Medical Literature - 2010

Tom Bowen, Marco Cicardi, Henriette Farkas, Konrad Bork, Hilary J Longhurst, Bruce Zuraw, Emel Aygoeren-Pürsün, Timothy Craig, Karen Binkley, Jacques Hebert, Bruce Ritchie, Laurence Bouillet, Stephen Betschel, Della Cogar, John Dean, Ramachand Devaraj, Azza Hamed, Palinder Kamra, Paul K Keith, Gina Lacuesta, Eric Leith, Harriet Lyons, Sean Mace, Barbara Mako, Doris Neurath, Man-Chiu Poon, Georges-Etienne Rivard, Robert Schellenberg, Dereth Rowan, Anne Rowe, Donald Stark, Smeeksha Sur, Ellie Tsai, Richard Warrington, Susan Waserman, Rohan Ameratunga, Jonathan Bernstein, Janne Björkander, Kristylea Brosz, John Brosz, Anette Bygum, Teresa Caballero, Mike Frank, George Fust, George Harmat, Amin Kanani, Wolfhart Kreuz, Marcel Levi, Henry Li, Inmaculada Martinez-Saguer, Dumitru Moldovan, Istvan Nagy, Erik W Nielsen, Patrik Nordenfelt, Avner Reshef, Eva Rusicke, Sarah Smith-Foltz, Peter Späth, Lilian Varga and Zhi Yu Xiang 07/2010 Allergy, Asthma & Clinical Immunology

Background: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.

Objective: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010).

Methods: The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) http://www.haecanada.com website 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: .aacijournal.com/content/6/1/24

Marco Cicardi, Andrea Zanichelli 07/2010 Allergy, Asthma & Clinical Immunology

Acquired angioedema (AAE) is characterized by acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and angioedema symptoms mediated by bradykinin released by inappropriate activation of the contact-kinin system. Angioedema recurs at unpredictable intervals, lasts from two to five days and presents with edema of the skin (face, limbs, genitals), severe abdominal pain with edema of the gastrointestinal mucosa, life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue. AAE recurs in association with various conditions and particularly with different forms of lymphoproliferative disorders. Neutralizing autoantibodies to C1-INH are present in the majority of patients. The therapeutic approach to a patient with AAE should first be aimed to avoid fatalities due to angioedema and then to avoid the disability caused be angioedema recurrences. Acute attacks can be treated with plasma-derived C1-INH, but some patients become non-responsive and in these patients the kallikrein inhibitor ecallantide and the bradykinin receptor antagonist icatibant can be effective. Angioedema prophylaxis is performed using antifibrinolytic agents and attenuated androgens with antifibrinolytic agents providing somewhat better results. Treatment of the associated disease can resolve AAE in some patients.

Available online at: aacijournal.com/content/6/1/14

Chinen J, Shearer WT. 3/2010 Journal of Allergy and Clinical Immunology

In 2009, reports on basic and clinical immunology had an increased focus on human disease mechanisms and management. The molecular pathogenesis of familial angioedema associated with estrogen was further explored to find possible factors affecting severity, including polymorphisms in enzymes and receptors related to bradykinin pathways. A placebo-controlled clinical trial of C1 esterase inhibitor concentrate in patients with hereditary angioedema demonstrated the safety of its use and its efficacy to reduce the duration of angioedema attacks. The interaction of innate immunity and adaptive responses was further examined in several reports, establishing the significant role of Toll-like receptor stimulation for the development of optimal specific antibody responses. The 2009 update of the classification of primary immunodeficiencies introduced more than 15 new genetic defects related to the immune response, including of dedicator of cytokinesis 8 (DOCK8) mutations, which are responsible for the autosomal recessive form of the hyper-IgE syndrome. Other reports expanded the clinical spectrum of disease and improved the characterization of conditions such as warts, hypogammaglobulinemia, and myelokathexis syndrome or the occurrence of mucormycosis and Serratia species infections in patients with chronic granulomatous disease. The frequent presentation of gastrointestinal disorders in patients with humoral immunodeficiencies was recognized, and recommendations for management were reviewed. Clinical research focused on severe combined immunodeficiency included the development and implementation of a state-wide newborn screening program for this condition, a desired goal considering the significant reduction of mortality rate when the diagnosis is made early before opportunistic infections occur. [References: 41].

