12 mutations in women with edema attacks without associated wheals and with normal C1-inhibitor levels, particularly when they develop symptoms during hyperestrogenic states or are of Western European or African origin.
    Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(16)30627-5/fulltext

    Hereditary angioedema with normal C1 inhibitor and factor XII mutation: A series of 57 patients from the French National Center of Reference for Angioedema

    Deroux A, Boccon-Gibod I, Fain O, Pralong P, Ollivier Y, Pagnier A, Djenouhat K, Du-Thanh A, Gompel A, Faisant C, Launay D, Bouillet L. 9/2016 Clinical and Experimental Immunology

    Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P=0.003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.
    Copyright © 2016 British Society for Immunology.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991515/

    High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibitor deficiency.[Erratum appears in Br J Haematol. 2016 Oct;175(2):351; PMID: 27734497]

    Castelli R, Wu MA, Arquati M, Zanichelli A, Suffritti C, Rossi D, Cicardi M. 3/2016 British Journal of Haematology

    Marginal zone lymphoma represents about 10% of all non-Hodgkin lymphomas (NHLs). 33% of patients with acquired angioedema (AAE) due to acquired C1-inhibitor (C1-INH) deficiency (C1-INH-AAE) have or will develop NHLs. C1-INH-AAE is a rare condition. We report the follow-up of 72 C1-INH-AAE patients, followed for a median of 15 years (range 1-24). Median age was 71 (range 64-79) years; median age at onset of angioedema symptoms was 57.5 (range 50-66) years and it was 63 [range 45-80) years at diagnosis]. Twenty patients were diagnosed with low-grade non-follicular B-cell lymphomas (75% were splenic MZL), one with follicular and three with high-grade lymphomas (two diffuse large B-cell lymphomas and one mantle cell lymphoma). Fifteen NHLs were diagnosed at onset of AAE or thereafter (3 months to 7 years), eight had already been diagnosed at onset of angioedema. Two of 24 patients remain on watchful wait. Thirthen of 24 received chemotherapy, two received rituximab. Three underwent splenectomy. All 18 patients receiving therapy for NHL experienced post-treatment reduction in AAE symptoms. Our study suggests that clonal B-cell proliferation is the pathology underlying AAE leading to production of C1-INH-neutralizing autoantibodies and to NHLs. The post-germinal centre origin of NHL suggests that immune stimulation may contribute to lymphomagenesis.

    Copyright © 2016 John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/bjh.13908/full

    Icatibant as acute treatment for hereditary angioedema in adults

    Farkas H. 6/2016 Expert Review of Clinical Pharmacology

    INTRODUCTION: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by recurrent, unpredictable episodes of cutaneous and/or mucosal edema. Bradykinin, released by the activation of the contact system, binds to bradykinin B2 receptors on the endothelial cell surface to enhance vascular permeaility, which leads to angioedema.

    AREAS COVERED: C1-INH-HAE therapy is aimed at the inhibition of bradykinin release, as well as at the blockage of its effects mediated by its receptor. Three controlled trials, three open-label extensions, and two open-label studies, and a prospective, observational study have confirmed the safety and efficacy of the bradykinin B2 receptor antagonist, icatibant administered as acute treatment for HAE attacks in adult patients with C1-INH-HAE. Expert commentary: The ready-to-use, pre-filled syringes of icatibant can be self-administered easily, effectively, safely and, importantly, conviently. – This has resulted in patients being able to quickly treat an attack and realize a dramatic change for the better in their lives.

    Available from: http://www.tandfonline.com/doi/full/10.1080/17512433.2016.1182425

    Idiopathic histaminergic angioedema without wheals: a case series of 31 patients

    Faisant C, Boccon-Gibod I, Mansard C, Dumestre Perard C, Pralong P, Chatain C, Deroux A, Bouillet L. 7/2016 Clinical and Experimental Immunology

    Idiopathic histaminergic acquired angioedema (IH-AAE) is a common cause of recurrent angioedema without wheals. It is a mast cell-mediated disease thought to belong to the same clinical entity as chronic urticaria (CU). The objective of this study was to describe the clinical and epidemiological characteristics of IH-AAE patients. From 2014 to 2015, 534 patients were seen at our national reference centre for angioedema and/or urticaria. Among them, we identified 31 patients with idiopathic histaminergic acquired angioedema without wheals (IH-AAE). Thirty-one patients (15 men and 16 women) with a mean age of 50 years met the criteria for IH-AAE. The average delay in diagnosis was 6.3 years. A history of allergy was found in 12 patients (38.7%), nine suffering from allergic rhinitis. The mean duration of attacks was 28.1 h. The AE attack was located in the upper respiratory tract in 54.8% of cases (17 patients). A lingual location was found in 29% of patients. Men were more likely than women to have an upper airway involvement. No intubations or admissions to intensive care units were reported. The dosage of anti-histamines to control the symptoms was onefold the recommended dose in 51.6% of patients (16 patients), twofold in 32% (10 patients) and three-fourfold in 16.1% (five patients). IH-AAE is characterized by an important delay in diagnosis, a frequent involvement of the upper airway and a benign course during attacks. As in CU, a trial of up to fourfold dose of H1-anti-histamines may be necessary to control symptoms.

    Copyright © 2016 British Society for Immunology.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/cei.12789/full

    Management of children with hereditary angioedema due to C1 inhibitor deficiency

    Frank MM, Zuraw B, Banerji A, Bernstein JA, Craig T, Busse P, Christiansen S, Davis-Lorton M, Li HH, Lumry WR, Riedl M, US Hereditary Angioedema Association Medical Advisory Board. 11/2016 Pediatrics

    Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient’s Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient’s Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE.
    Copyright © 2016 by the American Academy of Pediatrics.

    Available from: http://pediatrics.aappublications.org/content/138/5/e20160575.long

    Managing the female patient with hereditary angioedema

    Banerji A, Riedl M. 6/2016 Women's Health (London, England)

    Hereditary angioedema (HAE) is a rare disorder resulting from decreased functional levels of C1-inhibitor (C1-INH), which manifests as periodic episodes of localized edema which can be extremely painful, debilitating and even fatal if the swelling affects the larynx. HAE can complicate many aspects of obstetric/gynecologic care, and an awareness of the disease is critical for clinicians involved in the care of women because of potential HAE-related complications pertaining to pregnancy, labor and delivery, and other women’s health issues. This article provides a review of published literature specific to HAE and its management in female patients, including important concerns regarding obstetric/gynecologic care. A growing body of relevant experience is presented to help guide the care of women with HAE.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384520/

    Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting

    Zanichelli A, Longhurst HJ, Maurer M, Bouillet L, Aberer W, Fabien V, Andresen I, Caballero T, IOS Study Group. 10/2016 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.

    OBJECTIVE: To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).

    METHODS: The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.

    RESULTS: In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).

    CONCLUSION: From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.

    TRIAL REGISTRATION: ClinicalTrials.gov: NCT01034969.
    Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(16)30537-3/fulltext

    Nanofiltrated C1-esterase-inhibitor in the prophylactic treatment of bradykinin-mediated angioedema

    Greve J, Hahn J, Nordmann M, Schuler PJ, Bas M, Hoffmann TK, Hajdu Z, Buchberger M, Strassen U. 5/2016 Transfusion

    BACKGROUND: Patients suffering from bradykinin-induced angioedema show recurrent swelling of subcutaneous and submucosal structures. Increased bradykinin levels lead to an increase in vascular permeability and edema formation. Current therapy consists of B2 bradykinin receptor antagonists, C1-esterase-inhibitor (C1-INH) concentrate, or the kallikrein inhibitor ecallantide. In most cases the treatment of acute attacks is sufficient. Prophylactic therapy is recommended only in severe cases. C1-INHc has been shown a safe and efficient option. Its effect on the quality of life has not yet been analyzed.

    STUDY DESIGN AND METHODS: Patients with inadequate disease control despite an “on-demand therapy” including C1-INHc and/or the B2 receptor antagonist icatibant were switched to long-term prophylaxis consisting in an individual dose of intravenous C1-INHc (Cinryze). None of the patients had been previously treated with ecallantide. Disease-specific quality-of-life questionnaires and patient records were used for evaluation. Disease control, quality of life, adverse events, and administered dosage per month were compared for 6 months on on-demand therapy and the following 6 months under prophylactic therapy.

    RESULTS: Data of seven patients with hereditary angioedema (HAE) and one patient with acquired angioedema were evaluated. Prophylactic therapy with Cinryze led to a significant and clinically relevant reduction in the overall attack frequency from 6.7 to 2.3 per month without relevant side effects. The frequency of severe attacks was reduced by 89% and quality of life significantly improved.

    CONCLUSION: Prophylaxis with Cinryze led to a significantly improved quality of life in our cohort of patients with high-frequency bradykinin-induced angioedema attacks that were not sufficiently treated with on-demand medication.
    Copyright © 2016 AABB.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/trf.13462/full

    Novel usage of fresh frozen plasma in hereditary angioedema

    Hanizah N, Affirul CA, Farah NA, Shamila MA, Ridzuan MI. 11/2016 La Clinica Terapeutica

    Hereditary angioedema (HAE) is a rare and potentially life threatening autosomal dominant disease characterized by recurrent episodes of cutaneous and mucosal oedema. It results from reduced expression or loss of function of CI-esterase inhibitors (C1-INH). As opposed to the more common histamine-mediated angioedema, HAE does not respond well to conventional treatments with anti-histamines, steroids and adrenaline. Early recognition and timely intervention with the correct treatment are crucial particularly preventing airway obstruction. New disease specific treatment including plasma derived or recombinant C1-INH, ecallantide and icatibant have recently emerged and its appropriate use can reduce HAE-associated mortality and morbidity. However due to its costs, these disease specific treatments have yet to reach Malaysia. Despite that no randomized clinical trial on FFP has been performed, its efficacy in treating acute attacks of HAE is only demonstrated in case studies. This case report illustrates the successful treatment of acute HAE episode with FFP in a Malaysian government hospital setting.

     

    Novelties in the diagnosis and treatment of angioedema

    Cicardi M, Suffritti C, Perego F, Caccia S. /2016 Journal of Investigational Allergology and Clinical Immunology

    Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired angioedema of unknown etiology (idiopathic histaminergic acquired angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary angioedema and C1-INH-acquired angioedema), mutations in coagulation factor XII (FXII-hereditary angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI-acquired angioedema). Etiology remains unclear in acquired angioedema (idiopathic nonhistaminergic acquired angioedema) and in 1 type of hereditary angioedema (hereditary angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis.

    Available from: http://www.jiaci.org/summary/vol26-issue4-num1380

    Off-label use of agents for management of serious or life-threatening angiotensin converting enzyme inhibitor-induced angioedema

    Culley CM, DiBridge JN, Wilson GL Jr. 1/2016 The Annals of Pharmacotherapy

    OBJECTIVE: To evaluate the place in therapy of fresh frozen plasma (FFP), C1 esterase concentrate (C1-INH), ecallantide, and icatibant in the management of angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-IA).

    Available from: http://journals.sagepub.com/doi/pdf/10.1177/1060028015607037

    Perioperative course in patients with hereditary or acquired angioedema

    MacBeth LS, Volcheck GW, Sprung J, Weingarten TN. 11/2016 Journal of Clinical Anesthesia

    PURPOSE: Two types of bradykinin-mediated angioedema, hereditary angioedema (HAE) and acquired angioedema (AAE), result from deficiency or dysfunction of C1 esterase inhibitor, leading to an overproduction of bradykinin, which can lead to vascular permeability and life-threatening angioedema of the airway. The objective of this study was to review perioperative outcomes in a series of patients with HAE and AAE and to review current knowledge about anesthetic complications in patients with HAE or AAE.

    METHODS: Medical records were retrospectively reviewed for perioperative complications in patients with HAE or AAE who underwent general anesthesia from January 1, 2000, to December 31, 2014, at our institution.

    RESULTS: Twenty-four patients (13 with HAE, 10 with AAE, and 1 with unspecified angioedema) underwent 38 instances of general anesthesia with airway manipulation. All except 4 received prophylactic therapy. One patient, a 67-year-old woman who was pretreated with stanozolol and fresh frozen plasma required reintubation after postoperative airway edema developed.

    CONCLUSION: Life-threatening episodes of angioedema of the airway occur infrequently, but they can occur in patients who received pretreatment and in patients who have previously undergone anesthesia uneventfully. Anesthesiologists must be ready to emergently manage a difficult airway and must be familiar with recommendations provided in consensus guidelines for the treatment of HAE and AAE patients.
    Copyright © 2016 Elsevier Inc. All rights reserved.

    Available from: http://www.jcafulltextonline.com/article/S0952-8180(16)30194-5/fulltext

    Potential roles for C1 inhibitor in transplantation

    Berger M, Baldwin WM 3rd, Jordan SC. 7/2016 Transplantation

    Complement is a major contributor to inflammation and graft injury. This system is especially important in ischemia-reperfusion injury/delayed graft function as well as in acute and chronic antibody-mediated rejection (AMR). The latter is increasingly recognized as a major cause of late graft loss, for which we have few effective therapies. C1 inhibitor (C1-INH) regulates several pathways which contribute to both acute and chronic graft injuries. However, C1-INH spares the alternative pathway and the membrane attack complex (C5-9) so innate antibacterial defenses remain intact. Plasma-derived C1-INH has been used to treat hereditary angioedema for more than 30 years with excellent safety. Studies with C1-INH in transplant recipients are limited, but have not revealed any unique toxicity or serious adverse events attributed to the protein. Extensive data from animal and ex vivo models suggest that C1-INH ameliorates ischemia-reperfusion injury. Initial clinical studies suggest this effect may allow transplantation of donor organs which are now discarded because the risk of primary graft dysfunction is considered too great. Although the incidence of severe early AMR is declining, accumulating evidence strongly suggests that complement is an important mediator of chronic AMR, a major cause of late graft loss. Thus, C1-INH may also be helpful in preserving function of established grafts. Early clinical studies in transplantation suggest significant beneficial effects of C1-INH with minimal toxicity. Recent results encourage continued investigation of this already-available therapeutic agent.

    Available from: https://journals.lww.com/transplantjournal/Fulltext/2016/07000/Potential_Roles_for_C1_Inhibitor_in.11.aspx

    Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency

    Greve J, Strassen U, Gorczyza M, Dominas N, Frahm UM, Muhlberg H, Wiednig M, Zampeli V, Magerl M. 3/2016 Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG

    Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach–in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.

    Copyright © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/doi/10.1111/ddg.12856/full

    Registries as useful tools in characterization of allergic manifestations

    Jares EJ, Badellino HA, Ensina LF. 6/2016 Current Opinion in Allergy and Clinical Immunology

    PURPOSE OF REVIEW: Registries are useful to discover the applicability of data generated from randomized clinical trials (RCTs) into daily practice, and to search for real-life data usually not covered by them.

    RECENT FINDINGS: In allergy, registry research brought clues to important epidemiological and clinical problems hardly accessible with other methods. The increase in the asthma prevalence in Sweden in contrast with stabilization in Denmark; the association of the prevalence of asthma and environmental factors; the knowledge of existing rhinitis international guidelines, but the poorly complacence of some of their recommendations; the low epinephrine use in anaphylaxis and the difference among European and Latin American elicitors; the predominance of beta lactams or NSAIDs as drug hypersensitivity reactions inducers in different regions; the fact that most of the hereditary angioedema patients were receiving long-term prophylaxis with attenuated androgens; all the mentioned are clear examples of relevant and important data provided by current registries.

    SUMMARY: Registries in allergy enlighten knowledge in areas not covered by classical investigational methods. As the number and importance of registries is growing, its contribution to the knowledge and management of allergic diseases will increase in the near future.

    Available from: https://journals.lww.com/co-allergy/Abstract/2016/06000/Registries_as_useful_tools_in_characterization_of.9.aspx

    Risk of thromboembolism in patients with hereditary angioedema treated with plasma-derived C1-inhibitor

    Farkas H, Kohalmi KV, Veszeli N, Zotter Z, Varnai K, Varga L. 3/2016 Allergy and Asthma Proceedings

    BACKGROUND: Plasma-derived C1-inhibitor (C1-INH) concentrates (pdC1-INH) have been used as safe and effective treatments for hereditary angioedema with C1-INH deficiency (C1-INH-HAE) for >30 years. Notwithstanding this, sporadic reports and a study into the high-dose therapy of neonates with C1-INH concentrate administered in an off-label indication raised concerns that this drug might increase the risk of thromboembolism.

    OBJECTIVE: To investigate the incidence of thromboembolism and the background of the risk factors related to treatment with pdC1-INH.

    METHODS: Our retrospective cohort study of 144 patients with C1-INH-HAE compared the incidence of thromboembolism and its risk factors in patients who received pdC1-INH with those who did not receive pdC1-INH as well as with those treated with danazol or with tranexamic acid.

    RESULTS: During the observation period (29 years), 104 of the 144 subjects received pdC1-INH. The average dose per treatment was 573.59 IU. None of the patients used an indwelling central venous catheter. Multiple risk factors for thromboembolism were identified in 93 of the 104 patients treated with pdC1-INH. The incidence rate of thromboembolism was 0.0019/100 person-years in patients treated with pdC1-INH, whereas it was 0.0211/100 person-years in the not-treated group.

    CONCLUSION: Our cohort study did not find any evidence for an increased risk of thromboembolism during treatment with pdC1-INH, despite the presence of multiple predisposing factors.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2016/00000037/00000002/art00013

     

    Safety and usage of C1-inhibitor in hereditary angioedema: Berinert Registry data

    Riedl MA, Bygum A, Lumry W, Magerl M, Bernstein JA, Busse P, Craig T, Frank MM, Edelman J, Williams-Herman D, Feuersenger H, Rojavin M, Berinert Registry Investigators. 9/2016 The Journal of Allergy and Clinical Immunology. In Practice

    BACKGROUND: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; “pnfC1-INH”) is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis.

    OBJECTIVE: The objective of this study was to describe safety and usage patterns of pnfC1-INH.

    METHODS: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason.

    RESULTS: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (n = 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation.

    CONCLUSIONS: The findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use.
    Copyright © 2016. Published by Elsevier Inc.

    Available from: https://www.sciencedirect.com/science/article/pii/S2213219816301283?via%3Dihub

    Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: Phase 1 study

    Cornpropst M, Collis P, Collier J, Babu YS, Wilson R, Zhang J, Fang L, Zong J, Sheridan WP. 12/2016 Allergy

    BACKGROUND: Avoralstat is a potent small-molecule oral plasma kallikrein inhibitor under development for treatment of hereditary angioedema (HAE). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of avoralstat.

    METHODS: This double-blind, placebo-controlled, ascending-dose cohort trial evaluated avoralstat single doses of 50, 125, 250, 500, and 1000 mg and multiple doses up to 2400 mg daily (100, 200, 400, and 800 mg every 8 h [q8 h] up to 7 days).

    RESULTS: Avoralstat (n = 71) was generally well tolerated with no signals for a safety concern; there were no serious adverse events (AEs) or discontinuations due to AEs, and compared to placebo (n = 18), no notable difference in AEs. Four moderate severity AEs were reported in two subjects; syncope after a single 250 mg dose (one subject) and abdominal pain, back pain, and eczema after multiple doses of 800 mg avoralstat (one subject). For multiple-dose cohorts, the incidence of gastrointestinal AEs was highest at the 2400 mg/day dose. Elimination of avoralstat was bi-exponential with a terminal half-life of 12-31 h. Inhibition of plasma kallikrein was observed at all doses, and the degree of inhibition was highly correlated with avoralstat concentrations (R = 0.93). Mean avoralstat concentrations at doses >=400 mg q8 h met or exceeded plasma kallikrein EC<sub>50</sub> values throughout the dosing interval.

    CONCLUSION: Avoralstat was well tolerated, and drug exposure was sufficient to meet target levels for inhibition of plasma kallikrein. Based on these results, the 400 mg q8 h dose was selected for further evaluation in patients with HAE.
    Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/all.12930/full

    Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in patients with hereditary angioedema

    Riedl MA, Lumry WR, Li HH, Banerji A, Bernstein JA, Ba M, Bjrkander J, Magerl M, Maurer M, Rockich K, Chen H, Schranz J. 11/2016 Allergy and Asthma Proceedings

    BACKGROUND: The currently approved method of C1 inhibitor (C1 INH) administration for patients with hereditary angioedema with C1 INH deficiency (HAE) is by intravenous injection. A C1 INH subcutaneous formulation may provide an attractive mode of administration for some patients.

    OBJECTIVE: To evaluate efficacy and safety of two doses of subcutaneous, plasma-derived C1 INH with the dispersing agent, recombinant human hyaluronidase (rHuPH20) to prevent angioedema attacks in patients with HAE.

    METHODS: A randomized, double-blind, dose-ranging, crossover study, patients 12 years of age (n = 47) with a confirmed diagnosis of HAE were randomly assigned to receive subcutaneous injections of 1000 U C1 INH with 24,000 U rHuPH20 or 2000 U C1 INH with 48,000 U rHuPH20 every 3 or 4 days for 8 weeks and then crossed-over for another 8-week period. The primary efficacy end point was the number of angioedema attacks during each treatment period.

    RESULTS: The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20 in 45% of patients. The mean standard deviation number of angioedema attacks during the 8-week treatment periods were 1.58 1.59 with 1000 U C1 INH and 0.97 1.26 with 2000 U. The mean (95% confidence interval [CI]) within-patient difference (2000 U-1000 U, respectively) was 0.61 (95% CI, 1.23 to 0.01) attacks per month (p = 0.0523), and 0.56 (95% CI, 1.06 to 0.05) attacks that required acute treatment, (p = 0.0315). No deaths or other serious adverse events were reported. Injection-site reaction was the most common adverse event.

    CONCLUSION: Despite early termination, this study demonstrated a clinically and statistically significant difference in burden of disease, which favored 2000 U C1 INH, without associated serious adverse events.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2016/00000037/00000006/art00017

    Swedish children with hereditary angioedema report good overall health and quality of life despite symptoms

    Nygren A, Nordenfelt P, Lindfors A, Mallbris L, Bjorkander J, Wahlgren CF. 5/2016 Acta Paediatrica

    AIM: Few studies have been published on children with hereditary angioedema (HAE), an autosomal dominant disease caused by mutations on chromosome 11. This study explored various aspects of the disease in the Swedish paediatric population.

    METHODS: A retrospective questionnaire was sent to all 36 Swedish children known to have HAE, and a physician carried out follow-up telephone interviews.

    RESULTS: Most of the questionnaires were completed by the parents of 31 (86%) children with HAE, with or without their input, at a median age of nine years (range 1-17), and the physician also interviewed 29. HAE symptoms were experienced by 23 children, including abdominal attacks (96%), skin swelling (78%) and swelling in the mouth and/or upper airways (52%). Psychological stress was the most common trigger for abdominal attacks and trauma and sports triggered skin swelling. The majority (n = 19) had access to complement-1 esterase inhibitor concentrate at home. Current health and quality of life were generally rated as good, independent of whether the child had experienced HAE symptoms or not.

    CONCLUSION: Most children with HAE had experienced abdominal attacks and skin swelling, but their overall health and quality of life were generally perceived to be good.

    Copyright ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/apa.13345/full

    The case for a national service for primary immune deficiency disorders in New Zealand

    Ameratunga R, Steele R, Jordan A, Preece K, Barker R, Brewerton M, Lindsay K, Sinclair J, Storey P, Woon ST. 6/2016 The New Zealand Medical Journal

    Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

    Available from: https://www.nzma.org.nz/journal/read-the-journal/all-issues/2010-2019/2016/vol-129-no-1436-10-june-2016/6921

    The effect of long-term danazol treatment on haematological parameters in hereditary angioedema

    Kohalmi KV, Veszeli N, Zotter Z, Csuka D, Benedek S, Imreh E, Varga L, Farkas H. 2/2016 Orphanet Journal of Rare Diseases

    BACKGROUND: The 17-alpha-alkylated derivatives of testosterone are often used for the prevention of oedematous episodes in hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). However, these agents can have many adverse effects, including erythrocytosis and polyglobulia. Our aim was to investigate occurrence of erythrocytosis and polyglobulia after long-term danazol prophylaxis in C1-INH-HAE.

    METHODS: During the initial stage of our retrospective study, we explored whether C1-INH-HAE is associated with susceptibility to erythrocytosis and/or polyglobulia. In the second stage, we analyzed the haematological parameters of 39 C1-INH-HAE patients before, as well as after treatment with danazol for 1, 3, or 5 years. In the third stage, we studied the incidence of erythrocytosis and of polyglobulia after dosing with danazol for more than 5 years.

    RESULTS: We did not find any significant difference between C1-INH-HAE patients not receiving danazol and healthy controls as regards the occurrence of erythrocytosis or polyglobulia. The haematological parameters did not change after treatment with danazol for 1, 3, or 5 years. Platelet count was an exception-it decreased significantly (p=0.0115) versus baseline, but within the reference range. Treatment-related polyglobulia did not occur. We observed erythrocytosis in a single female patient after 1-year-and in three female patients after more than 5-year long-treatment with danazol. Erythrocytosis did not require intervention or the discontinuation of danazol therapy.

    CONCLUSIONS: We conclude that neither erythrocytosis, nor polyglobulia occurs more often in C1-INH-HAE patients than in healthy individuals; it can be observed only sporadically even after treatment with danazol.

    Available from: http://pubmedcentralcanada.ca/pmcc/articles/PMC4766663/

    The Icatibant Outcome Survey: Treatment of laryngeal angioedema attacks

    Longhurst HJ, Aberer W, Bouillet L, Caballero T, Maurer M, Fabien V, Zanichelli A, IOS Study Group. 6/2016 European Journal of Emergency Medicine: Official Journal of the European Society for Emergency Medicine

    OBJECTIVE: To characterize the management and outcomes of life-threatening laryngeal attacks of hereditary angioedema (HAE) treated with icatibant in the observational Icatibant Outcome Survey (NCT01034969) registry.

    METHODS: This retrospective analysis was based on data from patients with HAE type I/II who received healthcare professional-administered or self-administered icatibant to treat laryngeal attacks between September 2008 and May 2013.

    RESULTS: Twenty centers in seven countries contributed data. Overall, 42 patients with HAE experienced 67 icatibant-treated laryngeal attacks. Icatibant was self-administered for 62.3% of attacks (healthcare professional-administered, 37.7%). One icatibant injection was used for 87.9% of attacks, with rescue or concomitant medication used for 9.0%. The median time to treatment was 2.0h (n=31 attacks) and the median time to resolution was 6.0h (n=35 attacks).

