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/

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)

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

Volume 49(1): pages: 37-44

Not available online.

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

Not available online.

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)

40(160):563-564

Not available online.

Oct;40(160):563-564.

Not available online.

Oct;64(10):1049-1050.

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

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)

Mar;191(3):209-219.

Not available online.

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

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

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)

Apr;42(166):317-339.

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

May;27(5):193-195.

Not available online.

Jun;5(3):174-180.

Not available online.

May;66(5):437-438.

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

Jul 7;2(7819):41.

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

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

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

2(7824):325

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

2(7830):680

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

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

Not available online.

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

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

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)

Jan 4;288(1):53.

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

May;99(5):388-389.

Not available online.

Feb 2;1(7849):169.

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

Dec;135(6):391-398.

Not available online.

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

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/

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.

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

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.

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)

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.

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.

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)

Sep;85(3):399-400.

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

1976;89:122-132.

Not available online.

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)

5(Suppl 3):38-43.

Not available online.

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)

238(19):2009-2010

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

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.

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/

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)

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)

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.

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)

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.

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)

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/

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.

Nov;22(11):1295-1299.

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

Nov;26(2):1-37.

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

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/

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

Not available online.

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.

1980;28(1):31-35

Not available online.

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)

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)

1980;16(1):499-507.

Not available online.

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)

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)

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.

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)

1980;23(5):185-190

Not available online.

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

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

Not available online.

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)

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.

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)

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/

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)

Apr;2(2):65-68.

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

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

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)

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)

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/

Feb;31(2):124.

Not Available online.

Apr;22(3):141-147.

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

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.

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)

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)

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.

;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.

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)

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)

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.

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)

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.

Oct;85(10):1090-1092.

Not available online.

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/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.

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/

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 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

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.

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

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/

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 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

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)

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.

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)

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.

;247B:79-86.

Not available online.

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.

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.

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.

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

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.

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)

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)

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

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 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)

Oct;26(10):1251-1252.

Not available online.

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

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)

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)

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.

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 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.

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

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.

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)

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)

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 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.

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

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)

Feb;99(2):194-196.

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

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)

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

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)

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)

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)

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)

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 (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

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

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

May;69(1):54-57

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

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

(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.

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)

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)

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 (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

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)

Jan;32(1):17-21

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

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

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/

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

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)

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/

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

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

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)

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)

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)

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

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)

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)

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

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)

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)

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

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)

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)

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

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 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

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] 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)

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)

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

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

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

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)

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

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

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

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)

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

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)

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 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.

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 (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)

Dec;67(12):654-657

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

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)

Dec;61(12):1490-1492

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

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)

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

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)

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

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/

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)

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

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)

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)

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)

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

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

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

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)

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

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)

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)

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)

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)

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

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)

Oct;39(8):253-258

Not available online.

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

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)

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 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)

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

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)

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

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)

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)

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)

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)

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)

Jan;100(1 Suppl 2):S47-8

Available online at: http://www.annallergy.org/article/S1081-1206%2810%2960586-8/fulltext (small fee)

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)

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 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

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)

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

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)

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

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

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.

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)

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)

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)

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 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

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

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)

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)

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

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)

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

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)

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 (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)

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)

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)

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

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)

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

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)

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)

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)

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 (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

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/

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 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 (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

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.

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

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

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

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, 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 (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

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.

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

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

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

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

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

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

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

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 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

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856042/

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

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.

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

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/

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

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

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

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.

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

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

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

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.

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

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/

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

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

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

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)

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.

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

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

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.

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

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

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

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

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

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)

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

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)

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

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 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

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

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

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 (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 (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

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

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

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

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

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

Available from : http://secure.medicalletter.org/w1378d

Available from: http://www.managedcaremag.com/content/insurers-will-find-icatibant-lifesaving-expensive-treatment

Available from: http://www.bmj.com/content/343/bmj.d6607

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

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)

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

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

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)

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

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)

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

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

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

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

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

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

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

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

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

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)

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)

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

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

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

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

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)

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 (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

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.

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

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

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

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/

Available from: http://www.magonlinelibrary.com/doi/full/10.12968/hmed.2012.73.3.148 (small fee)

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

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

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

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

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

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 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 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/

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 (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

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, 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

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

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)

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

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)

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

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

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

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

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

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.

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

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

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

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/

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

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

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

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.

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 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

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)

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

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

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

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

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

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)

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

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

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

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

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

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)

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)

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

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)

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.

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

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

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/

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)

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)

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

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)

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)

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

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

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)

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)

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

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

Available from: http://www.annallergy.org/article/S1081-1206%2812%2900939-8/fulltext

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)

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

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

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

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)

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)

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

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)

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)

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

Available from: https://www.karger.com/Article/FullText/351228

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)

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

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)

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

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.

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)

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680557/

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

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)

Available from: http://www.jacionline.org/article/S0091-6749%2812%2901451-0/fulltext

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)

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

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)

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)

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

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/

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)

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)

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

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

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

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)

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

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)

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)

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)

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

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)

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

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

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

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

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

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

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

2014;24(4):271-273

Available from: http://www.jiaci.org/issues/vol24issue4/vol24issue04-9.htm (free)

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)

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

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

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)

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/

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

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

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)

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)

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

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

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

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

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

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, 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)

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

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

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

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)

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

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

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)

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

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)

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)

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)

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)

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

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)

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)

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/

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

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

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

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

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

Available from: http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1835&html=1

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 (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

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

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

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)

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)

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

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.

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