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC2841291/

Firszt R, Frank MM. 12/2010 American Journal of Clinical Dermatology

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin. Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

Available from: ncbi.nlm.nih.gov/pubmed/20866113

Cicardi M, Zanichelli A. 12/2010 Internal and Emergency Medicine

Angioedema is a recurrent, non-pitting, non-pruritic, self-limiting swelling due to transient increase of endothelial permeability in the capillaries of the deep cutaneous and mucosal layers. Two main groups of angioedema should be distinguished based on the response to treatment: those responding to antihistamine and those that do not. Among the last ones, angioedema due to inherited (hereditary angioedema) and acquired (acquired angioedema) C1 inhibitor deficiency are the best defined, and are known to be mediated by bradykinin. The clinical picture is characterized by cutaneous, abdominal, and laryngeal symptoms that are highly disabling, and can be lethal when they affect the larynx, or if they are not promptly and adequately treated. Important advances in diagnosis and treatment of C1 inhibitor deficiency have been made in recent years, and today, we can rely on different therapeutic options to prevent symptoms or to treat those already present. Because of these advances, in patients properly diagnosed and treated, the mortality for the disease has dropped close to zero, and the quality of life for patients approaches that of normal subjects.

Available from: link.springer.com/article/10.1007%2Fs11739-010-0408-3

Davis AE 3rd, Lu F, Mejia P. 11/2010 Thrombosis and Haemostasis

C1 inhibitor (C1INH) is a serpin that regulates both complement and contact (kallikrein-kinin) system activation. It consists of a serpin domain that is highly homologous to other serpins and an amino terminal non-serpin mucin-like domain. Deficiency of C1INH results in hereditary angioedema, a disease characterised by episodes of angioedema of the skin or the mucosa of the gastrointestinal tract or the oropharynx. Although early data suggested that angioedema was mediated via complement system activation, the preponderance of the data indicate that bradykinin is the mediator. In the past few years, it has become apparent that C1INH has additional anti-inflammatory functions independent of protease inhibition. These include interactions with leukocytes that may result in enhanced phagocytosis, with endothelial cells via E- and P-selectins that interfere with leukocyte rolling and in turn results in suppression of transmigration of leukocytes across the endothelium, and interactions with extracellular matrix components that may serve to concentrate C1INH at sites of inflammation. In addition, C1INH suppresses gram negative sepsis and endotoxin shock, partly via direct interaction with endotoxin that interferes with its interaction with macrophages, thereby suppressing tumour necrosis factor-a and other inflammatory mediators. C1INH treatment improves outcome in a number of disease models, including sepsis and other bacterial infections, possibly malaria, ischaemia-reperfusion injury (intestinal, hepatic, muscle, cardiac, brain), hyper-acute transplant rejection, and other inflammatory disease models. Recent data suggest that this effectiveness is the result of mechanisms that do not require protease inhibition, in addition to both complement and contact system activation.

Available from: schattauer.de/index.php?id=5236&mid=13518

Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kreuz W. 8/2010 American Journal of Obstetrics and Gynecology

OBJECTIVE: The objective of the study was to investigate the rates and characteristics of hereditary angioedema (HAE) attacks associated with pregnancy, delivery, and the postpartum period and their treatment with C1 esterase inhibitor (INH) concentrate.

STUDY DESIGN: This was an observational study including 22 women with type I HAE, with data collected before, during, and after 35 pregnancies (37 children) based on patient diaries, interviews, and case report forms.