    CONCLUSIONS: This analysis describes successful use of icatibant for the treatment of laryngeal HAE attacks in a real-world setting.

    Available from: https://journals.lww.com/euro-emergencymed/Fulltext/2016/06000/The_Icatibant_Outcome_Survey___treatment_of.13.aspx

    The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity

    Wu MA, Castelli R. 2/2016 Clinical Chemistry and Laboratory Medicine

    Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.

    Available from: https://www.degruyter.com/view/j/cclm.2016.54.issue-2/cclm-2015-0195/cclm-2015-0195.xml

    The story of angioedema: from Quincke to Bradykinin

    Reshef A, Kidon M, Leibovich I. 10/2016 Clinical Reviews in Allergy and Immunology

    The term “swelling” has been used in the old scriptures to illustrate a change of normal figure and, as such, an expression of illness. It should be noted that in ancient times, human diseases were very often regarded a punishment from God. Hence, it is not surprising that one of the oldest tests for infidelity involved swelling as an inflicted punishment. The great Greek physician Hippocrates (377-460 BC), considered one of the most outstanding figures in the history of medicine and “Father of the Western Medicine,” already used the term oidema to describe swelling of organs. It took many centuries later until the first description of angioedema as a distinct medical entity was minted by Quinke in 1882. The historical progression in angioedema research has been characterized by intermittent “leaps” in interest and scientific achievements. As an example, it took 75 years from the accurate description of hereditary angioedema (HAE) by Osler (1888), until a group of researchers headed by Donaldson (1963) disclosed the central role of C1 inhibitor in angioedema pathophysiology. What followed was a result of a collective effort by many researchers and scientific groups who were able to elucidate the intricate connections between the implicated biochemical pathways. Still, scientific progress was hardly translated into effective therapy, and another 45 years had to elapse until the renewed interest in HAE was boosted by studies on the efficacy and safety of novel therapies about 10 years ago. In the twenty-first century, HAE ceased to be an “orphan disease” and its future is far more optimistic. It is better managed now by specialized angioedema centers, harmonized clinical guidelines, educational programs, laboratory services, and continued basic and clinical research. Patient associations worldwide are offering support and guidance, and governments and healthcare systems are gradually addressing patient and family needs.

    Available from: http://link.springer.com/article/10.1007%2Fs12016-016-8553-8

    Thyroid hormones and complement parameters in hereditary angioedema with C1-inhibitor deficiency

    Czaller I, Csuka D, Zotter Z, Veszeli N, Takacs E, Imreh E, Varga L, Farkas H. 8/2016 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Thyroid hormones control and up-regulate the synthesis of many plasma proteins.

    OBJECTIVE: To explore possible associations between thyroid hormone and complement levels in patients with hereditary angioedema resulting from the deficiency of the C1-inhibitor (C1-INH-HAE).

    METHODS: In this case-control study, serum thyrotropin, free triiodothyronine (FT3), and free thyroxine (FT4) levels, anti-thyroid peroxidase and antithyroglobulin antibody titers, and C1-INH concentrations were measured in 117 euthyroid patients with C1-INH-HAE and compared with their clinical properties. The control group comprised 150 healthy, age- and sex-matched, euthyroid individuals.

    RESULTS: The thyrotropin and antithyroglobulin levels were similar between the patients and the controls. Significantly lower FT3 (P < .001) and FT4 (P = .002) levels, as well as higher anti-thyroid peroxidase titers (P < .001), were seen in the patients with C1-INH-HAE. The proportion of patients with reduced C1-INH activity was greater among those with below-median FT4 levels than among those with above-median values (P = .02). Patients who experienced more edematous attacks per year had lower FT4 levels (within the normal range) than those afflicted by fewer episodes (P = .01). The FT3 and FT4 levels were significantly higher in patients undergoing long-term danazol therapy than in those who did not receive this drug (P = .01 and P = .02, respectively). The proportion of patients with FT4 levels in the below-median range was higher in the subset with increased d-dimer concentration (P = .009).

    CONCLUSION: Minor variations of the thyroid hormone levels (within the reference range) can influence the function of C1-INH in C1-INH-HAE. Our findings suggest a role for the endocrine system in the pathophysiology of C1-INH-HAE.
    Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(16)30317-9/fulltext

    Tolerability and effectiveness of 17-alpha-alkylated androgen therapy for hereditary angioedema: A re-examination

    Zuraw BL, Davis DK, Castaldo AJ, Christiansen SC. 9/2016 The Journal of Allergy and Clinical Immunology. In Practice

    BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. 17-alpha-Alkylated androgens (AA) have been used prophylactically to reduce HAE severity, but there are many questions about the efficacy and tolerability of AA.

    OBJECTIVE: The objective of this study was to investigate the tolerability and effectiveness of AA therapy in a large cohort of patients with HAE.

    METHODS: We performed a retrospective cross-sectional study on 650 subjects with HAE utilizing a one time, anonymous, web-based survey. Based on an initial questionnaire, patients were routed to one of the following questionnaires: currently using AA, previously used but discontinued AA, or never used AA.

    RESULTS: Statistical analysis revealed that androgens decreased attack frequency and severity in previous AA users (P < .0001) and current AA users (P < .0001). Substantial variability in the effectiveness was observed. Users who discontinued AA reported significantly lesser benefit. No dose effect was seen for the beneficial effect of AA; however, almost all users reported frequent side effects that were dose related and often severe.

    CONCLUSIONS: AA therapy is usually effective for the treatment of HAE although a substantial fraction of patients with HAE do not achieve adequate benefit. In contrast, the side effects of AA are seen in almost all subjects who take the medicines. If used, AA should only be recommended in the lowest effective and tolerated dose for carefully selected patients.
    Copyright © 2016. Published by Elsevier Inc.

    Available from: https://www.sciencedirect.com/science/article/pii/S2213219816301088?via%3Dihub

    Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema

    Caballero T, Maurer M, Longhurst HJ, Aberer W, Bouillet L, Fabien V, IOS Study Group. /2016 Journal of Investigational Allergology & Clinical Immunology

    Available from: http://www.jiaci.org/summary//vol26-issue6-num1433

    Use of a C1 inhibitor concentrate in adults >=65 years of age with hereditary angioedema: Findings from the International Berinert (C1-INH) Registry

    Bygum A, Martinez-Saguer I, Bas M, Rosch J, Edelman J, Rojavin M, Williams-Herman D, Berinert Registry Investigators. 11/2016 Drugs & Aging

    BACKGROUND: Treatment of hereditary angioedema (HAE) in ‘older adults’ (those aged >=65 years) has not been well studied. The international Berinert Patient Registry collected data on the use of intravenous plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH; Berinert<sup></sup>/CSL Behring) in patients of any age, including many older adults.

    METHODS: This observational registry, conducted from 2010 to 2014 at 30 US and seven European sites, gathered prospective (post-enrollment) and retrospective (pre-enrollment) usage and adverse event (AE) data on subjects treated with pnfC1-INH.

    RESULTS: The registry documented 1701 pnfC1-INH infusions in 27 older adults. A total of 1511 HAE attacks treated with pnfC1-INH administration were reported among 25 of the 27 (92.6 %) older adults. Among the older adults, mean (standard deviation [SD]) (8.8 [4.1] IU/kg) and median (6.4 IU/kg) pnfC1-INH doses were lower than those reported for 252 ‘younger adults’ (those aged <65 years: 12.9 [6.2], 12.5 IU/kg, respectively). A total of 19 AEs occurred in 8 of 23 (34.8 %) older adults with prospective data, for rates of 0.83 events per subject and 0.02 events per infusion, similar to corresponding rates in younger adults (0.91 and 0.03, respectively). None of the AEs were considered related to pnfC1-INH, and all but two events (prostatectomy, gastrointestinal bleeding) were mild or moderate in severity. Administration of pnfC1-INH outside of a healthcare setting was reported for 1609 infusions in 16 older adults, representing 94.6 % of all pnfC1-INH infusions in this age group. There were no recorded instances of difficulty with self-administration of intravenous pnfC1-INH.

    CONCLUSIONS: These findings suggest a high degree of safety with intravenous pnfC1-INH use in older adults with HAE, regardless of administration setting. Trial Registration Clinicaltrials.gov NCT01108848.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107191/

    Acute management of hereditary angioedema attacks [Review]

    Katelaris CH 8/2017 Immunology and allergy clinics of North America

    Several treatment modalities have become available for management of acute hereditary angioedema (HAE) attacks in the last 15 years. Most are now available to patients in North America, Europe, United Kingdom, and Australia, but few options exist in developing countries. Preferred contemporary use of the treatments to be discussed is “on demand,” because control remains with the patient and delays in treatment access avoided. Four treatments-plasma-derived C1 inhibitor concentrate, recombinant C1 inhibitor concentrate, ecallantide, and icatibant-are reviewed in this article. All have been shown to be superior to placebo and effective in the management of all HAE attacks.
    Copyright © 2017 Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S0889856117300437?via%3Dihub

     

    An ABC of the warning signs of hereditary angioedema

    Grumach AS, Ferraroni N, Olivares MM, Lopez-Serrano MC, Bygum A. 10/2017 International Archives of Allergy and Immunology

    Hereditary angioedema (HAE) with C1 inhibitor deficiency is a genetic disorder that clinically manifests with attacks of angioedema in the subcutaneous and submucosal tissues, mainly in the extremities, abdomen, and upper airway. During attacks, vascular permeability is increased due to increased bradykinin (BK). This means that special therapies are needed for attacks that do not respond to traditional antiallergic therapies involving antihistamines, corticosteroids, and epinephrine. The recurring attacks may disable patients and lead to frequent visits to emergency rooms where misdiagnoses are common. HAE attacks may be fatal when upper-airway edema occurs, if proper treatment with a C1 inhibitor concentrate or BK receptor antagonist is not administered or an emergency tracheostomy is not performed. We propose a mnemonic method for the warning signs of HAE for the use as a diagnostic tool, i.e., the so-called “ABC” of the warning signs of HAE. The letters represent the following: A = Angioedema, B = Bradykinin, C = C1 inhibitor, D = Distress factors, E = Epinephrine nonresponsive, F = Family history, and G = Glottis/Gastrointestinal edema. To avoid fatalities, medical staff and patients, including family members, must be aware of HAE. An alphabetical mnemonic method has been developed and we hope it may benefit patients.
    Copyright © 2017 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/Abstract/479839

    Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all

    Tse KY, Zuraw BL, Chen Q, Christiansen SC. 4/2017 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17alpha-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost.

    OBJECTIVE: To examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities.

    METHODS: Patients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities.

    RESULTS: Patients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia.

    CONCLUSION: Our data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE.
    Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(17)30019-4/fulltext

    Angioedema

    LoVerde D, Files DC, Krishnaswamy G. 4/2017 Critical Care Medicine

    OBJECTIVES: Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment.

    DATA SOURCES: A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema.

    STUDY SELECTION: Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications.

    DATA EXTRACTION: Data from the relevant publications were reviewed, summarized and the information synthesized.

    DATA SYNTHESIS: The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes.

    CONCLUSIONS: Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology.

    Available from: https://journals.lww.com/ccmjournal/Abstract/2017/04000/Angioedema.20.aspx

    Angiotensin-converting enzyme inhibitor-induced angioedema: a review of the literature [Review]

    Brown T, Gonzalez J, Monteleone C 12/2017 Journal of Clinical Hypertension

    According to the National Health and Nutrition Examination Survey 2012, one third of antihypertensive prescriptions in the United States in the past decade were for angiotensin-converting enzyme inhibitors (ACEIs). An important and serious side effect of ACEIs is angioedema caused by a reduction in bradykinin degradation. In a national medical chart abstraction study conducted at the US Veterans Affairs Health Care System in 2008, 0.20% of ACEI initiators developed angioedema while on the medication. The angiotensin-converting enzyme is a part of the renin-angiotensin system that converts angiotensin I to angiotensin II. It is additionally responsible for the degradation of bradykinin, which is generated from high molecular weight kininogen by kallikrein. Via bradykinin 2 receptors, bradykinin affects vascular permeability and stimulates the release of substance P, which is a peptide that causes vasodilation and fluid extravasation into tissues. Inhibition of the angiotensin-converting enzyme and subsequent blockade of bradykinin degradation is thought to be a likely explanation for ACEI-induced angioedema. Studies have shown that blacks, women, and smokers are at an increased risk for ACEI-induced angioedema. A 2005 study identified black race, history of drug rash, age older than 65 years, and seasonal allergies as independent risk factors for angioedema related to enalapril. Angioedema may occur at any time during treatment with ACEIs and may continue after the medication is discontinued. The degree of ACEI-angiotensin receptor blocker angioedema cross-reactivity is difficult to determine from the literature. However, multiple studies have reported relatively low rates of native angioedema with angiotensin receptor blockers (approximately half that of ACEIs, or 0.1%) and a low incidence of cross-reactivity (<10%). Common treatments for angioedema, such as antihistamines and glucocorticoids, have not been shown to be effective in ACEI-induced angioedema. However, medications that have been used for acute treatment of hereditary angioedema and target the factors that cause ACEI-mediated angioedema are being explored.
    Copyright ©2017 Wiley Periodicals, Inc.

    Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/jch.13097

    Clinical characteristics and real-life diagnostic approaches in all Danish children with hereditary angioedema

    Aabom A, Andersen KE, Fagerberg C, Fisker N, Jakobsen MA, Bygum A. 3/2017 Orphanet Journal of Rare Diseases

    BACKGROUND: With a potentially early onset, hereditary angioedema (HAE) requires special knowledge also in infancy and early childhood. In children from families with HAE, the diagnosis should be confirmed or refuted early, which can be difficult. Studies of childhood HAE and the diagnostic approaches are limited. Our aim was to investigate the entire Danish cohort of children with HAE and non-HAE children of HAE patients for diagnostic approaches and clinical characteristics.

    RESULTS: We included 41 children: 22 with HAE and 19 non-HAE. Of the HAE children, 14 were symptomatic-median age at onset was 4 [1-11] years. The first attack was peripheral in 8/14 children and abdominal in 6/14 children, i.e. no one had their first attacks in the upper airways. Most children had less than one attack per month. All of the symptomatic children had been treated with tranexamic acid and/or C1 inhibitor concentrate. Unlike in other countries, androgens were not used in our pediatric cohort. Home therapy with C1 inhibitor concentrate was established in 9 cases: 6 children were trained in self-administration and 3 children were treated by parents. Of the children, 10 had been diagnosed by symptoms, including 3 without family history-median age of diagnosis among these children was 5.35 [2-13.2] years. In 31 children, HAE was diagnosed or refuted before symptoms by blood samples. In 23 of these children, complement values were investigated, and in 9 cases genetic testing was added to the complement measurements. In 8 children recently investigated, genetic testing was first choice. Cord blood was used for complement measurements in 9 children and for genetic testing in 4 children. Results of complement measurements were equivocal in several cases, especially in the cord blood samples, and the sensitivity of low complement C4 for the diagnosis of HAE was 75%.

    CONCLUSIONS: We investigated clinical characteristics in all Danish children with HAE. The rate of home therapy was high and androgens had been avoided. Complement values were often equivocal, especially in cord blood samples. Consequently, we have changed diagnostic practice to early genetic testing in children where the family mutation is known.

    Available from: https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0604-6

    Comparing acquired angioedema with hereditary angioedema (types I/II): Findings from the Icatibant Outcome Survey

    Longhurst HJ, Zanichelli A, Caballero T, Bouillet L, Aberer W, Maurer M, Fain O, Fabien V, Andresen I, IOS Study Group. 4/2017 Clinical and Experimental Immunology

    Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P=0.035) and had a significantly later mean (95% confidence interval) age of symptom onset [57.9 (51.33-64.53) versus 14.0 (12.70-15.26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12.3 months versus 118.1 months; P=0.006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P=0.064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P<0.001). Median total attack duration was 5.0 h and 9.0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.
    Copyright © 2016 British Society for Immunology.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343339/

    Complement factor C4 activation in patients with hereditary angioedema

    Aabom A, Bygum A, Koch C. 10/2017 Clinical Biochemistry

    OBJECTIVES: Low complement factor C4 is usually considered a valuable screening tool for patients with the potentially life-threatening hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE). However, there are patients with C1-INH-HAE presenting with normal C4 levels. This means, that C1-INH-HAE may potentially be overlooked, if screening is performed only by measurement of C4. It has been suggested that measurement of C4 activation products is better suited to avoid false negative results. Our aim was to investigate whether total antigenic C4 or non-functional C4c is a better measure of the increased C4 activation in C1-INH-HAE patients.

    DESIGN AND METHODS: Two different monoclonal antibodies (mAb) to human C4 were produced: one had specificity for the beta-chain of C4 and would thus react with both functional and non-functional C4, and the other was developed against the factor I cleavage site on the alpha<sub>3</sub>-domain of C4 and was thus specific for activated, non-functional C4c. With these mAb we investigated plasma from 19 Danish C1-INH-HAE patients in three different enzyme-linked immunosorbent assays (ELISAs): a total antigenic C4 assay, a functional C4 assay and an assay measuring non-functional C4c.

    RESULTS: The amount of total antigenic C4 varied considerably between patients and 2 patients had total antigenic C4 levels in the normal area. Functional C4 was low in all C1-INH-HAE patients. A C4c/C4 ratio showed that around half the C4 measured in patients was non-functional and captured all C1-INH-HAE patients.

    CONCLUSIONS: This study shows that the C4c/C4 ratio seems to be a better diagnostic measure than total antigenic C4 alone. Our findings underline that screening with total antigenic C4 implies a risk of overlooking C1-INH-HAE patients.
    Copyright © 2017. Published by Elsevier Inc.

    Available from: https://www.sciencedirect.com/science/article/pii/S0009912017300139?via%3Dihub

    Diagnosis, course, and management of angioedema in patients With acquired C1-inhibitor deficiency

    Zanichelli A, Azin GM, Wu MA, Suffritti C, Maggioni L, Caccia S et al. 9/2017 The journal of allergy and clinical immunology. In practice

    BACKGROUND: Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease with no prevalence data or approved therapies.

    OBJECTIVE: To report data on patients with C1-INH-AAE followed at Angioedema Center, Milan (from 1976 to 2015).

    METHODS: Diagnostic criteria included history of recurrent angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of angioedema and C1-INH deficiency.

    RESULTS: In total, 77 patients (58% females; median age, 70 years) were diagnosed with C1-INH-AAE and 675 patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) (1 patient with C1-INH-AAE/8.8 patients with C1-INH-HAE). Median age at diagnosis was 64 years. Median time between symptom onset and diagnosis was 2 years. Sixteen patients (21%) died since diagnosis, including 1 because of laryngeal edema. Angioedema of the face was most common (N = 63 [82%]), followed by abdomen (N = 51 [66%]), peripheries (N = 50 [65%]), and oral mucosa and/or glottis (N = 42 [55%]). Forty-eight of 71 patients (68%) had autoantibodies to C1-INH. In total, 56 patients (70%) used on-demand treatment for angioedema including intravenous pdC1-INH 2000 U (Berinert, CSL Behring, Marburg, Germany) (N = 49) and/or subcutaneous icatibant 30 mg (Firazyr, Shire; Milano, Italy) (N = 27). Eventually, 8 of 49 patients receiving pdC1-INH became nonresponsive; all had autoantibodies. Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effective in 8).

    CONCLUSIONS: The incidence of C1-INH-AAE was 1 for every 8.8 patients with C1-INH-HAE. Thirty percent of the deaths were related to the disease. Treatments approved for C1-INH-HAE are effective in C1-INH-AAE, although with minimal differences.
    Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S2213219817300211?via%3Dihub

    Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema

    Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ. 7/2017 The Journal of Allergy and Clinical Immunology

    BACKGROUND: The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients.

    OBJECTIVE: We sought to test the hypothesis that a bradykinin B<sub>2</sub> receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema.

    METHODS: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge.

    RESULTS: Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients.

    CONCLUSIONS: This study does not support clinical efficacy of a bradykinin B<sub>2</sub> receptor antagonist in ACE inhibitor-associated angioedema.
    Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.jacionline.org/article/S0091-6749(16)31376-8/fulltext

    Efficacy of recombinant human C1 esterase inhibitor for the treatment of severe hereditary angioedema attacks

    Li HH, Reshef A, Baker JW, Harper JR, Relan A 11/2017 Allergy and asthma proceedings

    BACKGROUND: Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources.

    OBJECTIVE: This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks.

    METHODS: In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of >=50 mm, with severe attacks defined as >=75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed <84 kg; 4200 IU for patients who weighed >=84 kg) or placebo. Also, in an open-label extension (OLE) study of rhC1-INH, oropharyngeal-laryngeal attacks were analyzed. Rescue therapy with rhC1-INH 50 IU/kg (<=4200 IU) was permitted after 4 hours or for life-threatening symptoms (in the RCT) or after 1 hour (in the OLE study). The primary end point measured the time to the beginning of symptom relief by using the Treatment Effects Questionnaire.

    RESULTS: Of 75 adults in the RCT, 43 had severe attacks and received either rhC1-INH (n = 24) or placebo (n = 19). The median (95% confidence interval) time to the onset of symptom relief totaled 90.0 minutes (95% confidence interval, 47.0-120.0 minutes) versus 334.0 minutes (95% confidence interval, 105.0 to not calculable minutes; hazard ratio, 2.5; p = 0.02), for rhC1-INH and placebo, respectively. Open-label rhC1-INH rescue therapy was administered to 1 of 24 in the rhC1-INH group (4.2%) and 10 of 19 in the placebo group (52.6%). During the OLE study, the median onset of symptom relief with rhC1-INH for eight oropharyngeal-laryngeal HAE attacks was 69.0 minutes (95% confidence interval, 59.0-91.0 minutes).

    CONCLUSION: In the current study, rhC1-INH was efficacious in resolving severe HAE attacks, including oropharyngeal-laryngeal attacks. The rhC1-INH rescue treatment rapidly improved symptoms for patients who received placebo and who experienced worsening or sustained symptoms.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2017/00000038/00000006/art00010#

    Emerging therapies in hereditary angioedema. [Review] [Erratum appears in Immunol Allergy Clin North Am. 2017 Nov;37(4):xiii; PMID: 28965642]

    Chen M, Riedl MA 8/2017 Immunology and allergy clinics of North America

    Remarkable progress has been made in the treatment of bradykinin-mediated angioedema with the advent of multiple new therapies. Patients now have effective medications available for prophylaxis and treatment of acute attacks. However, hereditary angioedema is a burdensome disease that can lead to debilitating and dangerous angioedema episodes associated with significant costs for individuals and society. The burden of treatment must be addressed regarding medication administration difficulties, treatment complications, and adverse side effects. New therapies are being investigated and may offer solutions to these challenges. This article reviews the emerging therapeutic options for the treatment of HAE.
    Copyright © 2017 Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S0889856117300310?via%3Dihub

    Health-related quality of life with hereditary angioedema following prophylaxis with subcutaneous C1-inhibitor with recombinant hyaluronidase

    Weller K, Maurer M, Fridman M, Supina D, Schranz J, Magerl M. 3/2017 Allergy and Asthma Proceedings

    BACKGROUND: To estimate health-related quality-of-life changes in patients with hereditary angioedema due to C1-inhibitor (C1-INH) deficiency who received subcutaneous C1-INH with recombinant hyaluronidase (rHuPH20) for attack prophylaxis in a randomized, double-blind, dose-ranging, cross-over study.

    METHODS: Patients with type I/II hereditary angioedema received 1000 U of C1-INH with 24,000 U of rHuPH20 or 2000 U of C1-INH with 48,000 U of rHuPH20 every 3-4 days for 8 weeks and then crossed over for another 8-week period. The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20. The Angioedema Quality of Life questionnaire (AE-QoL) was administered at weeks 1 and 5 of both periods, and at 1 week after the second treatment period. Changes in AE-QoL scores were calculated over both treatment periods and within each treatment period for patients with >=4 weeks of treatment.

    RESULTS: Forty-one patients had evaluable AE-QoL data, and 22 patients completed treatment. At screening, 43% of the patients were receiving intravenous C1-INH. A significant average AE-QoL total score decline (improvement) of -8.1 (95% confidence interval, -13.7 to -2.5) was observed from baseline to the end of the study, and significant AE-QoL score declines were observed in the Functioning, Fear/Shame, and Nutrition domains. Patients on 2000 U reported higher mean AE-QoL score declines in Functioning and Nutrition domains relative to the 1000 U dose. Overall, 43.9% of all the patients, 45.5% of the study completers, and 46.7% of the nonprophylaxis users at baseline on high treatment doses achieved a reduction in the AE-QoL total score of six points.

    CONCLUSION: Despite early termination and prestudy prophylactic intravenous C1-INH use by 43% of the patients, improved AE-QoL scores were observed after <=16 weeks of subcutaneous C1-INH-rHuPH20 prophylaxis.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2017/00000038/00000002/art00014

    Hereditary angioedema with normal C1 inhibitor: Clinical characteristics and treatment response with plasma-derived human C1 inhibitor boncentrate (Berinert) in a French cohort

    Bouillet L, Boccon-Gibod I, Gompel A, Floccard B, Martin L, Blanchard-Delaunay C, Launay D, Fain O. 3/2017 European Journal of Dermatology: EJD

    Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria. Berinert (CSL Behring) is a plasma-derived human C1 inhibitor (C1-INH) concentrate, approved for the treatment of HAE with C1-INH deficiency (C1-INH-HAE), however, it is often used off-label in Europe to treat HAE with normal C1-INH. To report the clinical characteristics of patients with HAE with normal C1-INH (with F12 gene mutation; FXII-HAE) or of unknown origin (U-HAE), and their response to Berinert. Data from 2007 to 2016 (obtained retrospectively from the French Cohort BeRinert Angioedeme [COBRA] registry of HAE patients with everyday use of Berinert<sup></sup>) were analysed; no control group was included. Diagnostic criteria for FXII-HAE and U-HAE included a normal C1-INH antigenic level and function and refractoriness to high-dose antihistamines. For FXII-HAE, diagnosis also included F12 gene mutation, and U-HAE a positive family history for the disease. To date, 28 patients with FXII-HAE or U-HAE were identified (mean age: 27 years; first angioedema attack at 19.8 years; 85.7% female) with 78 documented Berinert<sup></sup>-treated attacks, the majority occurring in the laryngeal and abdominal regions. Efficacy assessment of Berinert<sup></sup> was available for 38 of 78 documented Berinert<sup></sup>-treated attacks; 22 improved within 60 minutes of treatment initiation, nine within 60-180 minutes, four after 180 minutes, and three showed no improvement. No severe or serious adverse effects were reported. Data to date suggest that Berinert<sup></sup> may be a safe and efficacious treatment option for the majority of HAE patients.

    Available from: https://link.springer.com/article/10.1684/ejd.2016.2948

    Hereditary angioedema with normal C1 inhibitor: Update on evaluation and treatment. [Review]

    Magerl M, Germenis AE, Maas C, Maurer M 8/2017 Immunology and allergy clinics of North America

    A new form of hereditary angioedema (HAE) was identified in the year 2000. Its clinical appearance resembles HAE types I and II, which are caused by mutations that result in a deficiency of C1 inhibitor (C1-INH). In patients with the new form of HAE, C1-INH plasma levels and function values are normal, so it’s termed HAE with normal C1-INH (HAE-nC1). HAE-nC1, in a subgroup of patients, is thought to be caused by mutations that affect the F12 gene. The diagnosis of HAE-nC1 is based on history and clinical criteria. There are no licensed drugs with proven treatment effects for HAE-nC1.
    Copyright © 2017 Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S0889856117300450?via%3Dihub

    Inhibiting plasma kallikrein for hereditary angioedema prophylaxis

    Banerji A, Busse P, Shennak M, Lumry W, Davis-Lorton M, Wedner HJ, Jacobs J, Baker J, Bernstein JA, Lockey R, Li HH, Craig T, Cicardi M, Riedl M, Al-Ghazawi A, Soo C, Iarrobino R, Sexton DJ, TenHoor C, Kenniston JA, Faucette R, Still JG, Kushner H, Mensah R, Stevens C, Biedenkapp JC, Chyung Y, Adelman B. 2/2017 The New England Journal of Medicine

    BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.

    METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.

    RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.

    CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

    Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1605767

    Novel therapies for angiotensin-converting enzyme inhibitor-induced angioedema: a systematic review of current evidence. [Review]

    Riha HM, Summers BB, Rivera JV, Van Berkel MA 11/2017 Journal of Emergency Medicine

    BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema can occur at any point during therapy and, when severe, can require mechanical ventilation. Standard agents for anaphylactic reactions have limited efficacy for bradykinin-mediated angioedema and, therefore, agents approved for hereditary angioedema are increasingly prescribed for these patients.

    OBJECTIVE OF THE REVIEW: This systematic review critically evaluates evidence describing the off-label use of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), complement 1 esterase inhibitor (C1-INH), icatibant, and ecallantide for treatment of ACEI-induced angioedema.

    DISCUSSION: A PubMed search was conducted and articles were cross-referenced for additional citations. All full-text clinical trials, case series, and case reports published in the English language describing pharmacologic treatment of ACEI-induced angioedema were included. Thirty-seven publications detailing FFP, PCC, and regimens approved for hereditary angioedema, including icatibant, ecallantide, and C1-INH, are reviewed extensively.

    CONCLUSIONS: While findings of decreased time to symptom resolution or a cessation in symptom progression have been reported with each of these therapies, additional data showing clinically relevant implications, such as reduced intensive care unit length of stay or avoidance of mechanical ventilation, are warranted, especially when taking cost into consideration. FFP has limited evidence demonstrating a benefit for treatment of ACEI-induced angioedema without consistent dosing strategies. However, given its wide availability and low potential for adverse reactions, FFP therapy may be reasonable. Of the novel agents traditionally used for hereditary angioedema, icatibant has the highest level of evidence and has been reported to be successful in limiting the progression of angioedema.
    Copyright © 2017 Elsevier Inc. All rights reserved.

    Available from: https://www.jem-journal.com/article/S0736-4679(17)30489-4/fulltext

    Outcomes of long term treatments of type I hereditary angioedema in a Turkish family

    Akoglu G, Kesim B, Yildiz G, Metin A 9/2017 Anais brasileiros de dermatologia

    BACKGROUND: Hereditary angioedema is a rare autosomal dominantly inherited immunodeficiency disorder characterized by potentially life-threatening angioedema attacks.

    OBJECTIVE: We aimed to investigate the clinical and genetic features of a family with angioedema attacks.

    METHODS: The medical history, clinical features and C1-INH gene mutation of a Turkish family were investigated and outcomes of long-term treatments were described.

    RESULTS: Five members had experienced recurrent swellings on the face and extremities triggered by trauma. They were all misdiagnosed as familial Mediterranean fever (FMF) depending on frequent abdominal pain and were on colchicine therapy for a long time. They had low C4 and C1-INH protein concentrations and functions. A mutation (c.1247T>A) in C1-INH gene was detected. They were diagnosed as having hereditary angioedema with C1-INH deficiency (C1-INH hereditary angioedema) for the first time. Three of them benefited from danazol treatment without any significant adverse events and one received weekly C1 esterase replacement treatment instead of danazol since she had a medical history of thromboembolic stroke.

    STUDY LIMITATIONS: Small sample size of participants.

    CONCLUSION: Patients with C1-INH hereditary angioedema may be misdiagnosed as having familial Mediterranean fever in regions where the disorder is endemic. Medical history, suspicion of hereditary angioedema and laboratory evaluations of patients and their family members lead the correct diagnoses of hereditary angioedema. Danazol and C1 replacement treatments provide significant reduction in hereditary angioedema attacks.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674698/

    Patient satisfaction and experience with intravenously administered C1-inhibitor concentrates in the United States

    Riedl MA, Banerji A, Busse PJ, Johnston DT, Davis-Lorton MA, Patel S, Parr H, Chiao J, Watson DJ, Burrell E, Machnig T. 7/2017 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. Intravenous C1 esterase inhibitor (C1-INH[IV]) is licensed and used to prevent HAE symptoms.

    OBJECTIVE: To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications.

    METHODS: Fifty adult members (>=18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy.

    RESULTS: Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months.

    CONCLUSION: The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration.
    Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(17)30405-2/fulltext

    Preventing hereditary angioedema attacks in children using cinryze: Interim efficacy and safety phase 3 findings

    Aygoren-Pursun E, Soteres D, Moldovan D, Christensen J, Van Leerberghe A, Hao J, Schranz J, Jacobson KW, Martinez-Saguer I. 7/2017 International Archives of Allergy and Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease causing unpredictable and potentially life-threatening subcutaneous and submucosal edematous attacks. Cinryze (Shire ViroPharma Inc., Lexington, MA, USA), a nanofiltered C1 inhibitor (C1-INH), is approved in Europe for the treatment, preprocedure prevention, and routine prophylaxis of HAE attacks, and for the routine prophylaxis of attacks in the USA. This phase 3 study assessed the safety and efficacy of 2 C1-INH doses in preventing attacks in children aged 6-11 years.

    METHODS: A randomized single-blind crossover study was initiated in March 2014. Results for the first 6 patients completing the study are reported here. After a 12-week qualifying observation period, patients were randomly assigned to 1 of 2 C1-INH doses, 500 or 1,000 U, every 3-4 days for 12 weeks and crossed over to the alternative dose for a second 12-week period. The primary efficacy endpoint was the number of angioedema attacks per month.

    RESULTS: Six females with HAE type I and a median age of 10.5 years received 2 doses of C1-INH (500 and 1,000 U). The mean (SD) difference in the number of monthly angioedema attacks between the baseline observation period and the treatment period was -1.89 (1.31) with 500 U and -1.89 (1.11) with 1,000 U. During the treatment periods, cumulative attack severity, cumulative daily severity, and the number of attacks needing acute treatment were lower. No serious adverse events or study drug discontinuations occurred.

    CONCLUSIONS: Interim findings from this study indicate that routine prevention with intravenous administration of C1-INH is efficacious, safe, and well tolerated in children >=6 years of age.
    Copyright © 2017 The Author(s) Published by S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/FullText/477541

    Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

    Longhurst H, Cicardi M, Craig T, Bork K, Grattan C, Baker J, Li HH, Reshef A, Bonner J, Bernstein JA, Anderson J, Lumry WR, Farkas H, Katelaris CH, Sussman GL, Jacobs J, Riedl M, Manning ME, Hebert J, Keith PK, Kivity S, Neri S, Levy DS, Baeza ML, Nathan R, Schwartz LB, Caballero T, Yang W, Crisan I, Hernandez MD, Hussain I, Tarzi M, Ritchie B, Kralickova P, Guilarte M, Rehman SM, Banerji A, Gower RG, Bensen-Kennedy D, Edelman J, Feuersenger H, Lawo JP, Machnig T, Pawaskar D, Pragst I, Zuraw BL, COMPACT Investigators. 3/2017 The New England Journal of Medicine

    BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks.

    METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (>=50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.

    RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo.

    CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

    Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1613627

    Prophylactic therapy for hereditary angioedema. [Review]

    Longhurst H, Zinser E 8/2017 Immunology and allergy clinics of North America

    Long-term prophylaxis is needed in many patients with hereditary angioedema and poses many challenges. Attenuated androgens are effective in many but are limited by side effect profiles. There is less evidence for efficacy of tranexamic acid and progestagens; however, the small side effect profile makes tranexamic acid an option for prophylaxis in children and progestagens an option for women. C1 inhibitor is beneficial, but at present requires intravenous delivery and may need dose titration for maximum efficacy. Short-term prophylaxis should be considered for all procedures. New therapies are promising in overcoming many problems encountered with current options for long-term prophylaxis.
    Copyright © 2017 Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S0889856117300449?via%3Dihub

    Recombinant human C1 esterase inhibitor for acute hereditary angioedema attacks with upper airway involvement

    Riedl MA, Li HH, Cicardi M, Harper JR, Relan A 11/2017 Allergy and asthma proceedings

    BACKGROUND: Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treatment of hereditary angioedema (HAE) in adolescents and adults. HAE attacks that involve the upper airway can be life threatening, and data on the administration of rhC1-INH for these types of attacks are currently limited.

    OBJECTIVE: To evaluate the efficacy and safety of rhC1-INH for treatment of acute HAE attacks with upper airway involvement.

    METHODS: A pooled analysis of data from three clinical trials with open-label extensions examined rhC1-INH for treatment of acute HAE attacks with upper airway involvement. Patients with functional plasma C1 esterase inhibitor <50% of normal who had experienced an acute upper airway HAE attack and received rhC1-INH were identified retrospectively based on severity of breathing or swallowing symptoms. The primary end point was the time to beginning of relief (time at which the overall visual analog scale score [0-100 mm] decreased from baseline by >=20 mm for two consecutive time points [persistence]).

    RESULTS: Of 683 acute HAE attacks treated with rhC1-INH, data for 45 attacks with upper airway involvement were included. The median time to the beginning of symptom relief was 67 minutes (95% confidence interval, 60-120 minutes) and did not differ by attack number or by baseline breathing or swallowing symptom severity. Most attacks (91.1%) achieved the beginning of relief within 4 hours of rhC1-INH treatment. All attacks resolved without the need for any additional medication, and no patients required intubation or tracheostomy. Treatment with rhC1-INH was well tolerated, with no adverse events reported in more than one patient (except HAE reported as an adverse event [n = 2]).

    CONCLUSION: This pooled analysis of clinical trial data supports the efficacy of rhC1-INH for treatment of acute HAE attacks with upper airway involvement.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2017/00000038/00000006/art00011#

    Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial

    Riedl MA, Grivcheva-Panovska V, Moldovan D, Baker J, Yang WH, Giannetti BM, Reshef A, Andrejevic S, Lockey RF, Hakl R, Kivity S, Harper JR, Relan A, Cicardi M 9/2017 Lancet

    BACKGROUND: Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema.

    METHODS: We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739.

    FINDINGS: Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2.7 attacks [SD 2.4]) and once weekly (4.4 attacks [3.2]) versus placebo (7.2 attacks [3.6]), with mean differences of -4.4 attacks (p<0.0001) and -2.8 attacks (p=0.0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported.

    INTERPRETATION: Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor.

    FUNDING: Pharming Technologies.
    Copyright © 2017 Elsevier Ltd. All rights reserved.

    Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31963-3/fulltext

    Recombinant human C1-esterase inhibitor to treat acute hereditary angioedema attacks in adolescents

    Baker JW, Reshef A, Moldovan D, Harper JR, Relan A, Riedl MA. 7/2017 The Journal of Allergy and Clinical Immunology. In Practice

    BACKGROUND: Recombinant human C1-esterase inhibitor (rhC1-INH) is efficacious and well tolerated for managing hereditary angioedema (HAE) attacks in adults. However, there are insufficient data on its efficacy and safety in adolescents.

    OBJECTIVE: To evaluate the efficacy and safety profiles of rhC1-INH for acute HAE attacks in adolescents.

    METHODS: Adolescents (aged 12-18 y) with HAE enrolled in 2 randomized controlled trials and 2 open-label extension trials were included and received intravenous rhC1-INH for acute attacks. Times to the beginning of sustained symptom relief (visual analog scale change from baseline >=20 mm) and minimal symptoms (visual analog scale score of <20 mm across locations) were assessed. Safety parameters included hypersensitivity reactions, anti-rhC1-INH antibodies, and host-related impurities.

    RESULTS: Sixteen adolescents (50 attacks, aged 14-18 y) received rhC1-INH. Attacks were managed with single-dose rhC1-INH 50 U/kg (46.0%) and single-dose rhC1-INH 2100 U (16%), and 32.0% were treated with additional doses after receiving an initial rhC1-INH 2100 U dose (total dose, 4200-6300 U). Most attacks (88.0%) occurred at a single location; 59.1% (26 of 44) were abdominal. Across the first 5 attacks, median times to the beginning of symptom relief ranged from 19.0 to 78.5 minutes; median times to minimal symptoms ranged from 120 to 190 minutes. Pharmacokinetics showed that rhC1-INH restored functional plasma C1-esterase inhibitor levels to the normal (>70%) range for almost all evaluable patients. No severe or drug-related adverse events or hypersensitivity reactions occurred. No treatment-emergent antibodies to rhC1-INH or host-related impurities were observed.

    CONCLUSIONS: rhC1-INH is efficacious and well tolerated among adolescents with HAE.
    Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.jaci-inpractice.org/article/S2213-2198(16)30562-1/fulltext

    Safety of a C1-inhibitor concentrate in pregnant women with hereditary angioedema

    Fox J, Vegh AB, Martinez-Saguer I, Wuillemin WA, Edelman J, Williams-Herman D, Rojavin M, Rosenberg T. 5/2017 Allergy and Asthma Proceedings

    BACKGROUND: Increased estrogen levels during pregnancy can exacerbate hereditary angioedema (HAE), yet disease and treatment ramifications remain poorly studied in pregnant women.

    OBJECTIVE: Data from the international Berinert Patient Registry were used to evaluate outcomes of pregnancies exposed to plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) during routine HAE management.

    METHODS: This observational registry, conducted between 2010 and 2014 at 30 U.S. and 7 European sites, gathered data on 318 subjects and 15,000 pnfC1-INH infusions. Whenever possible, the subjects who used pnfC1-INH during pregnancy were followed up to term to assess neonatal outcomes and to collect maternal adverse events (AE) that occurred up to 1 month after pnfC1-INH administration.

    RESULTS: The registry data base included 11 pregnancies in 10 subjects who used pnfC1-INH for HAE attack treatment and/or prophylaxis (>261 doses during pregnancy). Eight pregnancies concluded in the birth of a healthy baby. Of the remaining three pregnancies: one was voluntarily terminated at 9 weeks of gestation; a second ended as a first-trimester spontaneous abortion 1 week after the subject’s most recent pnfC1-INH infusion and was considered unrelated to pnf-C1INH treatment; and the third occurred in a subject who exited the registry approximately 2 months before her due date, with no further follow up. As assessed for 30 days after each pnfC1-INH infusion, there were no AEs that were considered related to pnfC1-INH therapy.

    CONCLUSION: Administration of pnfC1-INH during pregnancy was generally safe and not associated with any treatment-related AEs. In all registry pregnancies followed up to term, the birth of a healthy baby was reported.

    Available from: http://www.ingentaconnect.com/content/ocean/aap/2017/00000038/00000003/art00014#

    Screening for hereditary angioedema (HAE) at 13 emergency centers in Osaka, Japan: A prospective observational study

    Hirose T, Kimbara F, Shinozaki M, Mizushima Y, Yamamoto H, Kishi M, Kiguchi T, Shiono S, Noborio M, Fuke A, Akimoto H, Kimura T, Kaga S, Horiuchi T, Shimazu T. 2/2017 Medicine

    Hereditary angioedema (HAE) with deficiency of C1 inhibitor (C1-INH) is an autosomal-dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The objective is to study the incidence of HAE among patients who visit the emergency department.This was a 3-year prospective observational screening study involving 13 urban tertiary emergency centers in Osaka prefecture, Japan. Patients were included if they met the following criteria: unexplained edema of the body, upper airway obstruction accompanied by edema, anaphylaxis, acute abdomen with intestinal edema (including ileus and acute pancreatitis), or asthma attack. C1-INH activity and C4 level were measured at the time of emergency department admission during the period between July 2011 and June 2014.This study comprised 66 patients with a median age of 54.0 (IQR: 37.5-68.3) years. Three patients were newly diagnosed as having HAE, and 1 patient had already been diagnosed as having HAE. C1-INH activity levels of the patients with HAE were below the detection limit (<25%), whereas those of non-HAE patients (n = 62) were 106% (IQR: 85.5%-127.0%) (normal range, 70%-130%). The median level of C4 was significantly lower in the patients with HAE compared with those without HAE (1.2 [IQR: 1-3] mg/dL vs 22 [IQR: 16.5-29.5] mg/dL, P < 0.01) (normal range, 17-45 mg/dL).Three patients with undiagnosed HAE were diagnosed as having HAE in the emergency department during the 3-year period. If patients have signs and symptoms suspicious of HAE, the levels of C1-INH activity and C4 should be measured.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313030/

    Short-term prophylactic use of C1-inhibitor concentrate in hereditary angioedema: Findings from an international patient registry

    Magerl M, Frank M, Lumry W, Bernstein J, Busse P, Craig T, Martinez-Saguer I, Riedl MA, Shapiro R, Edelman J, Williams-Herman D, Wood DN, Feuersenger H, Rojavin M, Berinert Registry Investigators. 1/2017 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    Available from: http://www.annallergy.org/article/S1081-1206(16)31197-8/fulltext

    Subcutaneous icatibant for the treatment of hereditary angioedema attacks: Comparison of home self-administration with administration at a medical facility

    Otani IM, Lumry WR, Hurwitz S, Li HH, Craig TJ, Holtzman NS, Iandoli MI, Tucker J, Riedl MA, Zuraw BL, Banerji A. 3/2017 The Journal of Allergy and Clinical Immunology. In Practice

    BACKGROUND: Hereditary angioedema (HAE) is a life-threatening disorder characterized by recurrent angioedema. Icatibant, a subcutaneous bradykinin-B2-receptor antagonist, is an effective on-demand therapy. Data outside the United States suggest that self-administration is tolerated and patient-preferred compared with administration by health care professionals at medical facilities (HCP-administration).

    OBJECTIVE: A prospective, multicenter study was conducted in the United States to compare icatibant self-administration and HCP-administration.

    METHODS: Subjects 18 years or older with type I or II HAE were recruited. The first 2 HAE attacks after enrollment were treated at medical facilities. Subjects were instructed by a health care professional on self-administration during icatibant treatment for the second HAE attack. Icatibant was self-administered for all subsequent attacks. For each treated HAE attack, efficacy, safety, and tolerability data were recorded.

    RESULTS: Nineteen patients with HAE received icatibant for 79 distinct HAE attacks. Mean attack duration was significantly shorter with self-administration (n = 50; 547 +/- 510 minutes) than with HCP-administration (n = 29; 968 +/- 717 minutes; P = .006). Mean time to treatment was significantly shorter with self-administration (143 +/- 226 minutes) than with HCP-administration (361 +/- 503 minutes; P < .0001). Shorter times to treatment were associated with shorter time from treatment to symptom resolution (r = 0.35; P = .02). Improvements in visual analog scale score and patient symptom score from pretreatment to 4 hours postinjection were comparable between self-administration and HCP-administration. There were no serious adverse events or discontinuations due to adverse events with self-administration or HCP-administration.

    CONCLUSIONS: Icatibant self-administration shortened attack duration and time to treatment, with no difference in safety or local tolerability compared with HCP-administration. These findings support icatibant as an effective on-demand option for home-based treatment.
    Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.jaci-inpractice.org/article/S2213-2198(16)30424-X/fulltext

    Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks

    Bernstein JA, Relan A, Harper JR, Riedl M. 4/2017 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Symptoms of hereditary angioedema (HAE) attacks can recur soon after initial treatment; the durability of response for recombinant human C1 esterase inhibitor (rhC1INH) treatment is unknown.

    OBJECTIVE: To examine the efficacy and durability of rhC1INH for acute HAE attacks.

    METHODS: In this pooled post hoc analysis of 2 trials, patients with type I or II HAE (functional C1INH levels <50% of normal) and a baseline visual analog scale score of at least 50 mm were included if they had received at least 1 intravenous dose of 50 IU/kg of rhC1INH. Response was defined as symptom relief within 4 hours after treatment with persistence (>=20-mm decrease in visual analog scale scores [0 mm {“no symptoms at all”} to 100 mm {“extremely disabling”}] at 2 consecutive time points) during the 4 hours. Durability was the response without an increase of at least 20 mm in the minimum post-treatment visual analog scale score up to 24 hours. Recurrence and new attack symptoms were determined for patients with 72-hour post-treatment data.

    RESULTS: Data were analyzed for 127 patients treated with 50 IU/kg of rhC1INH in 2 studies. Most attacks (90.7%) responded within 4 hours, with differences in response rates among attack locations (61.5%-94.4%). The median time to the beginning of symptom relief was 75.0 minutes (95% confidence interval 65.0-80.0). No relapse occurred during 24 hours for attacks that initially responded. Only 7.1% of attacks were associated with symptom recurrence within 72 hours of initial rhC1INH treatment.

    CONCLUSION: This integrated analysis supports the efficacy of rhC1INH for treatment of acute HAE across multiple attacks, with a sustained response for at least 3 days.

    TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00225147 and NCT00262301.
    Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: http://www.annallergy.org/article/S1081-1206(17)30100-X/fulltext

    The Icatibant Outcome Survey: Experience of hereditary angioedema management from six European countries

    Caballero T, Aberer W, Longhurst HJ, Maurer M, Zanichelli A, Perrin A, Bouillet L, Andresen I, IOS Study Group 7/2017 Journal of the European Academy of Dermatology and Venereology : JEADV

    BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults.

    OBJECTIVE: To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK.

    METHODS: The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009-April 2015.

    RESULTS: Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany-Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany-Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany-Austria) to 18.5 (France) h].

    CONCLUSION: These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.
    Copyright © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575527/

    Treatment effect and safety of icatibant in pediatric patients with hereditary angioedema

    Farkas H, Reshef A, Aberer W, Caballero T, McCarthy L, Hao J, et al. 11/2017 The journal of allergy and clinical immunology. In practice

    BACKGROUND: Clinical manifestations of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) usually begin in childhood, often intensifying during puberty. Currently there are insufficient efficacy/safety data for HAE therapies in children and adolescents due to the small number of pediatric patients enrolled in studies.

    OBJECTIVE: The objective of this phase 3 study was to evaluate the efficacy/safety of a single subcutaneous dose of icatibant (0.4 mg/kg; maximum 30 mg) in pediatric patients with C1-INH-HAE.

    METHODS: Patients aged 2 years to younger than 18 years were categorized as prepubertal (children) and pubertal/postpubertal (adolescents). The primary end point was time to onset of symptom relief-earliest time posttreatment to 20% or more improvement in composite symptom score.

    RESULTS: Thirty-two patients received icatibant (safety population: 11 children with attack, 10 adolescents without attack, and 11 adolescents with attack). The efficacy population consisted of 11 children and 11 adolescents with edematous attacks. Most attacks in the efficacy population (16 [72.7%]) were cutaneous, 5 (22.7%) were abdominal, and 1 (4.5%) was both cutaneous and abdominal; none was laryngeal. Overall, the median time to onset of symptom relief was 1.0 hour, the same for children and adolescents. Thirty-two treatment-emergent adverse events (all mild or moderate) occurred in 9 (28.1%) patients. Gastrointestinal symptoms were most common (9 events in 3 [9.4%] patients). Injection-site reactions affected most (90.6%) patients (particularly erythema and swelling), but almost all resolved by 6 hours postdose. Icatibant demonstrated a monophasic plasma concentration-time profile. Time to peak concentration was approximately 0.5 hours postdose.

    CONCLUSIONS: Symptom relief was rapid, and a single icatibant injection in pediatric patients with C1-INH-HAE was well tolerated (ClinicalTrials.gov identifier, NCT01386658).
    Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S2213219817302532

    Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII)

    Bork K, Wulff K, Witzke G, Hardt J. 2/2017 Allergy

    Hereditary angioedema with normal C1 esterase inhibitor and mutations in the F12 gene (HAE-FXII) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. It occurs nearly exclusively in women. We report our experience treating HAE-FXII with discontinuation of potential trigger factors and drug therapies. The study included 72 patients with HAE-FXII. Potential triggers included estrogen-containing oral contraceptives (eOC), hormonal replacement therapy, or angiotensin-converting enzyme inhibitors. Drug treatment comprised plasma-derived C1 inhibitor (pdC1-INH) for acute swelling attacks and progestins, tranexamic acid, and danazol for the prevention of attacks. Discontinuation of eOC was effective in 25 (89.3%) of 28 women and led to a reduction in the number of attacks (about 90%). After ending hormonal replacement therapy, three of eight women became symptom-free. Three women with exacerbation of HAE-FXII during intake of quinapril or enalapril had no further HAE-FXII attacks after discontinuation of those drugs. Eleven women were treated with pdC1-INH for 143 facial attacks. The duration of the treated facial attacks (mean: 26.6 h; SD: 10.1 h) was significantly shorter than that of the previous 88 untreated facial attacks in the same women (mean: 64.1 h; SD: 28.0 h; P < 0.01). The mean reduction in attack frequency was 99.8% under progestins after discontinuing eOC (16 women), 93.8% under tranexamic acid (four women), and 100% under danazol (three women). For patients with HAE-FXII, various treatment options are available which completely or at least partially reduce the number or duration of attacks.
    Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Available from: http://onlinelibrary.wiley.com/wol1/doi/10.1111/all.13076/full

    Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina

    Malbran E, Menendez A, Malbran A 4/2017 Medicina

    The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina’s C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

    Available from: http://www.medicinabuenosaires.com/PMID/28825570.pdf

    Clinical features of hereditary angioedema in Korean patients: a nationwide multicenter study

    Jung JW, Suh DI, Park HJ, Kim S, Kwon HS, Yang MS, Park CS, Kim JH, Kim SH, Lee YW, Hur GY, Ye YM, Kwon YE, Park HK, Kim CW, Koh YI, Park JW, Lee JM, Min KU, Wickner P, Kang HR 3/2018 International Archives of Allergy & Immunology

    BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea.

    METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed.

    RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 +/- 14.1 years. The age at diagnosis was 36.5 +/- 15.8 years, with a mean time delay of 7.8 +/- 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far.

    CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries.
    Copyright © 2018 S. Karger AG, Basel.

    Available from: https://www.karger.com/Article/Abstract/488350

    Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial

    Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, Davis-Lorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M, HELP Investigators 11/2018 JAMA

    Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations.

    Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.

    Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.

    Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.

    Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.

    Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).

    Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.

    Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

    Available from: https://jamanetwork.com/journals/jama/fullarticle/2716564

    Efficacy of C1 inhibitor concentrate in hereditary angioedema with C1 inhibitor deficiency: analysis in a French cohort

    Belbezier A, Boccon-Gibod I, Thanh AD, Fain O, Bouillet L, for CREAK 10/2018 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    Available from: https://www.annallergy.org/article/S1081-1206(18)30521-0/fulltext

    Efficacy of recombinant human C1 esterase inhibitor across anatomic locations in acute hereditary angioedema attacks

    Baker JW, Bernstein JA, Harper JR, Relan A, Riedl MA. 9/2018 Allergy and Asthma Proceedings

    BACKGROUND: Hereditary angioedema (HAE) may occur at or spread to multiple anatomic locations during an acute attack. Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treating acute HAE attacks.

    OBJECTIVE: To examine the time to the beginning of symptom relief with rhC1-INH by attack location.

    METHODS: Data for patients >=12 years of age with an acute HAE attack who received rhC1-INH 50 IU/kg or placebo were pooled from two double-blind clinical trials with open-label extensions. The time to the beginning of symptom relief was defined as the first time point that the visual analog scale severity score at an attack location decreased by >=20 mm versus baseline, with persistence. Data were reported as median time values (95% confidence interval [CI]).

    RESULTS: For abdominal attacks, the median time to the beginning of symptom relief was 60.0 minutes (95% CI, 47.0-62.0 minutes; n = 194 attacks) with rhC1-INH versus 240.0 minutes (95% CI, 45.0-720.0 minutes; n = 15 attacks) with placebo. The median time to the beginning of symptom relief for peripheral attacks was 105.0 minutes (95% CI, 90.0-120.0 minutes; n = 169 attacks) with rhC1-INH versus 303.0 minutes (95% CI, 180.0-720.0 minutes; n = 17 attacks) with placebo. For oro-facial-pharyngeal-laryngeal attacks or urogenital attacks, the median time to the beginning of symptom relief with rhC1-INH was 64.5 minutes (95% CI, 60.0-120.0 minutes; n = 36 attacks) and 119.0 minutes (95% CI, 40.0-270.0 minutes; n = 13 attacks), respectively, versus 306.0 minutes (95% CI, 30.0-495.0 minutes; n = 6 attacks) and 320.0 minutes (n = 1 attack) with placebo.

    CONCLUSION: In shortening the median time to the beginning of symptom relief of acute HAE attacks, rhC1-INH 50 IU/kg was efficacious, regardless of attack location.

    Available from: https://www.ingentaconnect.com/content/ocean/aap/2018/00000039/00000005/art00006%3bjsessionid=52ip9ffuv2glg.x-ic-live-01#

    Efficacy of treatment of non-hereditary angioedema [Review]

    van den Elzen M, Go MFCL, Knulst AC, Blankestijn MA, van Os-Medendorp H, Otten HG 6/2018 Clinical Reviews in Allergy & Immunology

    Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. In this systematic review, we searched PubMed, EMBASE, and Scopus to provide an overview of the efficacy of different treatment options for the abovementioned subtypes of refractory non-hereditary AE with or without wheals and with normal C1INH. After study selection and risk of bias assessment, 61 articles were included for data extraction and analysis. Therapies were described for angiotensin-converting enzyme inhibitor-induced AE (ACEi-AE), for idiopathic AE, and for AE with wheals. Described treatments consisted of ecallantide, icatibant, C1INH, fresh frozen plasma (FFP), tranexamic acid (TA), and omalizumab. Additionally, individual studies for anti-vitamin K, progestin, and methotrexate were found. Safety information was available in 26 articles. Most therapies were used off-label and in few patients. There is a need for additional studies with a high level of evidence. In conclusion, in acute attacks of ACEi-AE and idiopathic AE, treatment with icatibant, C1INH, TA, and FFP often leads to symptom relief within 2 h, with limited side effects. For prophylactic treatment of idiopathic AE and AE with wheals, omalizumab, TA, and C1INH were effective and safe in the majority of patients.

    Available from: https://link.springer.com/article/10.1007%2Fs12016-016-8585-0

    Epidemiology of bradykinin-mediated angioedema: a systematic investigation of epidemiological studies

    Aygoren-Pursun E, Magerl M, Maetzel A, Maurer M. 5/2018 Orphanet Journal of Rare Diseases

    BACKGROUND: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.

    METHODS: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.

    RESULTS: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.

    CONCLUSIONS: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935942/?report=classic

    Evaluating satisfaction of patients with hereditary angioedema with their past and present treatments: Implications for future therapies

    Jose J, Lehman EB, Craig T 1/2018 Allergy and Asthma Proceedings

    BACKGROUND: Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration.

    OBJECTIVE: To understand patients’ impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments.

    METHODS: After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software.

    RESULTS: Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes.

    CONCLUSION: Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual’s personal goals.

    Available from: https://www.ingentaconnect.com/content/ocean/aap/2018/00000039/00000001/art00011

    Functional complement analysis can predict genetic testing results and long-term outcome in patients with complement deficiencies

    Blazina S, Debeljak M, Kosnik M, Simcic S, Stopinsek S, Markelj G, Toplak N, Kopac P, Zakotnik B, Pokorn M, Avcin T 3/2018 Frontiers in Immunology

    Background: Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries.

    Objective: The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD.

    Methods: CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD.

    Results: Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5-6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported.

    Conclusion: Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871747/

    Haegarda–a subcutaneous C1 esterase inhibitor for prevention of hereditary angioedema.

    Icatibant for the treatment of hereditary angioedema with C1-inhibitor deficiency in adolescents and in children aged over 2 years [Review]

    Farkas H, Kohalmi KV 6/2018 Expert Review of Clinical Immunology

    INTRODUCTION: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare disorder with life-threatening complications if untreated. It begins during childhood, and reduces the patient’s quality of life. Therefore, the availability of an easily administered agent to relieve unpredictable HAE episodes is indispensable for this age group. Areas covered: Randomized, double-blind, placebo-controlled, open-label extensions and prospective observational studies have proven the safety and efficacy of the subcutaneously administered bradykinin B2 receptor antagonist, icatibant, in the acute treatment of HAE episodes in adult C1-INH-HAE patients. Recently, a Phase 3, multicenter, open-label, non-randomized, single-arm study demonstrated the efficacy, safety, and tolerability of icatibant as an acute treatment for pediatric patients aged 2 years to less than 18 years. Expert commentary: The clinical study in pediatric patients showed that icatibant undergoes rapid absorption, reaches a therapeutic level, and promptly relieves the symptoms. It is well tolerated, and the subcutaneous preparation, presented in a pre-filled syringe, ensures ease of use. It can be administered anytime, anywhere, and instantly – even by the patients themselves, or – in the case of children and adolescents – by a caregiver. Icatibant may greatly contribute to the improvement of the quality of life of pediatric patients.

    Available from: https://www.tandfonline.com/doi/abs/10.1080/1744666X.2018.1476851?journalCode=ierm20

    Icatibant outcome survey in patients with hereditary angioedema: experience in Israel compared with other countries

    Toubi E, Kivity S, Graif Y, Reshef A, Botha J, Andresen I 4/2018 The Israel Medical Association Journal: IMAJ

    BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.

    OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.

    METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.

    RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.

    CONCLUSIONS: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

    Available from: https://www.ima.org.il/MedicineIMAJ/viewarticle.aspx?year=2018&month=04&page=227

    Investigational drugs in phase I and phase II clinical trials for hereditary angioedema [Review]

    Farkas H, Debreczeni ML, Kohalmi KV 1/2018 Expert opinion on investigational drugs

    INTRODUCTION: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required. Areas covered: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII. Expert opinion: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.

    Available from: https://www.tandfonline.com/doi/abs/10.1080/13543784.2018.1415325?journalCode=ieid20

    New treatments for hereditary angioedema [Review]

    Johnson NM, Phillips MA 1/2018 Skin Therapy Letter

    Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.

    Available from: http://www.skintherapyletter.com/angioedema/new-treatments/

    Oral plasma kallikrein inhibitor for prophylaxis in hereditary angioedema

    Aygoren-Pursun E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M. 7/2018 New England Journal of Medicine

    BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.

    METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.

    RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.

    CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

    Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1716995

    Pharmacological management of hereditary angioedema with C1-inhibitor deficiency in pediatric patients [Review]

    Farkas H 4/2018 Paediatric drugs

    Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a form of bradykinin-mediated angioedema. It is a rare disorder with an onset during childhood in most instances. Therefore, familiarity with the options for the management of pediatric cases is indispensable. The recurrent angioedematous episodes do not respond to conventional treatments and may evolve into a life-threatening condition. In view of the recommendations adopted by international consensus in 2016, patient management and follow-up should be guided by an individualized strategy. During the last decade, various medicinal products with novel modes of action and different posology have been developed for the treatment of C1-INH-HAE. These drugs either inhibit the release of bradykinin (plasma-derived C1-inhibitors, recombinant C1-inhibitors, kallikrein inhibitors) or prevent the released bradykinin from binding to its receptor (bradykinin B<sub>2</sub> receptor antagonists). This review summarizes the properties of the medicinal products currently available for the treatment of C1-INH-HAE, the indications for their use in pediatric patients, and the findings of the clinical trials conducted in this patient population. It is concluded by a brief outline of future therapeutic options.

    Available from: https://link.springer.com/article/10.1007%2Fs40272-017-0273-x

    Pharmacotherapy

    Fineman SM, Khan DA, Dinakar C, Lang DM, Tilles SA 7/2018 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    Available from: https://www.annallergy.org/article/S1081-1206(18)30374-0/fulltext

    Pharmacotherapy for angiotensin-converting enzyme inhibitor-induced angioedema: a systematic review [Review]

    Lawlor CM, Ananth A, Barton BM, Flowers TC, McCoul ED 2/2018 Otolaryngology - Head & Neck Surgery

    Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of “angioedema” and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema. Results Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy. Conclusion The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition.

    Available from: http://journals.sagepub.com/doi/abs/10.1177/0194599817737974

    Safety, effectiveness, and impact on quality of life of self-administration with plasma-derived nanofiltered C1 inhibitor (Berinert®) in patients with hereditary angioedema: the SABHA study

    Zanichelli A, Azin GM, Cristina F, Vacchini R, Caballero T 4/2018 Orphanet Journal of Rare Diseases

    BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. Self-treatment is recommended, in order to reduce admissions to the Emergency Room and the time between the onset of the attack and the treatment, resulting in a better treatment outcome and an improved quality of life (QoL). The purpose of this study is to assess the safety, tolerability, and effect on QoL of self-administration of pnf C1-INH for IV use (Berinert®).
    METHODS:
    An observational, monocenter, prospective study was designed. Patients referring to a center for angioedema that attended two sessions of self-infusion training course in the period March 2014-July 2015 were enrolled in the study. The primary endpoint was to monitor the safety and feasibility of pnf C1-INH self-infusion. The secondary endpoint was to evaluate the effect of self-infusion on the QoL, by means of the HAE-QoL questionnaire and the need for access to Emergency Room for infusion of Berinert®. Patients’ medical history data were collected upon the first visit and questionnaires were filled after each attack treated with Berinert® (diary and Treatment Satisfaction Questionnaire for Medication) and upon the first visit and the follow-ups (HAE-QoL).
    RESULTS:
    Twenty patients were enrolled (median age = 42, IQR: 39-49; 60% females). Fifteen patients completed the study. A total of 189 attacks were recorded (annual median rate of 4 attacks/patient). Patients waited a median of 2 h (IQR: 1-4) before self-administration, and the resolution of the attack occurred after a median of 6 h (IQR: 4-11). Most attacks were abdominal (39%) and peripheral (22%). 92% of the attacks were treated through self-/caregiver-administration. In most attacks no side effects were reported. The number of attacks with side effects decreased over time, from 37% to 13%. Global satisfaction grew over time during the study period, reaching statistical significance over the first 6 months. The median total HAE-QoL score at baseline was 86 (IQR: 76-103) and improved in a non-significant manner throughout the study period. 8% of the attacks treated with Berinert® required ER admission/healthcare professional help in the study period, compared with 100% in the 3 years before enrollment (p < 0.0001).
    CONCLUSIONS:
    Self-administration of pnf C1-INH is safe, and increases patients’ confidence in the treatment, showing also a trend towards an improvement in QoL. It reduces the need for ER admission/healthcare professionals help for the acute attacks, as well as the related costs.

    Subcutaneous C1-esterase inhibitor to prevent hereditary angioedema attacks: safety findings from the COMPACT trial

    Li HH, Mycroft S, Christiansen S, Wood DN, Feuersenger H, Pawaskar D, Jacobs I 9/2018 Allergy and Asthma Proceedings

    BACKGROUND: The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial.

    OBJECTIVE: This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs).

    METHODS: Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited.

    RESULTS: No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed.

    CONCLUSION: C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, <ext-link xmlns:xlink=”http://www.w3.org/1999/xlink” ext-link-type=”uri” xlink:href=”http://www.clinicaltrials.gov”>www.clinicaltrials.gov</ext-link>.

    Available from: https://www.ingentaconnect.com/content/ocean/aap/2018/00000039/00000005/art00007#

    Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency

    Loules G, Zamanakou M, Parsopoulou F, Vatsiou S, Psarros F, Csuka D, et al. 8/2018 Gene

    SERPING1 genotyping of subjects suspicious for hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is important for clinical practice as well as for research reasons. Conventional approaches towards the detection of C1-INH-HAE-associated SERPING1 variants are cumbersome and time-demanding with many pitfalls. To take advantage of the benefits of next-generation sequencing (NGS) technology, we developed and validated a custom NGS platform that, by targeting the entire SERPING1 gene, facilitates genetic testing of C1-INH-HAE patients in clinical practice. In total, 135 different C1-INH-HAE-associated SERPING1 variants, out of the approximately 450 reported, along with 115 negative controls and 95 randomly selected DNA samples from affected family members of C1-INH-HAE index patients, were included in the forward and reverse validation processes of this platform. Our platform’s performance, i.e. analytical sensitivity of 98.96%, a false negative rate of 1.05%, analytical specificity 100%, a false positive rate equal to zero, accuracy of 99.35%, and repeatability of 100% recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method. A noteworthy advantage of our platform is the concomitant detection of single nucleotide variants and copy number variations throughout the whole length of the SERPING1 gene, moreover providing information about the size and the localization of the latter. During our study, 15 novel C1-INH-HAE-related SERPING1 variants were detected.
    Copyright © 2018 Elsevier B.V. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S0378111918305122?via%3Dihub

    The Incidence and frequency of various causes of angioedema in emergency medicine

    Karadza-Lapic L, Pikivaca T, Pervan P, Jovic Zlatovic J, Delin S, Prkacin I 5/2018 Acta Medica Academica

    OBJECTIVE: Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.

    METHODS: The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.

    RESULTS: There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.

    CONCLUSION: Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.
    Copyright © 2018 by Academy of Sciences and Arts of Bosnia and Herzegovina.

    Available form: http://www.ama.ba/index.php/ama/article/view/325/pdf

    Treatment patterns and healthcare resource utilization among patients with hereditary angioedema in the United State

    Riedl MA, Banerji A, Manning ME, Burrell E, Joshi N, Patel D, Machnig T, Tai MH, Watson DJ 10/2018 Orphanet Journal of Rare Diseases

    BACKGROUND: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, >=1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for >=3 months following the first HAE prescription claim.

    RESULTS: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging >=1500 IU/week for >=13 weeks) in 155 patients; use of >=1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD.

    CONCLUSIONS: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186115/

    Value co-creation in healthcare: evidence from innovative therapeutic alternatives for hereditary angioedema

    Spano R, Di Paola N, Bova M, Barbarino A 7/2018 BMC Health Services Research

    BACKGROUND: Our research focuses on the co-creation of value in healthcare with reference to a case of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE). Our work is mainly based on the concept of value co-creation in healthcare. The aim of this study is to assess the impact of an alternative treatment strategy – self-administration – by focusing on treatment outcomes and costs to understand if innovative therapeutic solutions can create value for patients and healthcare systems.

    METHODS: This paper compares home-based and hospital-based therapeutic strategies (independent of treatment type) with a cost minimization analysis. It encompasses compliance issues and focuses on both payer and societal perspectives, also benefiting from an operationalization of the service-dominant logic model for healthcare delivery. Data were collected over a 6-month period (August 2014-January 2015) through monthly patient interviews. Archival data were used for variable measurement.

    RESULTS: Thirty-nine out of 62 patients enrolled in the study, experienced at least one HAE attacks, equally distributed between home and hospital-based strategies. No evidence of correlation between therapeutic strategy and disease severity score (p = 0.351), compliance (p = 0.399), and quality of life (p = 0.971), were found. Total direct cost per attack amounts to 1224 for home-based strategy with respect to 1454 for hospital-based strategy, with a savings of 230. The economic advantage of the home-based strategy almost doubles if the societal perspective was considered due to a further savings of 169 (less missed work/school days and no travel expenses).

    CONCLUSIONS: Our study suggests that home-based therapies represent a feasible strategy for managing C1-INH-HAE and may result in lower costs and increased value for both patients and the healthcare systems. The findings are relevant to the debate on and extend the extant literature to provide a broader view of value co-creation dynamics for home-based therapies in healthcare and their positive effects. The insights are relevant to practitioners and policy makers.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053759/

    A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema

    Aygoren-Pursun E, Soteres DF, Nieto-Martinez SA, Christensen J, Jacobson KW, Moldovan D, Van Leerberghe A, Tang Y, Lu P, Vardi M, Schranz J, Martinez-Saguer I 8/2019 Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology

    BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.

    METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).

    RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.

    CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.

    TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141. Copyright © 2019 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

    Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/pai.13060

    A review of kallikrein inhibitor lanadelumab in hereditary angioedema. [Review]

    Hwang G, Johri A, Ng S, Craig T 8/2019 Immunotherapy

    Hereditary angioedema with C1 esterase inhibitor deficiency is a rare disorder characterized by unpredictable swelling of the face, larynx and gastrointestinal tract. Kallikreins are serine proteases that cleave kininogens to produce bradykinin leading to inflammation. A new prophylactic drug is lanadelumab (DX-2930, SHP-643), a recombinant, fully human IgG1 monoclonal antibody kallikrein inhibitor. Pharmacokinetics show a half-life of 14 days with a dose-dependent effect. Completed trials for lanadelumab include two Phase III studies with updated efficacy in preventing angioedema in hereditary angioedema patients. Ongoing data show the safety of the targeted therapy along with less frequent administration requirements. Information on long-term safety is still needed, as well as, further studies on the correlation of subcutaneous administered dosing requirements and severity of side effects.

    Available from: https://dx.doi.org/10.2217/imt-2018-0197

    Advances in drug allergy, urticaria, angioedema, and anaphylaxis in 2018 [Review]

    Miller RL, Shtessel M, Robinson LB, Banerji A 8/2019 Journal of Allergy & Clinical Immunology

    Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify beta-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis. Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaci.2019.06.010

    An antibody against HK blocks Alzheimer’s disease peptide beta-amyloid-induced bradykinin release in human plasma

    Chen ZL, Singh P, Wong J, Horn K, Strickland S, Norris EH 11/2019 Proceedings of the National Academy of Sciences of the United States of America

    Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer’s disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent downstream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide beta-amyloid (Abeta)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies. Copyright © 2019 the Author(s). Published by PNAS.

    Available from: https://www.pnas.org/content/116/46/22921.long

    An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema

    Liu J, Qin J, Borodovsky A, Racie T, Castoreno A, Schlegel M, Maier MA, Zimmerman T, Fitzgerald K, Butler J, Akinc A 2/2019 RNA (New York, N.Y.)

    Hereditary angioedema (HAE) is a genetic disorder mostly caused by mutations in the C1 esterase inhibitor gene (C1INH) that results in poor control of contact pathway activation and excess bradykinin generation. Bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. We hypothesized that the use of RNA interference (RNAi) to reduce plasma Factor XII (FXII), which initiates the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. A subcutaneously administered GalNAc-conjugated small-interfering RNA (siRNA) targeting F12 mRNA (ALN-F12) was developed, and potency was evaluated in mice, rats, and cynomolgus monkeys. The effect of FXII reduction by ALN-F12 administration was evaluated in two different vascular leakage mouse models. An ex vivo assay was developed to evaluate the correlation between human plasma FXII levels and high-molecular weight kininogen (HK) cleavage. A single subcutaneous dose of ALN-F12 led to potent, dose-dependent reduction of plasma FXII in mice, rats, and NHP. In cynomolgus monkeys, a single subcutaneous dose of ALN-F12 at 3 mg/kg resulted in >85% reduction of plasma FXII. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular leakage, demonstrating that RNAi-mediated reduction of FXII can potentially mitigate excess bradykinin stimulation. Lastly, ex vivo human plasma HK cleavage assay indicated FXII-dependent bradykinin generation. Together, these data suggest that RNAi-mediated knockdown of FXII by ALN-F12 is a potentially promising approach for the prophylactic treatment of HAE.
    Copyright © 2019 Liu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

    Available from: https://rnajournal.cshlp.org/content/early/2018/11/21/rna.068916.118

    Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate

    Bork K, Staubach-Renz P, Hardt J 3/2019 Orphanet Journal of Rare Diseases

    BACKGROUND: Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is a serious condition that may result in life-threatening asphyxiation due to laryngeal edema. It is associated with malignant B-cell lymphoma and other disorders. The purpose of this study was to describe the characteristics and associated disorders of patients with AAE-C1-INH and assess the efficacy of plasma-derived C1-INH concentrate (pdC1-INH) in the treatment of AAE-C1-INH. Forty-four patients with AAE-C1-INH from the Angioedema Outpatient Service of Mainz were assessed for associated disorders. In 32 of these patients, the duration of swelling attacks was measured before and after treatment with pdC1-INH (Berinert R (CSL Behring, Marburg, Germany)). The time between injection and complete resolution of symptoms and treatment effectiveness was provided by the patients.

    RESULTS: The following underlying disorders were present: monoclonal gammopathy of undetermined significance (47.7%), non-Hodgkin lymphoma (27.3%), anti-C1-INH autoantibodies alone (11.4%), and other conditions (4.5%). In 9.1% patients, no associated disorder could be found. AAE-C1-INH led to the detection of lymphoma in 75% of patients with the malignancy. Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (+/- 32.8) hours (P < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (+/- 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (+/- 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (+/- 69.1) U in patients without autoantibodies.

    CONCLUSIONS: pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.

    Available from: https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1043-3

    C1 esterase inhibitor activity is reduced in the acute phase following burn injury: A prospective observational study

    Matsuura H, Osuka A, Hirose T, Ogura H, Ueyama M, Shimazu T 10/2019 Journal of Burn Care & Research

    Hereditary angioedema has been attributed to an inherited deficiency of C1 esterase inhibitor that increases vascular permeability. The role of C1 esterase inhibitor in burn patients has not been described previously. In this study, we attempted to identify the relationship between serial changes of C1 esterase inhibitor activity and the clinical course in major burn patients. This study was a single-center, prospective, observational study. C1 esterase inhibitor activity values were serially examined in major burn patients admitted into the burn center from April 2014 to December 2016. Inclusion criteria were age >=16 years old and %TBSA burned >=20%. This study included 38 patients with major burn. C1 esterase inhibitor activity after burn dropped acutely on days 1 and 2 but increased immediately until days 3 to 5, after which it continued to gradually increase to above the reference value. C1 esterase inhibitor activity on admission showed significant inverse correlation with the volume of infusion per body weight required in the first 24 hours after injury and %TBSA burned (r = -0.405, P = 0.01; r = -0.375, P = 0.02, respectively). C1 esterase inhibitor activity on admission was significantly lower in the nonsurvivors than in the survivors during the 28-day evaluation period (59% vs 90%, P = 0.01). These findings suggest that C1 esterase inhibitor may play a critical role in regulating vascular permeability in the acute phase following the burn injury. Copyright © American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

    Available from: https://dx.doi.org/10.1093/jbcr/irz109

    Current and emerging biologics for the treatment of hereditary angioedema [Review]

    Perego F, Wu MA, Valerieva A, Caccia S, Suffritti C, Zanichelli A, Bergamaschini L, Cicardi M 6/2019 Expert Opinion on Biological Therapy

    INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients.

    AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed.

    EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

    Available from: https://www.tandfonline.com/doi/abs/10.1080/14712598.2019.1595581?journalCode=iebt20

    Elevated thrombin generation and factor VIII activity during angioedema attack in patients with hereditary C1 inhibitor deficiency

    Obtulowicz K, Dyga W, Natorska J, Zabczyk M, Undas A 12/2019 Polish Archives Of Internal Medicine

    Available from: https://dx.doi.org/10.20452/pamw.15096

    Fixed-dose subcutaneous C1-inhibitor liquid for prophylactic treatment of C1-INH-HAE: SAHARA randomized study

    Lumry WR, Martinez-Saguer I, Yang WH, Bernstein JA, Jacobs J, Moldovan D, Riedl MA, Johnston DT, Li HH, Tang Y, Schranz J, Lu P, Vardi M, Farkas H, SAHARA study group 5/2019 The Journal of Allergy & Clinical Immunology in Practice

    BACKGROUND: Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues.

    OBJECTIVE: To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959).

    METHODS: Eligible patients were >=12 years with >=2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction >=50%, attack severity, number of attack-free days, and safety.

    RESULTS: Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had >=50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively).

    Available from: https://dx.doi.org/10.1016/j.jaip.2019.01.021

    Flow-mediated vasodilation assay indicates no endothelial dysfunction in hereditary angioedema patients with C1-inhibitor deficiency

    Nebenfuhrer Z, Szabo E, Kajdacsi E, Kohalmi KV, Karadi I, Zsary A, Farkas H, Cervenak L 1/2019 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype.

    OBJECTIVE: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls.

    METHODS: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers.

    RESULTS: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high-density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol.

    CONCLUSION: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis. Copyright © 2018. Published by Elsevier Inc.

    Available from: https://www.annallergy.org/article/S1081-1206(18)31295-X/fulltext

    Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema

    Qiu T, Chiuchiolo MJ, Whaley AS, Russo AR, Sondhi D, Kaminsky SM, Crystal RG, Pagovich OE 6/2019 Allergy

    BACKGROUND: Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes.

    METHODS: To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63+/-) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs.

    RESULTS: Systemic administration of AAVrh.10hC1EI to the S63+/- mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs.

    CONCLUSION: A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals. Copyright © 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752709

    Hereditary angioedema in children: a review and update [Review]

    Pancholy N, Craig T 12/2019 Current Opinion in Pediatrics

    PURPOSE OF REVIEW: Hereditary angioedema (HAE) most often presents in the first two decades of life. Despite these patients often see multiple doctors and go many years before confirmation of the diagnosis. the impact on quality of life, productivity and risk of anxiety, depression, and posttraumatic stress emphasizes the need for early diagnosis and appropriate treatment.

    RECENT FINDINGS: Over the past decade, therapy in the USA has emerged from fresh-frozen plasma and androgens to more than seven medications that are specific for bradykinin-induced disease. During the same time, treatment has evolved from intravenous to subcutaneous and the future will be a focus on oral therapy.

    SUMMARY: Much optimism exists that patients with HAE will live a life with minimal disease and impact on their quality of life making it even more important to diagnose children at an early age.

    Available from: https://journals.lww.com/co-pediatrics/Abstract/2019/12000/Hereditary_angioedema_in_children__a_review_and.26.aspx

    Hereditary angioedema, emergency management of attacks by a call center

    Javaud N, Altar A, Fain O, Reuter PG, Desmaizieres M, Petrovic T, Ghazali A, Durand-Zaleski I, Bouillet L, Vicaut E, Launay D, Martin L, Floccard B, Gompel A, Sobel A, Boccon-Gibod I, Kanny G, Lapostolle F, Adnet F 9/2019 European Journal of Internal Medicine

    OBJECTIVE: Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by recurrent, unpredictable, potentially life-threatening swelling. Objective is to assess the management of the acute HAE attacks in the real life setting through a call center in France.

    METHODS: A pre-specified ancillary study of SOS-HAE, a cluster-randomized prospective multicenter trial, was conducted. HAE patients were recruited from 8 participating reference centers. The outcome of interest was the rate of hospitalization.

    RESULTS: onerhundred patients were included. The median (quartile) age was 38 (29-53) years, and 66 (66%) were female. Eighty (80%) patients had HAE type I, 8 (8%) had HAE type II and 12 (12%) patients had FXII-HAE. Fifty-one (51%) patients had experienced at least one time the call center during the follow-up. Nine over 166 (5%) attacks for 9 different patients resulted in hospital admission to the hospital (in the short-stay unit, ie, <24h) during the follow-up period. During 2years, there were 166 calls to call center for 166 attacks. All attacks were treated at home after call center contact.

    CONCLUSIONS: Use of emergency departments and hospitalizations are reduced by the use of a coordinated national call center in HAE after therapeutic education program that promoted self-administration of specific treatment and use of call to call center.

    TRIAL REGISTRATION: clinicalTrials.gov identifier: NCT01679912. Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/abs/pii/S0953620519301529

    Hereditary angioedema: an update on causes, manifestations and treatment [Review]

    Longhurst HJ, Bork K 7/2019 British Journal of Hospital Medicine

    Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.

    Available from: https://www.magonlinelibrary.com/doi/full/10.12968/hmed.2019.80.7.391

    Hospitalizations due to angioedema without urticaria in a Portuguese center: five year retrospective study

    Cosme J, Spinola A, Ferreira MB, Barbosa MP 11/2019 Acta Medica Portuguesa

    INTRODUCTION: Hospitalizations due to angioedema are important especially in debilitating or life-threatening situations. The aim of this study was to evaluate the frequency and etiology of angioedema without urticaria in hospital admissions.

    MATERIAL AND METHODS: The admissions between 2009 and 2013 in Centro Hospitalar Lisboa Norte with a diagnosis grouped under the ICD9 codes of angioedema were retrospectively analysed. The episodes of angioedema with urticaria were excluded. The admissions were categorized into 2 groups: A – hospitalizations motivated by the angioedema; B – hospitalizations in which the angioedema was an incidental finding.

    RESULTS: There were 169 hospitalizations (52% females, 96% adults, mean age 52 +/- 20.8 years), distributed by 23 hospital departments, 51% in the Immunoallergology department. The mean annual angioedema admission rate was 72/100 000. In 68% of the cases, angioedema was the cause for the admission; in 32% an incidental finding. In 38% there was upper airway involvement. The etiologies were: hereditary angioedema in 24%, angiotensin converting enzyme inhibitor induced angioedema in 31%, idiopathic angioedema in 21%, thrombolysis induced angioedema in 13%, nonsteroidal anti-inflammatory drug-induced angioedema in 5%.

    DISCUSSION: The main etiology was angiotensin converting enzyme inhibitor angioedema, followed by hereditary angioedema and thrombolysis induced angioedema, and these findings concur with the international literature.

    CONCLUSION: The mean annual angioedema admission rate was 72/100 000 and there was airway involvement in 38% of hospitalizations.

    Available from: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/11893

     

    Idiopathic anaphylaxis [Review]

    Guo C, Greenberger PA 11/2019 Allergy & Asthma Proceedings

    Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely, but, if elevated in the absence of anaphylaxis, should suggest alternative diagnoses, including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient’s symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema or acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential diagnosis because urticaria does not usually accompany any of the above-mentioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year, or two or more episodes in 2 months are classified as having IA-frequent (IA-F). Patients who experience fewer episodes are classified as having IA-infrequent (IA-I). This distinction is important because patients with IA-F will initially require prednisone as disease-modifying therapy, whereas most patients who with IA-I will not require prednisone. Patients with IA must carry and know when and how to self-administer epinephrine.

    Available from: https://dx.doi.org/10.2500/aap.2019.40.4271

    Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks

    Bernstein JA, Li HH, Craig TJ, Manning ME, Lawo JP, Machnig T, Krishnarajah G, Fridman M 3/2019 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    Introduction: For prophylaxis of hereditary angioedema (HAE) attacks, replacement therapy with human C1-inhibitor (C1-INH) treatment is approved and available as intravenous [C1-INH(IV)] (Cinryze R) and subcutaneous [C1-INH(SC)] HAEGARDA R preparations. In the absence of a head-to-head comparative study of the two treatment modalities, an indirect comparison of data from 2 independent but similar clinical trials was undertaken.

    Methods: Two similar randomized, double-blind, placebo-controlled, crossover studies were identified which evaluated either C1-INH(SC) (COMPACT; NCT01912456; 16 weeks) or C1-INH(IV) (CHANGE; NCT01005888; 14 weeks) vs. placebo (on-demand treatment only) for routine prevention of HAE attacks. Individual patient data from each trial were used to conduct an indirect comparison of treatment effects. Attack reductions (absolute and percent of mean/median number of monthly HAE attacks reduction over placebo) were compared between the two C1-INH formulations at approved/recommended doses: C1-INH(SC) 60 IU/kg twice weekly (n = 45) and 1000 U of C1-INH(IV) twice weekly (n = 22). Point estimates were adjusted using mixed and quantile regression models that controlled for study design.

    Results: The absolute mean monthly numbers of HAE attack reductions were 3.6 (95% CI 2.9, 4.2) for C1-INH(SC) 60 IU/kg vs. placebo and 2.3 (1.4, 3.3) for C1-INH(IV) vs. placebo; between-product difference, 1.3 (0.1, 2.4; P = 0.034). The mean percent reduction in monthly attack rate was significantly greater with C1-INH(SC) as compared with C1-INH(IV) (84% vs. 51%; P < 0.001). The percentages of subjects experiencing >= 50%, >= 70%, and >= 90% reductions in monthly HAE attack rates versus placebo were significantly higher with C1-INH(SC) 60 IU/kg as compared to C1-INH(IV) 1000 U (>= 50% reduction: 91% vs. 50%, odds ratio [OR] = 10.33, P = 0.003; >= 70% reduction: 84% vs. 46%, OR = 6.19, P = 0.005; >= 90% reduction: 57% vs. 18%, OR = 6.04, P = 0.007).

    Conclusion: Within the limitations of an indirect study comparison, this analysis suggests greater attack reduction with twice-weekly C1-INH(SC) 60 IU/kg as compared to twice-weekly C1-INH(IV) 1000 U for the routine prevention of HAE attacks.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407188

    Lanadelumab for the prevention of attacks in hereditary angioedema [Review]

    Valerieva A, Senter R, Wu MA, Zanichelli A, Cicardi M 12/2019 Expert Review of Clinical Immunology

    Introduction: Hereditary angioedema (HAE) with C1 esterase inhibitor deficiency (C1-INH-HAE) is a rare disease that manifests with cutaneous and/or submucosal swellings due to uncontrolled activation of the contact/kinin system. Attacks recur with unpredictable frequency and severity, laryngeal edema is potentially lethal, and the disease burden may severely disrupt patients’ lives. Areas covered: This review provides an overview of lanadelumab, a human monoclonal antibody targeted against plasma kallikrein that was recently approved for prevention of symptoms in C1-INH-HAE. Expert opinion: The phase III HELP Study demonstrated the efficacy of lanadelumab in reducing HAE attacks. These positive results are being further confirmed in the open-label extension study. This agent addresses some of the limitations of existing prophylactic options as tolerability issues, the need for intravenous administration and frequent dosing. Therefore, lanadelumab can profoundly improve the quality of life of patients with C1-INH-HAE.

    Available from: https://dx.doi.org/10.1080/1744666X.2020.1693261

    Lanadelumab for the prophylactic treatment of hereditary angioedema with C1 Inhibitor Deficiency: a review of preclinical and phase I studies [Review]

    Busse PJ, Farkas H, Banerji A, Lumry WR, Longhurst HJ, Sexton DJ, Riedl MA 2/2019 BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy

    Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients’ daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged >= 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.

    Available from: https://link.springer.com/article/10.1007/s40259-018-0325-y

    Lanadelumab for the treatment of hereditary angioedema [Review]

    Wu MA 12/2019 Expert Opinion on Biological Therapy

    Introduction: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare yet still probably underdiagnosed clinical condition. Recurrent episodes of subcutaneous and sub-mucosal swelling may involve the skin, the gastrointestinal tract or even the upper airways, exposing the patients to the risk of death. With the aim of improving patients’ quality of life, the therapeutic scenario has expanded over the years. Areas covered: The focus of the present review is lanadelumab, a fully human, kappa-light-chain, monoclonal immunoglobulin G1 against plasma kallikrein, currently approved for long-term prophylaxis of C1-INH-HAE attacks in the USA and Canada and designated as an orphan drug by the European Medicines Agency. Expert opinion: Lanadelumab is able to inhibit plasma kallikrein with high selectivity and affinity. The subsequent phases of drug development and the ongoing open-label trial have proven its safety and efficacy. It overcomes some of the limitations of other drugs available for long-term prophylaxis, given the easy route of administration, the simple administration schedule and the possibility to tailor the treatment to each patient. Further studies are needed to test its efficacy also in other types of angioedema for which a central role of plasma kallikrein is envisaged.

    Available from: https://dx.doi.org/10.1080/14712598.2019.1685490

    Lanadelumab injection treatment for the prevention of hereditary angioedema (HAE): design, development and place in therapy [Review]

    Bova M, Valerieva A, Wu MA, Senter R, Perego F 11/2019 Drug Design, Development and Therapy

    Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives. Copyright © 2019 Bova et al.

    Available from: https://www.dovepress.com/lanadelumab-injection-treatment-for-the-prevention-of-hereditary-angio-peer-reviewed-fulltext-article-DDDT

    Lanadelumab to treat hereditary angioedema [Review]

    Wedi B 7/2019 Drugs of Today

    Lanadelumab is a human monoclonal antibody against plasma kallikrein indicated for prevention of attacks of hereditary angioedema (HAE). HAE is caused by SERPING1 gene mutations resulting in decreased or dysfunctional plasma protease C1 inhibitor (C1-INH) leading to a loss of inhibition of plasma kallikrein activity with subsequent cleavage of high-molecular weight kininogen and release of bradykinin. There is a clear need for a non-plasma-derived, safe, effective and convenient prophylaxis of HAE attacks to reduce patients’ daily burden of disease and disability. The percentage of patients who were attack-free for the last 16 weeks of a controlled study was 77% in the group receiving 300 mg lanadelumab every 2 weeks, compared with 3% with placebo. The most common side effects were mild injection-site reactions. Lanadelumab has the potential to change the approach from on-demand treatment to prophylaxis in HAE. Future studies will have to confirm long-term safety and efficacy of prophylactic long-term inhibition of plasma kallikrein. Copyright 2019 Clarivate Analytics.

    Available from: https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=2985293

    Lanadelumab: A review in hereditary angioedema [Review]

    Syed YY 11/2019 Drugs

    Lanadelumab (Takhzyro TM), a first-in-class fully human monoclonal antibody against plasma kallikrein, has been approved in several countries, including Australia, Canada, those of the EU, Switzerland and the USA, for the prevention of hereditary angioedema (HAE) attacks in patients aged >=12 years. Subcutaneous lanadelumab significantly reduced HAE attack rates relative to placebo in the pivotal HELP trial. The clinical benefits of lanadelumab were seen regardless of prior long-term prophylaxis use, baseline disease activity, sex or body mass index. Lanadelumab therapy was associated with clinically meaningful improvements in HAE-specific quality of life. Lanadelumab was generally well tolerated. The most common adverse events with lanadelumab were injection-site reactions, which were generally mild and transient. Lanadelumab has a low potential for immunogenicity. It offers the convenience of self-administered subcutaneous injections once every 2 weeks (starting dosage). Currently available data indicate that lanadelumab is an effective, well-tolerated, novel prophylactic option for patients with HAE aged >=12 years.

    Available from: https://dx.doi.org/10.1007/s40265-019-01206-w

    Long-term outcomes with subcutaneous C1-inhibitor replacement therapy for prevention of hereditary angioedema attacks

    Craig T, Zuraw B, Longhurst H, Cicardi M, Bork K, Grattan C, Katelaris C, Sussman G, Keith PK, Yang W, Hebert J, Hanzlikova J, Staubach-Renz P, Martinez-Saguer I, Magerl M, Aygoren-Pursun E, Farkas H, Reshef A, Kivity S, Neri S, Crisan I, Caballero T, Baeza ML, Hernandez MD, Li H, Lumry W, Bernstein JA, Hussain I, Anderson J, Schwartz LB, Jacobs J, Manning M, Levy D, Riedl M, Christiansen S, Feuersenger H, Pragst I, Mycroft S, Pawaskar D, Jacobs I, COMPACT Investigators 7/2019 The Journal of Allergy & Clinical Immunology in Practice

    BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT).

    OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC).

    METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353).

    RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment.

    CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaip.2019.01.054

    Management of patients with hereditary angioedema in Germany: comparison with other countries in the icatibant outcome survey

    Maurer M, Bork K, Martinez-Saguer I, Aygoren-Pursun E, Botha J, Andresen I, Magerl M 1/2019 Journal of the European Academy of Dermatology and Venereology: JEADV

    BACKGROUND: The Icatibant Outcome Survey (IOS; NCT01034969) is a Shire-sponsored, international, observational study monitoring the safety and effectiveness of icatibant, a bradykinin B2 receptor antagonist approved for the acute treatment of adults with hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH).

    OBJECTIVE: To report IOS data comparing demographic and icatibant treatment outcomes in patients with HAE-C1-INH from Germany to HAE-C1-INH patients from 11 other IOS countries.

    METHODS: A descriptive, retrospective, comparative analysis of data from 685 IOS patients with HAE-C1-INH from seven centres in Germany (n = 93) vs. centres from Austria, Brazil, Czech Republic, Denmark, France, Greece, Israel, Italy, Spain, Sweden and the United Kingdom (n = 592, July 2009-January 2017). Icatibant treatment outcomes were retrieved from patients with complete attack outcome data for time to treatment, time to resolution and attack duration (160 attacks in 42 German patients and 1442 attacks in 251 patients from other IOS countries).

    RESULTS: German patients reported significantly fewer severe/very severe attacks (38.7% vs. 57.5%, respectively; P < 0.001). The proportion of attacks treated with a single icatibant injection was significantly higher in German patients (97.1% vs. 91.6%, P = 0.0003). The median time to treatment (0.0 h vs. 1.5 h), time to resolution (3.0 h vs. 7.0 h) and attack duration (4.3 h vs. 10.5 h) in German patients vs. other IOS countries were all significantly shorter (all P < 0.0001). No meaningful differences were identified between patients from Germany and other countries with regard to sex, median age at enrolment, median age at symptom onset and median age at diagnosis.

    CONCLUSION: German IOS patients share similar demographic characteristics to patients from other IOS countries yet treat their attacks with icatibant significantly earlier and have markedly fewer severe or very severe attacks. Factors including regional access to and availability of icatibant may drive these outcomes and warrant further investigation.
    Copyright © 2018 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

    Available from:

    https://onlinelibrary.wiley.com/doi/full/10.1111/jdv.15232

    New monoclonal/bi-specific antibodies: reshaping transfusion medicine beyond replacement [Review]

    Goubran H, Goubran M, Seghatchian J, Burnouf T 4/2019 Transfusion and Apheresis science: Official Journal of the World Apheresis Association: Official Journal of the European Society for Haemapheresis

    Since the first successful transfusion in 1818, Transfusion Medicine has evolved significantly. The advent of plasma fractionation and availability of recombinant products allowed for precision replacement therapy to treat many hematological conditions, such as hemophilia, thrombotic thrombocytopenic purpura, and hereditary angioedema. A deeper understanding of the pathophysiology underlying those conditions along with the development of safer monoclonal and bispecific antibodies is now offering safe and effective alternatives to the simple conventional approach of replacing a missing plasma protein. Many biologicals are already in wide clinical use in areas such as rheumatology, gastroenterology, and medical oncology. The introduction of novel therapeutic antibodies within the realm of Transfusion Medicine will likely reshape the field and challenge the role of local blood establishments as the gate-keepers of such therapies. Copyright © 2019 Elsevier Ltd. All rights reserved.

    Available from: https://www.trasci.com/article/S1473-0502(19)30022-9/fulltext

    Novel, efficient, facile, and comprehensive protocol for post-column amino acid analysis of icatibant acetate containing natural and unnatural amino acids using the QbD approach

    Komaravolu Y, Dama VR, Maringanti TC 2/2019 Amino Acids

    Qualitative and quantitative determination of amino acid composition using amino acid analysis (AAA) is an important quality attribute and considered an identity of therapeutic peptide drugs by the regulatory agencies. Although huge literature is available on pre- and post- column derivatization AAA methods, arriving at an appropriate hydrolysis protocol coupled with adequate separation of the derivatized/underivatized amino acids is always challenging. Towards achieving a facile and comprehensive protocol for AAA, the present work is geared towards developing a deeper understanding of the extent of hydrolysis of peptide, and the nature and stability of amino acids present in the peptide backbone. This defines the suitability of the method in meeting the end goals and the regulatory requirement. Analysis of historical data generated during the method optimization of AAA for icatibant acetate (ICT) using head space oven hydrolysis (HSOH) and microwave-assisted hydrolysis (MAH) methods helped in arriving at fast (< 1 h) and efficient hydrolysis (0.9-1.1 of theoretical residue) conditions. Better separations for the natural and unnatural amino acids were achieved using 3.45 <= pH <= 10.85, and a column oven gradient program. This approach was useful in meeting the method quality attributes [resolution (Rs) > 2.0; plate count (N) > 5600; and USP tailing factor < 1.2] with a target analytical method profile of relative amino acid mole ratios (RAAMR) in the range of 0.9-1.1 for Ser, Oic, Tic, Hyp, Ala (Thi), Gly and Pro, and between 2.7 and 3.3 for Arg. The developed method was validated as per the ICH guidelines and is precise, accurate, linear and robust.

    Available from: https://link.springer.com/article/10.1007%2Fs00726-018-2665-9

    Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema [Review]

    Hwang JR, Hwang G, Johri A, Craig T 12/2019 Immunotherapy

    Hereditary angioedema (HAE) is rare disorder caused by a SERPING1 gene mutation that triggers severe swelling of the skin and upper airway. Treatment options for HAE with deficient and dysfunctional C1-inhibitor are expanding to include small-molecule drugs that inhibit protein interactions in the kallikrein-kinin system. Discovered by BioCryst Pharmaceuticals, BCX7353 is a synthetic, once-daily, small molecule drug that can be taken as an oral capsule to treat HAE attacks and for prophylaxis. This article will summarize recent and current BCX7353 clinical trials. Overall, results indicate BCX7353 is a promising form of therapy with a rapid 1 h onset of action, long duration of action, and acceptable tolerance.

    Available from: https://dx.doi.org/10.2217/imt-2019-0128

    Pediatricians diagnosed few patients with childhood-presented hereditary angioedema: Icatibant Outcome Survey findings

    Grumach AS, Longhurst HJ, Aberer W, Bouillet L, Caballero T, Bygum A, Zanichelli A, Botha J, Andresen I, Maurer M, Icatibant Outcome Survey investigators 3/2019 The Journal of Allergy & Clinical Immunology in Practice

    Available from: https://dx.doi.org/10.1016/j.jaip.2018.07.047

    Recombinant human C1 esterase inhibitor treatment for hereditary angioedema attacks in children

    Reshef A, Grivcheva-Panovska V, Kessel A, Kivity S, Klimaszewska-Rembiasz M, Moldovan D, Farkas H, Gutova V, Fritz S, Relan A, Giannetti B, Magerl M 8/2019 Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology

    BACKGROUND: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1-INH (rhC1-INH) for HAE attacks in children.

    METHODS: This open-label, phase 2 study included children aged 2-13 years with C1-INH-HAE. Eligible HAE attacks were treated intravenously with rhC1-INH 50 IU/kg body weight (maximum, 4200 IU). The primary end-point was time to beginning of symptom relief (TOSR; >=20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end-point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations).

    RESULTS: Twenty children (aged 5-14 years; 73 HAE attacks) were treated with rhC1-INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1-INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0-65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0-126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment-related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected.

    CONCLUSIONS: Recombinant human C1-INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults. Copyright © 2019 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

    Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/pai.13065

    Risk factors for diagnostic delay in Chinese patients with hereditary angioedema

    Liu S, Wang X, Xu Y, Xu Q, Zhi Y 9/2019 Allergy & Asthma Proceedings

    Background: Hereditary angioedema (HAE) is still underdiagnosed or diagnosed after a serious delay. This study aimed to evaluate the diagnostic delay (DD) and misdiagnosis of HAE, and to explore the risk factors associated with a longer DD. Methods: An Internet-based survey was sent to 129 patients with type 1 and 2 HAE who presented to the Allergy Department, Peking Union Medical College Hospital between 1983 and 2017; 107 patients (82.9%) responded, among whom, a total of 96 patients provided complete information about medical visits. DD was divided into two subperiods according to the lower quartile, i.e., DD <= 6 years and DD > 6 years. Results: The median DD of all 96 patients with HAE was 11.04 years (interquartile range [IQR], 6.06-18.27 years). A significant difference (p < 0.001) in the median DD was found between different decades of onset, i.e., before 1999 (19.75 years [IQR, 13.58-29.50 years]), between 2000 and 2009 (8.67 years [IQR, 5.67-11.04 years]), and between 2010 and 2017 (3.79 years [IQR, 2.29-5.71 years]). Patients with a previous misdiagnosis experienced a longer median delay to complement 1 inhibitor HAE diagnosis (13.17 years [IQR, 7.40-20.50 years]) compared with patients without a previous misdiagnosis (median 6.96 years [IQR, 2.83-10.65 years]; p <= 0.001). According to the logistic regression analysis, a younger age of onset and earlier decade of onset were significant predictors of a DD of >6 years. The most frequently visited departments and most frequently misdiagnosed diseases were summarized. Conclusion: The median DD of patients with HAE was 11.04 years (IQR, 6.06-18.27 years). A younger age of onset and earlier decade of onset were predictors of a DD of >6 years. Seventy-five percent of the patients reported receiving more than one previous misdiagnosis. The patients with a previous misdiagnosis had longer DDs compared with patients without a misdiagnosis.

    Available from: https://dx.doi.org/10.2500/aap.2019.40.4234

    Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: additional outcomes and subgroup analysis of a placebo-controlled randomized study

    Li HH, Zuraw B, Longhurst HJ, Cicardi M, Bork K, Baker J, Lumry W, Bernstein J, Manning M, Levy D, Riedl MA, Feuersenger H, Prusty S, Pragst I, Machnig T, Craig T, COMPACT Investigators 8/2019 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA R, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported.

    Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (>= 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response.

    Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect.

    Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714075

    The effectiveness and value of lanadelumab and C1 esterase inhibitors for prophylaxis of hereditary angioedema attacks

    Agboola F, Lubinga S, Carlson J, Lin GA, Dreitlein WB, Pearson SD. 2/2019 Journal of Managed Care & Specialty Pharmacy

    DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER’s annual policy summit is supported by dues from Aetna, AHIP Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Prime Therapeutics, Sanofi, Spark Therapeutics, Health Care Service Corporation, Editas, Alnylam, Regeneron, Mallinkrodt, Biogen, HealthPartners, and Novartis. Agboola, Dreitlein, and Pearson are ICER employees. Lin reports personal fees from ICER, during the conduct of this study, and grants from the National Institutes of Health and the California Department of Insurance, outside the submitted work. Carlson and Lubinga report grants from ICER, during the conduct of this study.

    Available from: https://www.jmcp.org/doi/10.18553/jmcp.2019.25.2.143

     

    The International/Canadian Hereditary Angioedema Guideline [Review]

    Betschel S, Badiou J, Binkley K, Borici-Mazi R, Hebert J, Kanani A, Keith P, Lacuesta G, Waserman S, Yang B, Aygoren-Pursun E, Bernstein J, Bork K, Caballero T, Cicardi M, Craig T, Farkas H, Grumach A, Katelaris C, Longhurst H, Riedl M, Zuraw B, Berger M, Boursiquot JN, Boysen H, Castaldo A, Chapdelaine H, Connors L, Fu L, Goodyear D, Haynes A, Kamra P, Kim H, Lang-Robertson K, Leith E, McCusker C, Moote B, O'Keefe A, Othman I, Poon MC, Ritchie B, St-Pierre C, Stark D, Tsai E 11/2019 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased health-related quality of life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful. Copyright © The Author(s) 2019.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878678

    Update on the use of C1-esterase inhibitor replacement therapy in the acute and prophylactic treatment of hereditary angioedema [Review]

    Henry Li H, Riedl M, Kashkin J 4/2019 Clinical Reviews in Allergy & Immunology

    In the vast majority of patients with hereditary angioedema (HAE), angioedema attacks are due to the quantitative or functional deficiency of C1-esterase inhibitor (C1-INH), which leads to increased vascular permeability and unregulated release of bradykinin. Exogenous administration of C1-INH is a rational way to restore the concentration and functional activity of this protein, regulate the release of bradykinin, and attenuate or prevent subcutaneous and submucosal edema associated with HAE. Recent international guidelines for the management of HAE include C1-INH as an option for acute treatment of HAE. In addition, these guidelines recommend C1-INH as first-line treatment for long-term prophylaxis and as the therapy of choice for short-term/preprocedural prophylaxis. Several C1-INH products are available, with approved indications varying across regions. For the acute treatment of HAE, both plasma-derived and recombinant C1-INH formulations have been shown to be effective and well tolerated in adolescents and adults with HAE, with onset of relief within 30 min to a few hours. Plasma-derived C1-INH is approved for use in children, and recombinant C1-INH is being evaluated in this population. Intravenous (IV) and subcutaneous (SC) formulations of C1-INH have been approved for routine prophylaxis to prevent HAE attacks in adolescents and adults. Both formulations when administered twice weekly have been shown to reduce the frequency and severity of HAE attacks. The SC formulation of C1-INH obviates the need for repeated venous access and may facilitate self-administration of HAE prophylaxis at home, as recommended in HAE treatment guidelines. As with most rare diseases, the costs of HAE treatment are high; however, the development of additional acute and prophylactic medications for HAE may result in competitive pricing and help drive down the costs of HAE treatment.

    Available from: https://link.springer.com/article/10.1007%2Fs12016-018-8684-1

    A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema [Review]

    Villavicencio MF, Craig T 5/2020 Expert review of clinical immunology

    INTRODUCTION: HAE is a very debilitating disease that causes significant distress for patients not only during an acute attack but also constant fear for a subsequent attack. It is important to address long-term prophylactic (LTP) therapy to prevent attacks, decrease morbidity and increase the quality of life. When discussing LTP, the drug burden, convenience and efficacy must be taken into account.

    AREAS COVERED: We review the literature and the different phases of clinical trials leading up to approval by the US FDA of subcutaneous highly concentrated C1-Inhibitor (SC-C1-INH), called Haegarda. The dose approved is of 60 IU/kg twice weekly showing significant improvement in the reduction of attacks and need for on-demand therapy for attacks with minimal side effects.

    EXPERT OPINION: SC-C1-INH has added significantly to the armamentarium of physicians that treat HAE. The ability to achieve a steady state of C1-INH above 40% function is key to the success of the drug. The drug burden is an SC injection twice a week that exceeds the newly approved lanadelumab. The benefit may be that the protein that is deficient in HAE is replaced and with this the complement, fibrinolytic, coagulation pathways, and contact system are also regulated; however, evidence that this is of benefit is still lacking.

    Available from: https://dx.doi.org/10.1080/1744666X.2020.1750953

    A lesson from a saboteur: High-MW kininogen impact in coronavirus-induced disease 2019

    Colarusso C, Terlizzi M, Pinto A, Sorrentino R 11/2020 British Journal of Pharmacology

    The newly identified coronavirus SARS-CoV-2 that spread from China is causing the pandemic COVID-19 with a fatality rate from 5-15%. It causes fever, cough, myalgia, fatigue up to dyspnoea, responsible for hospitalization and artificial oxygenation. SARS-CoV-2 infects human cells using ACE2, the transmembrane protease serine 2 (TMPRSS2) and the SARS-CoV-2 main protease (Mpro ). Once bound to ACE2 and the other two proteases in concert they allow the virus replication and spread throughout the body. Our attention has been focused on the role of ACE2 as its binding to by the virus increases bradykinin and its metabolites, which facilitate inflammation in the lung (causing cough and fever), coagulation and the complement system. These three systems are involved in angioedema, cardiovascular dysfunction and sepsis, pathologies which occur in COVID-19 patients. Thus, we propose that blocking the kallikrein-kinin system with lanadelumab, approved for hereditary angioedema, will prevent facilitation of these 3 systems. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc. Copyright © 2020 The British Pharmacological Society.

    Available from: https://dx.doi.org/10.1111/bph.15154

    Advances in hereditary angioedema: The prevention of angioedema attacks with subcutaneous C1-inhibitor replacement therapy

    Lumry W, Templeton T, Omert L, Levy D 5/2020 Journal of Infusion Nursing

    Hereditary angioedema (HAE) is a debilitating condition caused by a functional C1-inhibitor (C1-INH) deficiency and characterized clinically by episodes of subcutaneous or submucosal swelling. C1-INH replacement is highly effective for preventing HAE attacks and can improve health-related quality of life. Once available only for intravenous use, C1-INH is now available as a subcutaneous formulation for self-administration, shown to provide sustained plasma levels of C1-INH and reducing the monthly median HAE attack rate by 95% versus placebo in the phase 3 COMPACT study. Subcutaneously administered C1-INH satisfies multiple unmet needs in the management of patients with HAE.

    Available from: https://dx.doi.org/10.1097/NAN.0000000000000365

    Biological therapy in hereditary angioedema: Transformation of a rare disease [Review]

    Longhurst H, Farkas H 5/2020 Expert Opinion on Biological Therapy

    Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder. Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated. Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.

    Available from: https://dx.doi.org/10.1080/14712598.2020.1724280

    C1 inhibitor activity and angioedema attacks in patients with hereditary angioedema

    Kaplan AP, Pawaskar D, Chiao J 3/2020 The journal of allergy and clinical immunology. In practice

    Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. In vitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients’ risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH. Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/abs/pii/S2213219819308682

    Co-occurrence between C1 esterase inhibitor deficiency and autoimmune disease: a systematic literature review

    Levy D, Craig T, Keith PK, Krishnarajah G, Beckerman R, Prusty S 5/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    Background: Hereditary angioedema (HAE) is caused by a SERPING1 gene defect resulting in decreased (Type I) or dysfunctional (Type II) C1 esterase inhibitor (C1-INH). The prevalence of autoimmune diseases (ADs) in patients with HAE appears to be higher than the general population. A systematic literature review was conducted to examine the co-occurrence between HAE and ADs.

    Methods: PubMed/EMBASE were searched for English-language reviews, case reports, observational studies, retrospective studies, and randomized controlled trials up to 04/15/2018 (04/15/2015-04/15/2018 for EMBASE) that mentioned patients with HAE Type I or II and comorbid ADs. Non-human or in vitro studies and publications of C1-INH deficiency secondary to lymphoproliferative disorders or angiotensin-converting-enzyme inhibitors were excluded.

    Results: Of the 2880 records screened, 76 met the eligibility criteria and 155 individual occurrences of co-occurring HAE and AD were mentioned. The most common ADs were systemic lupus erythematosus (30 mentions), thyroid disease (21 mentions), and glomerulonephritis (16 mentions). When ADs were grouped by MedDRA v21.0 High Level Terms, the most common were: Lupus Erythematosus and Associated Conditions, n = 52; Endocrine Autoimmune Disorders, n = 21; Gastrointestinal Inflammatory Conditions, n = 16; Glomerulonephritis and Nephrotic Syndrome, n = 16; Rheumatoid Arthritis and Associated Conditions, n = 11; Eye, Salivary Gland and Connective Tissue Disorders, n = 10; and Immune and Associated Conditions Not Elsewhere Classified, n = 5.

    Conclusions: Based on literature reports, systemic lupus erythematosus is the most common AD co-occurring with HAE Type I and II. Cause and effect for co-occurring HAE and AD has not been clinically established but could be related to lack of sufficient C1-INH function. Copyright © The Author(s) 2020.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254644

    Current status of the management of hereditary angioedema in China: A patient-based, cross-sectional survey

    Liu S, Xu Q, Xu Y, Wang X, Zhi Y 4/2020 European Journal of Jermatology : EJD

    BACKGROUND: Hereditary angioedema (HAE) is a rare, inherited disorder characterized by unpredictable and recurrent cutaneous and mucosal oedema.

    OBJECTIVES: This study aimed to identify the current status of HAE management in China.

    MATERIALS AND METHODS: An internet-based survey was sent to 129 patients with type 1 and 2 HAE diagnosed between 1983 and 2017; a total of 107 patients provided complete disease management information.

    RESULTS: The survey response rate was 82.9% (107 responders). Ten patients reported 18 fresh frozen plasma (FFP) transfusions for the main purpose of treating lethal laryngeal oedema. Two patients reported adverse events. Eighty-nine (83.2%) patients had taken danazol for long-term prophylaxis, and 74 (69.2%) were on long-term danazol prophylaxis. Among patients on long-term prophylaxis, 56 (75.7%) patients reported a decrease in their annual attack frequency after taking danazol. Twenty-five (33.8%) patients had an attack frequency of no more than once per year. The most common side effects were menstrual disorders, weight gain, osteoarticular pain, acne, and sebaceous hypersecretion. Patients with higher education levels, positive family histories, and laryngeal oedema attacks before medication tended to show better adherence. Patients maintaining high or medium adherence showed better control of laryngeal and gastrointestinal involvement than patients with low adherence. Four (3.7%) patients reported current or past use of tranexamic acid.

    CONCLUSION: Attenuated androgen and FFP transfusions remain the mainstay in China, where specifically targeted drugs are currently lacking. Maintaining good medication adherence should be recommended to achieve improved disease control.

    Available from: https://dx.doi.org/10.1684/ejd.2020.3758

    Design, synthesis and characterization of a PEGylated stanozolol for potential therapeutic applications

    Vergallo C, Torrieri G, Provenzani R, Miettinen S, Moslova K, Varjosalo M, Cristiano MC, Fresta M, Celia C, Santos HA, Cilurzo F, Di Marzio L 1/2020 International Journal of Pharmaceutics

    Stanozolol (STZ) is a drug used to treat serious disorders like aplastic anemia and hereditary angioedema. It is also indicated as an adjunct therapy for the treatment of vascular disorders and growth failures. Encouraging results obtained using animal models demonstrated that STZ increases bone formation and mineralization, thus improving both density and biomechanical properties. Like natural androgens, such as TST and 5alpha-dihydrotestosterone (5alpha-DHT), STZ binds androgen receptor (AR) to activate AR-mediated signaling. Despite its therapeutic effects, this synthetic anabolic-androgenic steroid (AAS), or 5alpha-DHT derivative, due to its high lipophilicity, is poor soluble in water. Thus, to increase the water solubility and stability of STZ, as well as its bioavailability and efficacy, an innovative PEGylated STZ (STZ conjugated with (MeO-PEG-NH2)10kDa, (MeO-PEG-NH)10kDa-STZ) was synthesized. As confirmed by chromatography (RP-HPLC) and spectrometry (ATR-FTIR, 1H NMR, elemental CHNS(O) analysis, MALDI-TOF/TOF) analyses, a very pure, stable and soluble compound was obtained. Acetylcholinesterase (AChE) competitive ELISA demonstrated that the resulting PEGylated STZ competes against biological TST, especially at lower concentrations. Cytotoxicity of increasing concentrations (1, 10, 25 or 50microM) of STZ and/or (MeO-PEG-NH)10kDa-STZ was also evaluated for up 80h by performing the MTT assay on human osteosarcoma Saos-2 cells, which express AR and are responsive to STZ. PEGylation mitigated cytotoxicity of STZ, by increasing the cell viability values, especially at higher drug concentrations. Furthermore, these results suggest that (MeO-PEG-NH)10kDa-STZ is a promising and reliable drug to be used in clinical conditions in which TST is required. Copyright © 2019 Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.ijpharm.2019.118826

    Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study

    Hide M, Fukunaga A, Maehara J, Eto K, Hao J, Vardi M, Nomoto Y 4/2020 Allergology International

    BACKGROUND: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract.

    METHODS: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen.

    RESULTS: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache).

    CONCLUSIONS: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional. Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.alit.2019.08.012

    Evaluation of the efficacy and safety of home treatment with the recombinant human C1-inhibitor in hereditary angioedema resulting from C1-inhibitor deficiency

    Andrasi N, Veszeli N, Holdonner A, Temesszentandrasi G, Kohalmi KV, Varga L, Farkas H 3/2020 International Immunopharmacology

    OBJECTIVE: Conestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP).

    MATERIALS & METHOD: Our prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information.

    RESULTS: Time to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed.

    CONCLUSIONS: Treatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.intimp.2020.106216

    Evidence for bradykinin release in chronic spontaneous urticaria

    Hofman ZLM, van den Elzen MT, Kuijpers J, de Maat S, Hack CE, Knulst AC, Rockmann H, Maas C 3/2020 Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

    BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy weals and/or angioedema and is believed to be driven by mast cell activation. It was shown that excessive mast cell activation during anaphylaxis initiates contact activation, resulting in bradykinin release. Evidence for bradykinin release was never demonstrated in CSU.

    OBJECTIVE: To study biomarkers of bradykinin release in CSU.

    METHODS: Plasma samples of CSU patients were collected during routine visits at the outpatient clinic. Cleaved high molecular weight kininogen (cHK) was used as a biomarker for bradykinin release. cHK, factor XIIa-C1-inhibitor (FXIIa-C1-INH), kallikrein-C1-INH, plasmin-antiplasmin (PAP) complexes and soluble urokinase-type plasminogen activator receptor (suPAR) levels were determined by ELISA. Clinical data and data on tryptase levels were collected from medical records. cHK levels were compared to previously determined levels in hereditary angioedema (HAE).

    RESULTS: One hundred seventeen samples from 88 CSU patients and 28 samples from healthy controls were analysed. Median cHK level in CSU was 9.1% (range: 1.4%-21.5%), significantly increased compared to healthy controls (median 6.0% range: 0%-19.9%; P = .0005) and comparable to HAE (n = 46, median 10.3%, range 0%-44.3%, P > .9999). cHK levels normalized in patients during disease remission (median 6.5% range 1.5%-20.8%) but were not dependent on the presence of angioedema, acute angioedema attacks or response to antihistamines. Surprisingly, cHK levels were inversely correlated to serum tryptase (r = -0.65 P = .0137). C1-INH complexes and suPAR levels were not elevated in patients compared to healthy controls. PAP-complex levels in patients were elevated compared to healthy controls but there was no correlation between PAP-complex and cHK levels.

    CONCLUSIONS: cHK levels are elevated in symptomatic CSU patients compared to healthy controls, indicating increased bradykinin production. Increased cHK levels are not limited to patients with angioedema.

    CLINICAL RELEVANCE: If elevated bradykinin generation has clinical implications in the pathology of CSU is open to debate. Copyright © 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

    Available from: https://dx.doi.org/10.1111/cea.13558

    Exogenous hormones and hereditary angioedema [Review]

    Gompel A, Fain O, Boccon-Gibod I, Gobert D, Bouillet L 1/2020 International Immunopharmacology

    Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women. Copyright © 2019 Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.intimp.2019.106080

    Experience with intravenous plasma-derived C1-inhibitor in pregnant women with hereditary angioedema: A systematic literature review

    Brooks JP, Radojicic C, Riedl MA, Newcomer SD, Banerji A, Hsu FI 6/2020 The journal of allergy and clinical immunology. In practice

    Consensus guidelines recommend plasma-derived C1 inhibitor (C1-INH) as first-line treatment in pregnant women with hereditary angioedema (HAE). We conducted a systematic review of the literature that describes experience with plasma-derived C1-INH during pregnancy. A literature search of PubMed was conducted in November 2018 using variants of “hereditary angioedema” and “pregnancy.” English language articles that presented original data about the use of plasma-derived C1-INH during pregnancy were selected for data extraction. The search returned 253 unique records, of which 40 described the use of C1-INH during pregnancy (91 patients, 136 pregnancies). When the number of doses was reported, a total of 1562 doses were administered ranging from 500 to 3000 IU. Infusions were administered during all 3 trimesters and were most commonly administered during the third trimester. Overall, 1,490,500 IU of plasma-derived C1-INH were administered during pregnancy. Of the 128 fetuses for which outcomes were reported, 3 (2%) resulted in spontaneous abortion, 1 (1%) was stillborn, and 1 (1%) was a vanishing twin. Use of plasma-derived C1-INH in women with HAE during pregnancy has been widely reported in the scientific literature and has a favorable safety profile, supporting treatment guideline recommendations. Copyright © 2020. Published by Elsevier Inc.

    Available from: https://www.jaci-inpractice.org/article/S2213-2198(20)30250-6/pdf

    Hereditary angioedema [Review]

    Busse PJ, Christiansen SC 3/2020 New England Journal of Medicine

    Available from: https://dx.doi.org/10.1056/NEJMra1808012

    Hereditary angioedema due to C1-inhibitor deficiency in Romania: First national study, diagnostic and treatment challenges

    Gabos G, Nadasan V, Mihaly E, Dobru D 9/2020 Iranian journal of immunology : IJI

    BACKGROUND: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body.

    OBJECTIVE: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program.

    METHODS: This cross-sectional observational study included patients from the Romanian HAE Registry.

    RESULTS: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Forty-three (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks.

    CONCLUSION: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.

    Available from: https://dx.doi.org/10.22034/iji.2020.85416.1709

    Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German-speaking countries

    Wahn V, Aberer W, Aygoren-Pursun E, Bork K, Eberl W, Fashauer M, Kruger R, Magerl M, Martinez-Saguer I, Spath P, Staubach-Renz P, Weber-Chrysochoou C 11/2020 Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

    BACKGROUND/METHODS: At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients.

    RESULTS/CONCLUSION: Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short- and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2 years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety. Copyright © 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

    Available from: https://dx.doi.org/10.1111/pai.13309

    Hereditary angioedema: Investigational therapies and future research [Review]

    Kaplan AP 11/2020 Allergy and asthma proceedings

    The future therapies for hereditary angioedema will likely involve the development of oral agents as alternatives to parenteral administration of drugs, specific targeting of proteins and/or enzymes that are not yet possible (e.g., factor XIIa), new agents that target the beta2 receptor with sustained action properties, testing of products to determine whether the beta1 receptor contributes significantly to attacks of angioedema, disrupting protein synthesis by using RNA technology as an alternative to enzyme inhibition, and, finally, gene therapy to attempt to cure the disease. Complete inhibition of attacks may well require sustained blood levels of C1 inhibitor that exceed 85% of normal, and it may be possible to delete the prekallikrein gene (analogous to familial prekallikrein deficiency), which is the one factor that might alleviate bradykinin formation, even by factor XII-independent initiating mechanisms, with the possible exception of Mannose Associated Serine Protease 1 (MASP-1) cleavage of high molecular weight kininogen (HK). Deletion of the light chain of high-molecular-weight kininogen would eliminate all possibilities for bradykinin formation, except tissue kallikrein cleavage of low-molecular-weight kininogen to support normal physiologic function to at least 50%.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200056

    Hereditary angioedema: Long-term prophylactic treatment [Review]

    Li HH 11/2020 Allergy and asthma proceedings

    Hereditary Angioedema (HAE) is a potentially life-threatening condition. With episodic, unpredictable swelling, HAE negatively affect the quality of life for those affected individuals. To reduce the morbidity and mortality of HAE are the primary goal for the disease management. In addition to have access to therapeutic drugs for their acute HAE attacks, many patients require long term prophylaxis (LTP) to reduce their attack frequency and severity. Preventing HAE attack by regular administration of medicine has become an important part of HAE disease management. Over the past few years, growing number of therapeutic options for the HAE LTP have made it possible for physicians to choose the most appropriate and effective treatment for individual patients. C1 INH concentrate and plasma kallikrein inhibitors (IV or SC) have largely replaced the oder modality of treatment consisting different androgen derivatives or antifibrinolytics. Additional options, such as oral kallikrein inhibitor, antisense RNA/plasma kallikrein, anti-Factor 12a, bradykinin receptor blocker or future gene therapy are under clinical investigation. The significant cost and the uncertainty of its long term safety may be the primary limiting factors for its clinical application. The limited data for young children and pregnant women pose additional challenge for physicians to assess the risk and benefit when considering LTP treatment.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200092

    Hereditary angioedema: On-demand treatment of angioedema attacks [Review]

    Christiansen SC, Zuraw BL 11/2020 Allergy and asthma proceedings

    The availability of effective acute treatment for angioedema has been fundamental in reducing the burden of illness for patients with hereditary angioedema (HAE). In building on the foundation of scientific advances that elucidate the pathomechanism(s) of attacks related to vascular permeability, novel targeted on-demand treatments have been developed and approved. These therapies have provided the means to arrest episodes of swelling, which, in the past, had the potential to inexorably lead to morbidity, and even mortality, for patients with HAE. Access to these medications, along with an emphasis on early administration and guidance that all attacks are candidates for treatment, has shifted the management paradigm for HAE. Although unmet needs remain, these acute therapies, coupled with advances in prophylactic treatment, have furthered the goal for all patients with HAE to live a normal life.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200066

    Hereditary angioedema: Special considerations in children

    Johnston DT, Smith RC 11/2020 Allergy and asthma proceedings

    Patients with hereditary angioedema (HAE) can experience attacks at any age; however, the onset of swelling is typically in childhood. Unlike adults, this population is uniquely vulnerable; attacks in young children may be subtle, resemble other diseases, and often lead to a delay in diagnosis. Misdiagnosis contributes to significant delays in treatment, painful attacks, increased emotional stress, unnecessary procedures, and a potential risk of death. Older children may hide their symptoms due to anxiety or fear of social isolation. Attacks typically become more severe and more frequent during and after puberty. The impact of HAE attacks on school attendance and school performance may prevent future career or education opportunities. Living with HAE poses significant psychosocial stress on children and their families. In the United States, medical treatments for acute attacks in children approved for self-administration are limited to intravenous therapies, which complicates early treatment. To provide optimal care, we suggest that physicians screen all children with a family history of HAE, appreciate the dynamic nature of the disease during adolescence, proactively assess the psychosocial impact of disease, and continually reassess the treatment plan.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200042

    Hereditary angioedema: Special considerations in women [Review]

    Yakaboski E, Motazedi T, Banerji A 11/2020 Allergy and asthma proceedings

    There are several challenges that arise in caring for women with hereditary angioedema (HAE). Most notably, the disease course during pregnancy is unpredictable, but studies show that plasma-derived C1-inhibitor is effective and safe for treatment of attacks as well as long-term prophylaxis (LTP) in select patients. Vaginal deliveries are preferred to caesarean sections, and epidural anesthesia is preferred to general anesthesia in lowering the risk of an acute attack. Lactation postpartum may increase HAE attacks. With regard to contraception, combined oral contraceptive pills that contain estrogen exacerbate symptoms. Similarly, estrogen-replacement therapy in menopause may increase attacks and is contraindicated. Fertility is not impacted by HAE itself or by HAE medications. The risk of breast cancer and female reproductive cancer in women with HAE is comparable with that of the general population, but, in patients with HAE and breast cancer, LTP with androgens is contraindicated. Estrogen modulators, e.g., tamoxifen, should be used with caution. Here, we reviewed these special considerations and others that are vital to providers in caring for women with HAE.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200077

    Life-threatening laryngeal attacks in hereditary angioedema patients

    Piotrowicz-Wojcik K, Porebski G 3/2020 Otolaryngologia Polska

    BACKGROUND: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare genetic disease that runs in the family. As a result of the disease, acute swellings of the subcutaneous tissue and mucous membranes of the digestive and respiratory systems, including the larynx, occur. Any attack of the disease involving the throat and larynx is particularly dangerous and requires knowledge of clinical determinants of the disease and its proper management.

    Available from: https://dx.doi.org/10.5604/01.3001.0014.0619

    Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial

    Levy DS, Farkas H, Riedl MA, Hsu FI, Brooks JP, Cicardi M, Feuersenger H, Pragst I, Reshef A 2/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    Background: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial.

    Methods: In this multicenter, randomized, parallel-arm trial, eligible subjects (age >= 6 years with >= 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age >= 15 to <= 45 years), including subjects who became pregnant during the evaluation period.

    Results: Overall, 91% (69/76) of female subjects were classified as responders (>= 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities.

    Conclusions: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353. Copyright © The Author(s) 2020.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001333

    Long-term efficacy of subcutaneous C1 Inhibitor in pediatric patients with hereditary angioedema

    Levy D, Caballero T, Hussain I, Reshef A, Anderson J, Baker J, Schwartz LB, Cicardi M, Prusty S, Feuersenger H, Pragst I, Manning ME 9/2020 Pediatric allergy, immunology, and pulmonology

    Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects <=17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age >=6 years, with >=4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (<=17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were <=17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced >=50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Conclusions: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE. Copyright © Donald Levy et al., 2020; Published by Mary Ann Liebert, Inc.

    Available from: https://dx.doi.org/10.1089/ped.2020.1143

    Long-term safety and efficacy of subcutaneous C1-inhibitor in older patients with hereditary angioedema

    Bernstein JA, Schwartz L, Yang W, Baker J, Anderson J, Farkas H, Aygoren-Pursun E, Bygum A, Jacobs I, Feuersenger H, Pragst I, Riedl MA 9/2020 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy.

    OBJECTIVE: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial.

    METHODS: Eligible patients (>=4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years.

    RESULTS: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month).

    Available from: https://dx.doi.org/10.1016/j.anai.2020.05.015

    Manufacturing of plasma-derived C1-inhibitor concentrate for treatment of patients with hereditary angioedema [Review]

    Simon TL, Kalina U, Laske R, Mycroft S, Widmer E, Roth NJ 3/2020 Allergy & Asthma Proceedings

    Background: Replacement therapy with plasma-derived C1-inhibitor (C1-INH) has been used for decades to treat patients with hereditary angioedema (HAE) with C1-INH deficiency. Objective: This article reviewed the rationale for using C1-INH replacement therapy in patients with HAE and the process of manufacturing plasma-derived C1-INH. Methods: The manufacture of C1-INH is an involved and carefully monitored process that includes screening and selection of prospective donors, the collection of source plasma, and purification with dedicated pathogen reduction steps. Donor eligibility is determined by restrictive criteria established and monitored by regulatory agencies as well as voluntary standards implemented by plasma collection centers that exceed government regulations. Individual and pooled donations are tested for transfusion-transmissible infections, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, parvovirus B19, and hepatitis A virus, by using enzyme-linked immunosorbent assays or nucleic acid amplification technologies. Frozen plasma that is cleared for manufacturing undergoes controlled thawing and centrifugation, and the resulting supernatant (i.e., cryoprecipitate-depleted plasma) is used to manufacture several plasma-derived therapies, including C1-INH. In addition to chromatography steps, the manufacturing process consists of dedicated and effective pathogen reduction steps, including pasteurization, hydrophobic interaction chromatography or polyethylene glycol precipitation, and virus filtration. Manufacturers continuously monitor the safety profile of C1-INH products by robust pharmacovigilance processes that enable systematic collection and evaluation of all suspected adverse drug reaction reports as well as evaluation of safety information from all other sources. Results and Conclusion: These procedures used in donor screening, donation and manufacturing pool testing, manufacturing, and pharmacovigilance ensure that plasma-derived C1-INH products have the safety, quality, identity, potency, and purity that is necessary to provide the intended therapeutic effect.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.190021

    Modeling cost-effectiveness of on-demand treatment for hereditary angioedema attacks

    Bernstein JA, Tyson C, Relan A, Adams P, Magar R 2/2020 Journal of Managed Care & Specialty Pharmacy

    BACKGROUND: Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively.

    OBJECTIVE: To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks.

    METHODS: A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed.

    RESULTS: The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide.

    CONCLUSIONS: Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness.

    DISCLOSURES: Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

    Available from: https://dx.doi.org/10.18553/jmcp.2019.19217

    Parallel comparison of three methodologies for measuring functional C1-inhibitor in Hereditary angioedema patients

    Kapoor A, Garg BK, Zhou Z, Lu P, Chockalingam PS 4/2020 International Immunopharmacology

    Hereditary angioedema (HAE) types I and II are characterized by functional C1 inhibitor (fC1-INH) deficiency which results in bradykinin overproduction. Sensitive, specific and robust methods to quantitate fC1-INH in human samples are required for diagnosing HAE and/or to measure pharmacodynamic activity of C1-INH drugs in clinical studies. To date, three methods have been reported in literature to measure fC1-INH: conventional chromogenic assay measuring residual C1-esterase activity, and immunoassays based on functional binding to either activated complement C1s or Factor XIIa/kallikrein. We used three qualified/validated fit-for purpose methods to quantitate fC1-INH in human plasma and to conduct a parallel comparison for diagnostic purposes and as a read-out for pharmacodynamic activity. Sensitivity and specificity were determined from the Receiver Operator Characteristics (ROC) curve analysis of the three fC1-INH methods through testing of fifty healthy control vs. HAE plasma samples. fC1-INH profile of fifteen HAE subjects, who underwent different treatment regimen in a cross-over Shire C1-INH clinical study, was analyzed in these three methods in parallel. A correlation analysis performed between these methods using data generated from clinical samples showed that profiles obtained from different fC1-INH methods matched for individual HAE subjects. Our findings suggest that functional binding immunoassay methods serve as reliable alternates for conventional chromogenic method to quantitate fC1-INH in human plasma samples with a better dynamic range of detection and ease of use. Of the two immunoassays used in this study, FXIIa-binding method gave better sensitivity, specificity, and correlation to the chromogenic method as a diagnostic method to distinguish HAE samples from healthy controls. Copyright © 2020 Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.intimp.2020.106348

    Perioperative management of patients with hereditary angioedema with special considerations for cardiopulmonary bypass [Review]

    Tanaka KA, Mondal S, Morita Y, Williams B, Strauss ER, Cicardi M 7/2020 Anesthesia & Analgesia

    Hereditary angioedema (HAE) is a rare autosomal dominant disorder mostly due to the deficiency of C1-esterase inhibitor (C1-INH). Reduced C1-INH activity below ~38% disrupts homeostasis of bradykinin (BK) formation by increasing kallikrein activation and causes recurrent angioedema attacks affecting the face, extremities, genitals, bowels, oropharynx, and larynx. HAE symptoms can be debilitating and potentially life-threatening. The recent clinical developments of biological and pharmacological agents have immensely improved acute and long-term care of patients with moderate-to-severe HAE. The therapies are given as on-demand and/or prophylaxis, and self-administration is highly recommended and performed with some agents via intravenous or subcutaneous route. Perioperative clinicians need to be familiar with the symptoms and diagnosis of HAE as well as available therapies because of the potential need for airway management, sedation, or anesthesia for various medical and surgical procedures and postoperative care. Cardiovascular surgery using cardiopulmonary bypass is a unique condition in which heparinized blood comes into direct contact with an artificial surface while pulmonary circulation, a major reserve of angiotensin-converting enzyme (ACE), becomes excluded. These changes result in systemic kallikrein activation and BK formation even in non-HAE patients. The objectives of this review are (1) to review pathophysiology of HAE and laboratory testing, (2) to summarize pertinent pharmacological data on the prophylactic and on-demand treatment strategies, and (3) to discuss available clinical data for perioperative management in cardiovascular surgery.

    Available from: https://dx.doi.org/10.1213/ANE.0000000000004710

    Pharmacokinetics, pharmacodynamics, and exposure-response of Lanadelumab for hereditary angioedema

    Wang Y, Marier JF, Kassir N, Chang C, Martin P 11/2020 Clinical and translational science

    There are several challenges that arise in caring for women with hereditary angioedema (HAE). Most notably, the disease course during pregnancy is unpredictable, but studies show that plasma-derived C1-inhibitor is effective and safe for treatment of attacks as well as long-term prophylaxis (LTP) in select patients. Vaginal deliveries are preferred to caesarean sections, and epidural anesthesia is preferred to general anesthesia in lowering the risk of an acute attack. Lactation postpartum may increase HAE attacks. With regard to contraception, combined oral contraceptive pills that contain estrogen exacerbate symptoms. Similarly, estrogen-replacement therapy in menopause may increase attacks and is contraindicated. Fertility is not impacted by HAE itself or by HAE medications. The risk of breast cancer and female reproductive cancer in women with HAE is comparable with that of the general population, but, in patients with HAE and breast cancer, LTP with androgens is contraindicated. Estrogen modulators, e.g., tamoxifen, should be used with caution. Here, we reviewed these special considerations and others that are vital to providers in caring for women with HAE.

    Available from: https://dx.doi.org/10.1111/cts.12806

    Phlebotonics for venous insufficiency

    Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X 11/2020 The Cochrane Database of Systematic Reviews

    BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005.

    OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI.

    SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies.

    SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease.

    DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence.

    MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from ‘high’ to ‘moderate’ because of risk of bias concerns, and further to ‘low’ because of imprecision.

    AUTHORS’ CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    Available from: https://dx.doi.org/10.1002/14651858.CD003229.pub4

    Prospective analysis in patients with HAE under prophylaxis with Lanadelumab: A real-life experience

    Hahn J, Trainotti S, Wigand MC, Schuler PJ, Hoffmann TK, Greve J 10/2020 Journal of drugs in dermatology : JDD

    BACKGROUND AND OBJECTIVES: Patients with the rare disease hereditary angioedema (HAE) suffer from recurrent acute attacks of edema. There is no curative therapy, but the frequency of attacks and quality of life of severely affected patients can be improved by prophylactic therapy. The monoclonal antibody lanadelumab has been approved for routine prophylaxis in patients with HAE since November 2018.

    PATIENTS AND METHODS: In this prospective assessment, a long-term therapy with lanadelumab was initiated in 12 adult patients with HAE. We analyzed their course of disease 6 months after the start of long-term prophylactic therapy using a validated quality-of-life questionnaire and evaluated the frequency and severity of attacks as well as side effects. Furthermore, the therapy with lanadelumab was compared with the previous medication.

    RESULTS: To date, our study is the first prospective quality of life analysis in HAE patients under treatment with lanadelumab in real life conditions. Mean attack frequencies were reduced from 6.4 to 0.3 attacks per month and patient in our cohort (P<0.0001). No severe attacks occurred under lanadelumab prophylaxis. In all patients, quality of life increased significantly.

    CONCLUSIONS: Lanadelumab is an effective but expensive long-term prophylaxis for HAE patients. A favorable side-effect profile has been shown. J Drugs Dermatol. 2020;19(10):978-983. doi:10.36849/JDD.2020.5269.

    Available from: https://dx.doi.org/10.36849/JDD.2020.5269

    Real-world cohort study of adult and pediatric patients treated for hereditary angioedema in the United States

    Tachdjian R, Johnson KE, Casso D, Oliveria SA, Devercelli G, Jain G 5/2020 Allergy and asthma proceedings

    Background: There is limited real-world evidence on hereditary angioedema (HAE) patient characteristics and health-care resource utilization (HCRU); in addition, pediatric patients have been described in small cohorts. Objective: To describe patient characteristics, treatment patterns, and HCRU among adult and pediatric patients treated for HAE in a large U.S. cohort. Methods: This retrospective cohort study used an administrative claims data base (January 2006 to September 2015). Eligible patients with either >=1 pharmacy claim for HAE-indicated therapies (C1 inhibitors, ecallantide, icatibant) or >=2 medical claims with codes associated with HAE (per medical billing codes), and >=1 claim for androgens, fresh frozen plasma, tranexamic acid, or epsilon-aminocaproic acid formed a “treated cohort.” Three nonexclusive treated cohorts were assessed: overall, pediatric, and HCRU (>=2 years of continuous enrollment during 2010-2015). Results: Overall, 1429 patients received treatment (mean +/- standard deviation [SD] age, 38.8 +/-15.7 years; 62.4% female patients; mean +/- SD Charlson Comorbidity Index of 1.4 +/- 2.4). Common comorbidities were allergy or anaphylaxis (51.4%) and anxiety or depression (35.8%). Diagnoses indicative of HAE attacks included swelling and/or angioedema (78.5%), abdominal pain (55.6%), and asphyxiation (27.2%). Use of HAE-indicated medication rose between 2006 and 2015 to 81.8%, whereas androgen use declined (from 91.5% to 24.9%). Similar trends were observed in the pediatric treated cohort (n = 143). In the HCRU treated cohort (n = 538), HAE-related claims for emergency department and inpatient admissions were observed for 36.6% and 22.3% of patients, respectively. Conclusion: In a large U.S. cohort of adult and pediatric patients who received treatments indicated or used for HAE, common comorbidities and trends in resource use denoted the substantial burden of attacks, which reflected a continued need that recently approved long-term prophylactic treatments may help to address.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200011

    Recombinant human C1 esterase inhibitor as short-term prophylaxis in patients with hereditary angioedema

    Valerieva A, Staevska M, Jesenak M, Hrubiskova K, Sobotkova M, Zachova R, Hakl R, Andrejevic S, Suiter T, Grivcheva-Panovska V, Karadza-Lapic L, Soteres D, Shapiro R, Rumbyrt J, Tachdjian R, Mehta V, Hsu FI, Zanichelli A 2/2020 The journal of allergy and clinical immunology. In practice

    Available from: https://www.jaci-inpractice.org/article/S2213-2198(19)30717-2/fulltext

    Review of icatibant use in the Winnipeg Regional Health Authority

    Cai G, Barber C, Kalicinsky C 11/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    BACKGROUND: This is a retrospective review of the Winnipeg Regional Health Authority’s (WRHA) angioedema patients who were dispensed icatibant in hospital. Icatibant is a bradykinin B2 receptor antagonist indicated for Hereditary Angioedema (HAE) types I and II and is used off-label for HAE with normal C1INH (HAE-nC1INH) and ACE-inhibitor induced angioedema (ACEIIAE). The WRHA’s use of icatibant is regulated by the Allergist on call. We characterized icatibant’s use and the timeline from patient presentation, compared the real-world experience with the FAST-3 trial and hypothesized the factors which may affect response to icatibant.

    METHODS: Background data were collected on patients. Angioedema attack-related data included administered medications, performed investigations and the timeline to endpoints such as onset of symptom relief. Data was analyzed in R with the package “survival.” Time-to-event data was analyzed using the Peto-Peto Prentice method or Mann-Whitney U-test. Data was also compared with published clinical trial data using the Sign Test. Fisher’s Exact Test was used to produce descriptive statistics.

    RESULTS: Overall, 21 patients accounted for 23 angioedema attacks treated with icatibant. Approximately half the patients had a diagnosis of HAE-nC1IHN and half of ACEIIAE. Of those presenting with angioedema, 65% were first treated with conventional medication. Patients without a prior angioedema diagnosis were evaluated only 40-50% of the time for C4 levels or C1INH function or level. The median time from patients’ arrival to the emergency department until the Allergy consultant’s response was 1.77 h. Patients with HAE-nC1IHN had median times to onset of symptom relief and final clinical outcome (1.13 h, p = 0.34; 3.50 h, p = 0.11) similar to those reported in FAST-3 for HAE I/II. Patients with ACEIIAE had longer median times to onset of symptom relief (4.86 h, p = 0.01) than predicted.

    CONCLUSIONS: HAE-nC1INH may be an appropriate indication for treatment with icatibant. Conversely, the results of this study do not support the use of icatibant for the treatment of ACEIIAE, concordant with a growing body of literature. Patients should be stratified into groups of more- or less-likely icatibant-responders through history and laboratory investigations in order to prevent potential delays.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656671

    RLanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks

    Riedl MA, Maurer M, Bernstein JA, Banerji A, Longhurst HJ, Li HH, Lu P, Hao J, Juethner S, Lumry WR, HELP Investigators 11/2020 Allergy

    BACKGROUND: Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.

    OBJECTIVE: To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.

    METHODS: Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.

    RESULTS: One hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P <= .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.

    CONCLUSION: Protection with lanadelumab started from the first dose and continued throughout the entire study period. Copyright © 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

    Available from: https://dx.doi.org/10.1111/all.14416

    Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study

    Zanichelli A, Ghezzi M, Santicchia I, Vacchini R, Cicardi M, Sparaco A, Donati G, Rania V, Busa A 3/2020 PLoS ONE

    BACKGROUND: Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients’ records.

    RESULTS: Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them.

    CONCLUSIONS: Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.

    Available from: https://dx.doi.org/10.1371/journal.pone.0230128

    Thromboembolic risk of C1 esterase inhibitors: A systematic review on current evidence

    Burnham K, Reinert JP 7/2020 Expert Review of Clinical Pharmacology

    INTRODUCTION: The exact risk of developing a thromboembolic event (TEE) while using complement 1 esterase inhibitors (C1-INHs) is currently undetermined for patients with hereditary angioedema (HAE). This systematic review aimed to define the potential risk of TEEs from these agents.

    AREAS COVERED: This evaluation covers publications examining or mentioning the risk of TEEs in association with C1-INHs. A systematic literature search was conducted utilizing PubMed, Scopus, and ProQuest. This review utilized search results through January 2020 and followed the PRISMA recommendations for a systematic review. Articles not available in English and animal or in-vitro studies were excluded. For inclusion, studies had to be open-label, randomized-controlled, cross-sectional, or clinical observational studies. A total of 13 studies met inclusion criteria and yielded 1716 patients receiving at least one dose of C1-INH, though only 41 incidences of thrombosis were documented.

    EXPERT OPINION: Significant heterogeneity exists in the available literature concerning both study design and the reporting of data; therefore, interpretation of thrombotic risk is difficult. TEEs are rarely reported in the literature, and they seem unlikely to occur in patients without underlying risk factors. Important risk factors include those found in the prescribing information of C1-INHs.

    Available from: https://dx.doi.org/10.1080/17512433.2020.1776110

    Triggers and short-term prophylaxis in patients with hereditary angioedema [Review]

    Craig T 11/2020 Allergy and asthma proceedings

    Background: Hereditary angioedema (HAE) is a rare disease that affects 1 in 60,000; however, despite being extremely rare, the severity of the disease can cause significant limitations to quality of life. In addition, attacks can be fatal and require urgent care. Methods: We searched PubMed and Google for Hereditary Angioedema and prophylaxis, short term prophylaxis, surgery, medical procedures, dental work, triggers. Results: The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures. Prophylaxis is often used long term to prevent attacks; before known triggers, prophylaxis is referred to as short-term prophylaxis (STP). When to initiate STP, what to use, and what dose to use have not been adequately researched, but there is consensus that, whenever the upper airway is manipulated, STP is essential. In addition, consensus has been reached that an IV C1 inhibitor is the preferred STP agent, and it is my opinion that dosing at 20 units/kg allows dosing for all ages and also allows average-size adults to receive >1000 units because failures at 1000 units have been documented in the literature. Conclusions: This article focused on triggers and preprocedural STP and not on pre-event STP, which is often used before important life events; however, medications and dosing are the same for pre-event prophylaxis.

    Available from: https://dx.doi.org/10.2500/aap.2020.41.200058

    A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab

    McKenzie A, Roberts A, Malandkar S, Feuersenger H, Panousis C, Pawaskar D 12/2021 Clinical and translational science

    Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19). Copyright © 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

    Available from: https://dx.doi.org/10.1111/cts.13180

    Analysis of cold activation of the contact system in hereditary angioedema with normal C1 inhibitor

    Larrauri B, Hester CG, Jiang H, Miletic VD, Malbran A, Bork K, Kaplan A, Frank M 8/2021 Molecular immunology

    Hereditary angioedema (HAE) attacks are caused by excessive activation of the contact system. Understanding how the contact system is activated in HAE, especially in patients with normal C1 inhibitor (HAEnCI), is essential to effectively treat this disease. Contact system activation involves the cleavage of several proteins including Factor XII (FXII), high molecular weight kininogen (HK), prekallikrein, sgp120 (ITIH4) and C1 inhibitor (C1-INH) before the subsequent generation of bradykinin that mediates HAE. In this study, we evaluated the fragmentation and enzymatic activity of contact system proteins in HAEnCI plasma samples before and after contact system activation induced by incubation in the cold. Our results show that in contrast to normal plasma, cold activation induced contact system activation in the majority of the HAEnCI patient samples we tested, in which each contact system protein exhibited fragmentation, FXII and kallikrein enzymatic activity increased, and C1-INH functional activity decreased. HAEnCI samples with low FXII concentrations or functional activity were not affected by cold activation. One HAEnCI sample with a plasminogen gene mutation activated the fibrinolytic system, as shown by an increase in concentration of plasma D dimers. Our results suggest that cold activation seems to be initiated by the cleavage of prekallikrein, and that it needs FXII in order to occur. Reported to be susceptible to excessive contact system activation after incubation in the cold, we further applied this system of study to the evaluation of plasma from women undergoing estrogen treatment. Similar to plasma from HAEnCI patients, excessive contact system activation was demonstrated. Copyright © 2021. Published by Elsevier Ltd.

    Available from: https://www.sciencedirect.com/science/article/abs/pii/S016158902100184X?via%3Dihub

    Androgen use in hereditary angioedema: A critical appraisal and approaches to transitioning from androgens to other therapies

    Johnston DT, Henry Li H, Craig TJ, Bernstein JA, Anderson J, Joseph K, Riedl MA 1/2021 Allergy and asthma proceedings

    Background: Hereditary angioedema (HAE) is a rare genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. Attenuated androgens have been a prophylactic treatment option to reduce the frequency of HAE attacks for > 4 decades. However, the advent of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies has led to a decline in the use of attenuated androgens for the management of HAE in regions where newer therapies are available. A consensus about the best approach for discontinuing or tapering off attenuated androgen therapy does not exist. Objective: To develop a consensus on androgen tapering for patients with HAE. Methods: We sent an open-ended survey about androgen tapering to 21 physicians who treat HAE, 12 of whom responded. We reviewed the collective experience of the participating physicians in combination with results from a literature review on the topic. Results: The survey and literature review underscored potential concerns related to rapid androgen withdrawal in patients with HAE, including physician and patient concerns that the frequency and severity of attacks would abruptly worsen. In addition, discontinuation of attenuated androgens may have the potential for transient adverse effects, such as an increase in the rate of attacks or effects related to hormone withdrawal. Our survey showed that physicians often taper androgens to prevent increases in HAE attacks and possible withdrawal complications. Conclusion: Based on both experiences of the physicians who responded to our survey and reports in the endocrine literature, we provided recommendations for androgen tapering. However, we noted that the likelihood of adverse effects due to androgen withdrawal in patients with HAE is poorly understood and requires further study.

    Available from: https://dx.doi.org/10.2500/aap.2021.42.200106

    Angioedema and fatty acids [Review]

    Wada A, Sawada Y, Sugino H, Nakamura M 8/2021 International journal of molecular sciences

    Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid’s function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.

    Available from: https://www.mdpi.com/1422-0067/22/16/9000/htm

    Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema

    Castaldo AJ, Jervelund C, Corcoran D, Boysen HB, Christiansen SC, Zuraw BL 3/2021 Allergy and asthma proceedings

    Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

    Available from: https://dx.doi.org/10.2500/aap.2021.42.200127

    Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies [Review]

    Manning ME, Kashkin JM 7/2021 Allergy and asthma proceedings

    Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient’s quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages >= 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

    Available from: https://dx.doi.org/10.2500/aap.2021.42.210034

    Berotralstat (BCX7353): Structure-guided design of a potent, selective, and oral plasma kallikrein inhibitor to prevent attacks of hereditary angioedema (HAE)

    Kotian PL, Wu M, Vadlakonda S, Chintareddy V, Lu P, Juarez L, Kellogg-Yelder D, Chen X, Muppa S, Chambers-Wilson R, Davis Parker C, Williams J, Polach KJ, Zhang W, Raman K, Babu YS 9/2021 Journal of medicinal chemistry

    Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration’s approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

    Available from: https://dx.doi.org/10.1021/acs.jmedchem.1c00511

    Berotralstat (Orladeyo) for prevention of hereditary angioedema [Review]

    Berotralstat: First approval [Review]

    Lee A 2/2021 Drugs

    Berotralstat (ORLADEYO TM) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The inhibition of kallikrein by berotralstat decreases the production of bradykinin, which prevents the localised tissue oedema that occurs during attacks of HAE. Berotralstat has been approved in the USA, and subsequently in Japan, for prophylaxis to prevent attacks of HAE in adults and paediatric patients aged 12 years or older. This article summarises the milestones in the development of berotralstat leading to this first approval for prophylaxis to prevent attacks of HAE.

    Available from: https://dx.doi.org/10.1007/s40265-021-01475-4

    Clinical manifestations of hereditary angioedema and a systematic review of treatment options [Review]

    Rosi-Schumacher M, Shah SJ, Craig T, Goyal N 6/2021 Laryngoscope investigative otolaryngology

    Objective: This study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and specific therapies.

    Methods: A literature search of PubMed and Embase databases was conducted from start of the database to February 2021. Inclusion criteria included relevant systematic reviews, randomized control clinical trials, prospective and retrospective cohort studies, and outcomes research published in English and available in full-text. Out of 310 candidate articles, a total of 55 articles were included in our study.

    Results: The most common genetic form of HAE in up to 85% of cases is caused by low levels of C1 esterase inhibitor (C1-INH) protein, leading to a bradykinin-mediated increase in vascular permeability. During an attack of HAE, abortive treatment with C1-INH replacement is most commonly described, however, icatibant, ecallantide, or fresh frozen plasma are also used. Long-term prophylaxis in the form of C1-INH replacement (subcutaneous or intravenous), monoclonal antibodies targeting plasma kallikrein, attenuated androgens, and transexemic acid should be considered for those who suffer from frequent, severe attacks.

    Conclusion: Progressively distal involvement of the upper airway, especially the larynx, has been shown to pose an increased risk of asphyxiation and death in the acute presentation of HAE. Evaluation by an otolaryngologist is often sought during the emergent clinical management of HAE; therefore, it is prudent that the consulting physician is well-versed in the prompt recognition, triage of patients, and appropriate treatment modalities.

    Level of Evidence: 1A. Copyright © 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223449

    Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2 [Review]

    Fijen LM, Bork K, Cohn DM 8/2021 Clinical reviews in allergy & immunology

    Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema. Copyright © 2021. The Author(s).

    Available from: https://dx.doi.org/10.1007/s12016-021-08832-x

    Current medical management of hereditary angioedema: Follow-up survey of US physicians

    Riedl MA, Banerji A, Gower R 3/2021 Annals of Allergy, Asthma, & Immunology

    BACKGROUND: Physician surveys on hereditary angioedema (HAE) management in 2010 and 2013 revealed important trends in HAE care.

    OBJECTIVE: To evaluate current HAE management and the impact of new treatment options on physician practice patterns over time.

    METHODS: During June and July 2019, 5382 physicians were contacted by means of postal mail to complete a 47-question survey; 177 responded (3%).

    RESULTS: Across the 3 surveys, the home replaced the emergency department as the most typically reported setting for HAE attack treatment (54.3% vs 11.6% in 2010 and 32.5% in 2013; P < .001). Physicians reported C1 esterase inhibitor (C1-INH) as the most typically prescribed long-term prophylactic treatment (LTP) (60.0% vs 20.4% in 2010 and 56.7% in 2013; P < .001). Subcutaneous LTP medications were most typically prescribed over intravenous (C1-INH, 41.4%; subcutaneous lanadelumab, 21%; intravenous C1-INH, 18.6%). Danazol, the most frequently prescribed LTP treatment, dropped to 6.4% (55.8% in 2010 and 23.4% in 2013; P < .001). The strongest nonefficacy factor influencing clinician treatment choice changed over time, with cost and (or) insurance coverage increasing to 43.7% (from 24.4% in 2010 and 40.5% in 2013; P = .001), whereas the concern over adverse effects dropped to 16.2% (from 55.8% in 2010 and 29.5% in 2013; P < .001). Physician-reported patient satisfaction remains high, with only 1.5% of physicians indicating patients are not satisfied with treatment.

    CONCLUSION: The US physician survey data reflect improvements in the HAE management in recent years. Therapeutic advances in HAE have led to reported higher rates of home treatment of HAE attacks, reduced concern for adverse treatment effects, and high levels of patient satisfaction. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.anai.2020.10.009

    Efficacy of lanadelumab in acquired angioedema with C1-inhibitor deficiency

    Belbezier A, Boccon-Gibod I, Bouillet L 6/2021 The journal of allergy and clinical immunology. In practice

    Available from: https://www.sciencedirect.com/science/article/abs/pii/S221321982100581X

    Hereditary angioedema: How to approach it at the emergency department?

    Serpa FS, Mansour E, Aun MV, Giavina-Bianchi P, Chong Neto HJ, Arruda LK, Campos RA, Motta AA, Toledo E, Grumach AS, Valle SOR 4/2021 Einstein (Sao Paulo, Brazil)

    Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

    Available from: https://dx.doi.org/10.31744/einstein_journal/2021RW5498

    Impact of lanadelumab on health-related quality of life in patients with hereditary angioedema in the HELP study

    Lumry WR, Weller K, Magerl M, Banerji A, Longhurst HJ, Riedl MA, Lewis HB, Lu P, Devercelli G, Jain G, Maurer M, HELP Study Investigators 4/2021 Allergy

    BACKGROUND: An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health-related quality of life (HRQoL) in patients with hereditary angioedema (HAE).

    METHODS: Patients with HAE-1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0-182). The Angioedema Quality of Life Questionnaire (AE-QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ-5D-5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab-treated patients and (b) individual lanadelumab groups for changes in scores (day 0-182) and proportions achieving the minimal clinically important difference (MCID, -6) in AE-QoL total score.

    RESULTS: Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE-QoL total and domain scores (mean change, -13.0 to -29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ-5D-5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.

    CONCLUSION: Patients with HAE-1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE-QoL following lanadelumab treatment in the HELP Study. Copyright © 2020 Takeda Pharmaceuticals Company Limited. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

    Available from: https://dx.doi.org/10.1111/all.14680

    Indirect comparison of lanadelumab and intravenous C1-INH using data from the HELP and CHANGE studies: Bayesian and frequentist analyses

    Mendivil J, Malmenas M, Haeussler K, Hunger M, Jain G, Devercelli G 3/2021 Drugs in R&D

    BACKGROUND: Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is a rare disease associated with painful, potentially fatal swelling episodes affecting subcutaneous or submucosal tissues. HAE attacks recur with unpredictable severity and frequency throughout patients’ lives; long-term prophylaxis is essential for some patients. In the absence of head-to-head studies, indirect treatment comparison (ITC) of long-term prophylactic agents is a valid approach to evaluate comparative efficacy.

    METHODS: We conducted an ITC using data from the placebo-controlled HELP study (assessing patients receiving lanadelumab 300 mg every 2 or 4 weeks) and the 12-week, parallel arm, crossover CHANGE study (assessing intravenous C1-INH). Outcomes of interest were attack rate ratio (ARR) and time to attack after day 0 (TTA0) and after day 70 (TTA70). Two ITC methodologies were used: a Bayesian approach using study results to update non-informative prior distributions to posterior distributions on relative treatment effects, and a frequentist approach using patient-level data from HELP and CHANGE to generate Poisson regressions (for ARR) and Cox models (for TTA0 and TT70).

    RESULTS: Both Bayesian and frequentist analyses suggested that lanadelumab reduced HAE attack rate by 46-73% versus intravenous C1-INH. Relative to intravenous C1-INH, risk of first attack after day 0 was comparable between intravenous C1-INH and both lanadelumab doses; risk of first attack after day 70 was reduced by 81-83% with lanadelumab 300 mg every 2 weeks, compared with C1-INH.

    CONCLUSIONS: Findings from these two ITC methodologies support the favorable efficacy of lanadelumab in reducing the HAE attack rate and extending attack-free intervals in patients with HAE.

    Available from: https://dx.doi.org/10.1007/s40268-021-00337-4

    Lanadelumab (Takhzyro) for prevention of hereditary angioedema [Review]

    Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: Findings from the COMPACT open-label extension study

    Lumry WR, Zuraw B, Cicardi M, Craig T, Anderson J, Banerji A, Bernstein JA, Caballero T, Farkas H, Gower RG, Keith PK, Levy DS, Li HH, Magerl M, Manning M, Riedl MA, Lawo JP, Prusty S, Machnig T, Longhurst H, on behalf of the COMPACT Investigators 2/2021 Orphanet journal of rare diseases

    BACKGROUND: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.

    RESULTS: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within “normal” range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], – 1.23 [- 2.08, – 0.38]), HADS depression scale (- 0.95 [- 1.57, – 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], – 23.33% [- 34.86, – 11.81]), work productivity loss (- 26.68% [- 39.92, – 13.44]), and activity impairment (- 16.14% [- 26.36, – 5.91]). Clinically important improvements were achieved in >= 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.

    CONCLUSIONS: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .

    Available from: https://dx.doi.org/10.1186/s13023-020-01658-4

    Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks [Review]

    Hide M, Horiuchi T, Ohsawa I, Andresen I, Fukunaga A 1/2021 Allergology international : official journal of the Japanese Society of Allergology

    Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies. Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.alit.2020.07.008

    Managing chronic urticaria and recurrent angioedema differently with advancing age

    Longhurst HJ, Goncalo M, Godse K, Ensina LF 6/2021 The journal of allergy and clinical immunology. In practice

    Angioedema and urticaria affect people of all ages. Accurate diagnosis and optimum management is essential for healthy aging. Older people continue to experience mast cell-mediated urticaria and angioedema, with a higher prevalence of autoimmune and a lower prevalence of autoallergic disease. Bradykinin-mediated angioedemas are more common in the elderly because of their association with angiotensin-converting enzyme inhibitor (ACEI) treatment. Acquired C1-inhibitor deficiency, another bradykinin-mediated angioedema, occurs predominantly in older people, whereas hereditary angioedema due to C1-inhibitor deficiency continues to cause symptoms, even in old age. Drug-induced angioedemas disproportionately affect older people, the most frequent users of ACEIs, aspirin, and nonsteroidal anti-inflammatory drugs. Accurate diagnosis and targeted treatment prevent unnecessary morbidity and mortality. Second-generation antihistamines with omalizumab if required are effective and well tolerated in older people with mast cell-mediated urticaria. For bradykinin-mediated angioedemas, these drugs are ineffective. C1-inhibitor replacement or blockade of kallikrein or the bradykinin B2 receptor of the contact pathway is required to treat hereditary angioedema and may be considered in other bradykinin-mediated angioedemas, if supportive treatment is insufficient. For aspirin-related angioedema and urticaria, alternative medications or, exceptionally, desensitization may be required. Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaip.2021.03.034c

    Medicinal use of testosterone and related steroids revisited [Review]

    Tauchen J, Jurasek M, Huml L, Rimpelova S 2/2021 Molecules (Basel, Switzerland)

    Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.

    Available from: https://www.mdpi.com/1420-3049/26/4/1032/htm

    Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial

    Ohsawa I, Honda D, Suzuki Y, Fukuda T, Kohga K, Morita E, Moriwaki S, Ishikawa O, Sasaki Y, Tago M, Chittick G, Cornpropst M, Murray SC, Dobo SM, Nagy E, Van Dyke S, Reese L, Best JM, Iocca H, Collis P, Sheridan WP, Hide M 6/2021 Allergy

    BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.

    METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with >=2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (>=2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period.

    RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).

    CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan. Copyright © 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

    Available from: https://dx.doi.org/10.1111/all.14670

    Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial

    Zuraw B, Lumry WR, Johnston DT, Aygoren-Pursun E, Banerji A, Bernstein JA, Christiansen SC, Jacobs JS, Sitz KV, Gower RG, Gagnon R, Wedner HJ, Kinaciyan T, Hakl R, Hanzlikova J, Anderson JT, McNeil DL, Fritz SB, Yang WH, Tachdjian R, Busse PJ, Craig TJ, Li HH, Farkas H, Best JM, Clemons D, Cornpropst M, Dobo SM, Iocca HA, Kargl D, Nagy E, Murray SC, Collis P, Sheridan WP, Maurer M, Riedl MA 7/2021 The Journal of allergy and clinical immunology

    BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.

    OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).

    METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.

    RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.

    CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaci.2020.10.015

    Orladeyo (Berotralstat): A novel oral therapy for the prevention of hereditary angioedema

    Powell J, Piszczatoski C, Rubido E 7/2021 The Annals of pharmacotherapy

    OBJECTIVE: The purpose of this article is to review the available trials that led to the Food and Drug Administration (FDA) approval of berotralstat, an oral kallikrein inhibitor, for the prevention of hereditary angioedema (HAE) attacks.

    DATA SOURCES: PubMed and ClincalTrials.gov were searched using key term berotralstat to identify phase III clinical trials related to the FDA approval of berotralstat from April 2018 to May 2021.

    STUDY SELECTION AND DATA EXTRACTION: Trials selected were those that influenced the FDA approval of berotralstat or provided novel information regarding the safety and efficacy of this therapy in the treatment of HAE.

    DATA SYNTHESIS: Both APeX-2 and ApeX-J found clinically significant benefit with berotralstat 150 mg daily for reduction in HAE attacks when compared with placebo (1.31 vs 2.35, P < 0.001, and 1.11 vs 2.18, P < 0.001, attacks in the APeX-2 and APeX-J trials, respectively). APeX-2 also showed a statistically significant benefit for berotralstat 110 mg daily (1.65 vs 2.35 attacks [1.65 attacks, P = 0.024]).

    RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: An advantage berotralstat has over the other approved therapies is that it is administered orally, which may garner patient preference because of ease of administration. Berotralstat has also shown a potential benefit in reducing the need for standard-of-care treatment for HAE attacks, which has not been studied with alternative agents.

    CONCLUSIONS: Berotralstat 150 mg daily has been proven safe and effective in clinical studies and appears to be a viable oral alternative to parenteral medications currently used in HAE prophylaxis.

    Available from: https://dx.doi.org/10.1177/10600280211032982

    Periodic severe angioedema without exogenous hormone exposure

    Nabavi M, Bahrami S, Arshi S, Rezaeifar A, Bemanian MH, Fallahpour M, Shokri S, Tehrani H 2/2021 Iranian journal of allergy, asthma, and immunology

    Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine/corticosteroid or adrenaline. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1-INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1-INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.

    Available from: https://ijaai.tums.ac.ir/index.php/ijaai/article/view/2841

    Population Pharmacokinetics and Exposure-Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema

    Wang Y, Jomphe C, Marier JF, Martin P 4/2021 Journal of clinical pharmacology

    Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE. Copyright © 2020 Takeda Pharmaceutical Company Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

    Available from: https://dx.doi.org/10.1002/jcph.1768

    Population pharmacokinetics of recombinant human C1 esterase inhibitor in children with hereditary angioedema

    Hayes S, Farrell C, Relan A, Anderson J 6/2021 Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

    BACKGROUND: Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for the treatment of acute hereditary angioedema (HAE) attacks in adolescents and adults; it is also indicated in Europe for children aged 2 years and older. A need exists for further insight into potential pharmacokinetic (PK) differences in functional C1-INH levels by age (ie, children, adolescents, and adults).

    OBJECTIVE: To perform population PK modeling to predict C1-INH levels by age after by age rhC1-INH administration.

    METHODS: Data from a phase 2 pediatric trial (children aged 4-13 years at screening) were added to a database of 6 trials in adults and adolescents. An unpublished population PK model was refined and used to simulate C1-INH exposure.

    RESULTS: Analysis included 153 individuals (14 healthy volunteers; 139 patients with HAE) and 1788 functional C1-INH measurements (59 from 20 patients in the pediatric trial). Bodyweight (population weight, 16-128 kg) was a key predictor of C1-INH volume of distribution. Age was not a predictor of C1-INH PK after the inclusion of bodyweight in the model. Simulations of the recommended rhC1-INH dosing regimen (bodyweight <84 kg, 50 U/kg; >=84 kg, 4200 U) revealed that overall C1-INH exposure was comparable among age groups. Predicted peak functional C1-INH concentrations were at or above the lower level of normal (>=0.7 U/mL) for 99.8% of adults (>=18 years), 99.8% of adolescents (14-17 years), and 96.0% of children (2-13 years).

    CONCLUSION: The analyses support the same weight-based rhC1-INH dosing for HAE attacks in children as currently recommended for adolescents and adults. These results support clinical trial data, which revealed similar safety and efficacy profiles across these age groups. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S1081120621001289?dgcid=rss_sd_all

    Preventive treatment of hereditary angioedema: A review of phase III clinical trial data for subcutaneous C1 inhibitor and relevance for patient management [Review]

    West JB, Poarch K, Lumry WR 12/2021 Clinical therapeutics

    PURPOSE: Hereditary angioedema (HAE), most often caused by a genetically mediated deficiency in the activity of C1 inhibitor (C1INH) protein, is characterized clinically by recurrent episodes of localized swelling without wheals. HAE attacks can be painful, debilitating, and even fatal, resulting in physical discomfort, emotional stress, and interruptions of work, school, and/or social activities, all of which can affect health-related quality of life (HRQoL). Subcutaneous C1INH (C1INH[SC]) is recommended as a first-line option for long-term prophylaxis (LTP) in HAE. This narrative review provides a concise but comprehensive overview of all published data generated from the pivotal Phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) study program, which evaluated the use of C1INH(SC) as LTP.

    METHODS: A PubMed search was performed using the search terms subcutaneous C1 inhibitor plus COMPACT with no filters, and another search was performed using the term subcutaneous C1 inhibitor, with output limited to clinical trial data only. All publications that reported data generated during the Phase III COMPACT study were included. Data presentation focused on the US Food and Drug Administration-approved dose of 60 IU/kg.

    FINDINGS: The search strategy identified a total of 11 publications that reported data and analyses from the Phase III COMPACT study. Publications reported overall findings from the double-blind, placebo-controlled, crossover COMPACT study and a subsequent long-term open-label extension (OLE) study. Other published analyses included pharmacokinetic/pharmacodynamic data, HRQoL assessments, and findings in patient subgroups including women, pediatric patients, and patients >=65 years of age. Subgroup analyses reported good safety and efficacy profiles among age-based subgroups from the COMPACT OLE, including pediatric patients, patients >=65 years of age with comorbidities, and among female patients, despite a tendency for HAE to be more severe in women. A number of significant HRQoL improvements were noted with C1INH(SC) use, including better overall health status, less anxiety, and less work- and activity-related impairment versus placebo (double-blind study), and compared with baseline (OLE).

    IMPLICATIONS: This review provides a concise overview of all published COMPACT study data with C1INH(SC). The data reviewed here portray a high level of efficacy and tolerability with C1INH(SC), even during periods of treatment that exceed 2 years, which does not appear to vary based on patient age or sex. Clinically relevant improvements in multiple facets of HRQoL were also reported, including better overall HRQoL, less anxiety and depression, and less disruptions in work attendance and productivity. These data should be useful for assessing the appropriateness of C1INH(SC) therapy for individual patients. Copyright © 2021. Published by Elsevier Inc.

    Available from: https://dx.doi.org/10.1016/j.clinthera.2021.10.008

    Psychiatric and clinical characteristics of hereditary angioedema patients who experienced attacks during COVID-19

    Mete Gokmen N, Kuman Tuncel O, Bogatekin G, Bulut G, Demir S, Gelincik A, Tunakan Dalgic C, Mungan D 7/2021 Journal of investigational allergology & clinical immunology

    Available from: https://dx.doi.org/10.18176/jiaci.0701

    Randomized trial of the efficacy and safety of berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: Results of APeX-2 through 48 weeks (Part 2)

    Wedner HJ, Aygoren-Pursun E, Bernstein J, Craig T, Gower R, Jacobs JS, Johnston DT, Lumry WR, Zuraw BL, Best JM, Iocca HA, Murray SC, Desai B, Nagy E, Sheridan WP, Kiani-Alikhan S 6/2021 The journal of allergy and clinical immunology. In practice

    BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile.

    OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks.

    METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability.

    RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (+/-standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (+/-0.25) and 1.06 (+/-0.25) in the berotralstat 150mg 48-week group and 2.97 (+/-0.21) and 1.35 (+/-0.33) in the berotralstat 110mg 48-week group.

    CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaip.2021.03.057

    Recombinant human C1 esterase inhibitor for hereditary angioedema attacks: A European registry

    Valerieva A, Staevska MT, Grivcheva-Panovska V, Jesenak M, Kohalmi KV, Hrubiskova K, Zanichelli A, Bellizzi L, Relan A, Hakl R, Farkas H 4/2021 The World Allergy Organization journal

    Background: Hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks. A European treatment registry was established to review the adverse event profile and efficacy of recombinant human C1 esterase inhibitor (rhC1-INH) for HAE attacks.

    Methods: Individuals with C1-INH-HAE were enrolled following a decision to treat with rhC1-INH and provision of written informed consent. Medical history and baseline HAE information were collected at screening. Healthcare providers entered data on HAE attacks, response to treatment, and adverse events using a web-based questionnaire.

    Results: From July 1, 2011, through December 1, 2019, 71 patients with C1-INH-HAE (30 male/41 female; mean age, 47.3 years; age range, 19-78 years) in 9 countries reported 2356 attacks and were treated with rhC1-INH. Before registry entry, patients, including 20 (28.2%) who were on maintenance therapy/prophylaxis at registry enrollment, experienced a mean of 25 HAE attacks per year (median, 16 [range, 0-185]). Most treated HAE attacks were abdominal (46.1%), followed by peripheral (38.3%), oro-facial-pharyngeal (14.8%), urogenital (3.2%), and laryngeal (2.6%). The mean rhC1-INH dose was 3307 U (43.3 U/kg). Patients reported symptom improvement within 4 h for 97.8% of attacks (2305/2356) with rhC1-INH; most attacks (99.8%; 2351/2356) required only 1 dose. Five attacks were treated with a second dose (total rhC1-INH dose administered for attack, 4200 U). No hypersensitivity, thrombotic/thromboembolic events, or drug-related serious adverse events were reported.

    Conclusion: The rhC1-INH treatment registry provided real-world data on the treatment of 2356 HAE attacks that were consistent with clinical trial data of rhC1-INH in patients with C1-INH-HAE. Copyright © 2021 The Authors.

    Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093463

    Recurrent and acute abdominal pain as the main clinical manifestation in patients with hereditary angioedema

    Cao Y, Liu S, Zhi Y 3/2021 Allergy and asthma proceedings

    Background: Hereditary angioedema (HAE) is a rare disease that often leads to misdiagnosis. The delay of diagnosis is > 10 years in China. Recurrent and acute abdominal pain is one of the common symptoms of HAE. Because of the high misdiagnosis rate, it usually results in unnecessary surgical procedures. This study focused on the clinical symptoms and management of HAE-related abdominal attacks in Chinese patients to provide some new insight for the emergency department (ED) physicians and gastroenterologists. Methods: A Web-based survey was conducted among 107 patients with HAE from 94 unrelated families. Detailed questions with respect to the abdominal attacks were asked, including the frequency, symptoms, and duration before and after confirmed diagnosis. The demographic characteristics, diagnosis process, and treatment outcomes were also included. Results: Approximately 70% of the patients with HAE presented with abdominal symptoms during the onset of edema, mostly characterized by pain (94.8%), nausea (83.1%), vomiting (83.1%), diarrhea (59.7%), and constipation (23.4%). The patients were easily misdiagnosed as having gastroenteritis (35.1%) and appendicitis (10.4%), and 24.7% of them received unnecessary appendectomy or laparotomy. Danazol, a widely used drug for long-term prophylaxis of HAE in China, can reduce the attack frequency and alleviate the abdominal symptoms, but the adverse effects are also significant and more severe in women. Conclusions: Abdominal symptoms are common and important clinical features of HAE but are easily confused with other gastrointestinal diseases. ED physicians and gastroenterologists should consider HAE when patients experience recurrent and unexplained abdominal pain. Proper medical treatment should be administered in a timely manner if an HAE diagnosis is confirmed and efforts are required to increase access in China to medications both for on-demand treatment and long-term prophylaxis.

    Available from: https://dx.doi.org/10.2500/aap.2021.42.210001

    Safety and outcomes associated with the pharmacological inhibition of the kinin-kallikrein system in severe COVID-19

    Mansour E, Palma AC, Ulaf RG, Ribeiro LC, Bernardes AF, Nunes TA, Agrela MV, Bombassaro B, Monfort-Pires M, Camargo RL, Araujo EP, Brunetti NS, Farias AS, Falcao ALE, Santos TM, Trabasso P, Dertkigil RP, Dertkigil SS, Moretti ML, Velloso LA 2/2021 Viruses

    Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

    Available from: https://dx.doi.org/10.3390/v13020309

    Short review of SEC, a potential dexamethasone-sparing regimen for glioblastoma: Spironolactone, ecallantide, clotrimazole

    Kast RE, Burns TC, Halatsch ME 9/2021 Neuro-Chirurgie

    This paper presents a short review of data supporting a dexamethasone sparing regimen, SEC, to reduce glioblastoma related brain edema. The conclusion of the reviewed data is that the rationale and risk/benefit ratio favors a pilot study to determine if the three drug regimen of SEC can reduce need for corticosteroid use during the course of glioblastoma. Details of how selected pathophysiological aspects of brain edema occurring during the course of glioblastoma and its treatment intersect with the established action of the three old drugs of SEC indicate that they can be repurposed to reduce that edema. Current first-line treatment of this edema is dexamethasone or related corticosteroids. There are multiple negative prognostic implications of both the edema itself and of dexamethasone, prime among them shortened survival, making a dexamethasone sparing regimen highly desirable. SEC uses spironolactone, an antihypertensive potassium-sparing diuretic acting by mineralocorticoid receptor inhibition, ecallantide acting to inhibit kallikrein activation marketed to treat hereditary angioedema, and clotrimazole, an old antifungal drug that inhibits intermediate conductance Ca++ activated K+ channel (KCa3.1). These three old drugs are well known to most clinicians, have a well-tolerated safety history, and have a robust preclinical database showing their potential to reduce the specific edema of glioblastoma. Additionally, these three drugs were chosen by virtue of each having preclinical evidence of glioblastoma growth and/or migration inhibition independent of their edema reduction action. A clinical study of SEC is being planned. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.neuchi.2020.12.008

    The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey

    Iwamoto K, Yamamoto B, Ohsawa I, Honda D, Horiuchi T, Tanaka A, Fukunaga A, Maehara J, Yamashita K, Akita T, Hide M 4/2021 Allergology international : official journal of the Japanese Society of Allergology

    BACKGROUND: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs.

    METHODS: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis.

    RESULTS: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect.

    CONCLUSIONS: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues. Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.alit.2020.09.008

    The importance of complement testing in acquired angioedema related to angiotensin-converting enzyme inhibitors

    Balla Z, Zsilinszky Z, Polai Z, Andrasi N, Kohalmi KV, Csuka D, Varga L, Farkas H 2/2021 The journal of allergy and clinical immunology. In practice

    BACKGROUND: Angiotensin-converting enzyme inhibitors may cause angioedema. Currently, no laboratory method is available for identifying acquired angioedema related to angiotensin-converting enzyme inhibitors. However, establishing the diagnosis is possible from the medical history and the preexisting angiotensin-converting enzyme inhibitor therapy, as well as by excluding other angioedema types.

    OBJECTIVE: To evaluate the results of complement testing in patients experiencing angioedema while taking angiotensin-converting enzyme inhibitors.

    METHODS: Between 2005 and 2019, a total of 149 patients taking angiotensin-converting enzyme inhibitors were referred to our Angioedema Center for the diagnostic evaluation of recurrent angioedema episodes. Complement measurement was performed on these patients.

    RESULTS: The mean age of the 149 patients treated with angiotensin-converting enzyme inhibitors at the onset of the index angioedema episode was 55.8 years. The mean interval between the introduction of angiotensin-converting enzyme inhibitor therapy and the occurrence of the initial symptoms of angioedema was 43 months. The most commonly used angiotensin-converting enzyme inhibitor was perindopril (32.9% of the patients). The initial angioedema episode involved the face in 50.3%, the lips in 40.9%, and the tongue in 33.5% of the patients. Angiotensin-converting enzyme inhibitors were discontinued in all 149 patients, and at the same time, a complement test was performed. The complement tests confirmed hereditary angioedema with C1-inhibitor deficiency in 2 patients and an additional 12 family members. Acquired angioedema with C1-inhibitor deficiency was found in 3 patients.

    CONCLUSIONS: Excluding hereditary angioedema and acquired angioedema with C1-inhibitor deficiency is indispensable for establishing the diagnosis of acquired angioedema related to angiotensin-converting enzyme inhibitors. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

    Available from: https://www.sciencedirect.com/science/article/pii/S2213219820309363

    Treatment of hereditary angioedema [Review]

    Caballero T 2/2021 Journal of investigational allergology & clinical immunology

    Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action.

    Available from: https://dx.doi.org/10.18176/jiaci.0653

    What’s new in the treatment of urticaria and angioedema

    Khan DA, Kocaturk E, Bauer A, Aygoren-Pursun E 6/2021 The journal of allergy and clinical immunology. In practice

    Chronic urticaria and angioedema are diseases often managed by Allergy and Immunology specialists. Recent international guidelines have outlined a stepwise approach to management of patients using dose escalation of second-generation antihistamines followed by use of omalizumab and finally cyclosporine in more refractory cases. In select patients (those with refractory chronic urticaria), nonbiologic alternative medications with anti-inflammatory or immunosuppressant activity may be considered. Angioedema without wheals may have several different pathophysiologic mechanisms. Optimal management of mast cell-mediated angioedema is less clear but is often managed similar to chronic spontaneous urticaria. Drug-induced angioedema due to angiotensin-converting enzyme inhibitors is a common cause of angioedema in the emergency department. Although bradykinin is thought to be a primary mediator for this type of angioedema, studies of targeted therapies have been generally disappointing. In contrast, several targeted therapies have been proven successful using acute and preventive approaches for management of hereditary angioedema. Further developments, including novel biologics, novel oral therapies, and gene therapy approaches, may hopefully continue to broaden therapeutic options to ensure optimal individual management of patients with hereditary angioedema. Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

    Available from: https://dx.doi.org/10.1016/j.jaip.2021.03.012

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