RESULTS: In 83% of pregnancies, attack rates increased during pregnancy; highest mean rates occurred in the second and third trimesters. C1-INH concentrate effectively controlled attacks and was safe for mothers and children. Low-plasma C1-INH activity during pregnancy tended to be associated with an increased chance of giving birth to a child with HAE.

CONCLUSION: Increased attack rates during pregnancy in women with HAE are well controlled with C1-INH concentrate, indicating the clear benefit of integrating the availability of C1-INH concentrate into the management plan for these women during pregnancy and delivery.Copyright (c) 2010 Mosby, Inc. All rights reserved.

Banerji A. 9/2010 Allergy and Asthma Proceedings

Hereditary angioedema (HAE) is a rare, potentially life-threatening disease that manifests as recurrent episodes of nonpruritic swelling that may affect the extremities, face, genitalia, gastrointestinal tract, and/or larynx. HAE is the result of a deficiency of functional C1-esterase inhibitor (C1-INH), a key regulator of the complement, coagulation, and kallikrein-kinin cascades. In HAE patients, overactivation of the kallikrein-kinin cascade results in excessive release of bradykinin, the mediator of the pain and swelling that is characteristic of HAE. Historically, treatment options for HAE have been limited, but newly approved and emerging therapies, such as C1-INH replacement products, a plasma kallikrein inhibitor, and a bradykinin B2-receptor antagonist, appear to provide safe and effective relief for a significant proportion of patients with HAE. Because they may have therapeutic and practical advantages over existing HAE therapies, the new agents have the potential to improve the overall management of patients with HAE. This article reviews the results from recent clinical trials of these drugs and considers their role in clinical practice.

Available from: ingentaconnect.com/content/ocean/aap/2010/00000031/00000005/art00012

Konrad Bork 07/2010 Allergy, Asthma & Clinical Immunology

Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/15

Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. 08/2010 New England Journal of Medicine

BACKGROUND: Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema.

METHODS: In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement.

RESULTS: A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events.

CONCLUSIONS: Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.).

Available from: nejm.org/doi/full/10.1056/NEJMoa0905079#t=article

Stolz LE, Horn PT. 8/2010 Drugs of Today

Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE.Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Available from: journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=4&p_RefId=1507205&p_IsPs=N

Garnock-Jones KP. 7/2010 Drugs

Ecallantide, a recombinant protein that is a selective, highly potent and reversible inhibitor of human plasma kallikrein, is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged >or=16 years. In the randomized, double-blind, placebo-controlled, multicentre, phase III trial EDEMA3, mean symptom response to treatment at 4 hours (assessed using the Treatment Outcome Score [TOS]; primary endpoint) was significantly greater with a single subcutaneous dose of ecallantide 30 mg than with placebo in patients with acute, moderate to severe attacks of HAE. In addition, the mean change from baseline in symptom severity at 4 hours (assessed using the Mean Symptom Complex Severity [MSCS] scale) was significantly greater with ecallantide than with placebo. At 4 hours in the similarly designed EDEMA4 trial, the mean change from baseline in MSCS score (primary endpoint) and mean TOS were both significantly greater in recipients of a single subcutaneous dose of ecallantide 30 mg than in placebo recipients. Subcutaneous ecallantide 30 mg was generally well tolerated in patients with acute attacks of HAE in the EDEMA3 and EDEMA4 trials. Adverse events were mostly of mild to moderate severity, and no event that was more common in ecallantide than placebo recipients occurred in >10% of patients. [References: 22].

Available from: springer.com/article/10.2165%2F11205850-000000000-00000

Bernstein JA, Qazi M. 1/2010 Expert Review of Clinical Immunology

Ecallantide (Kalbitor, Dyax Corporation) is a highly specific recombinant plasma kallikrein inhibitor developed for treatment of hereditary angioedema (HAE). Advantages of this agent over plasma-derived treatments are that it poses no risk of viral contamination, is highly selective, has a quick onset of action and can be administered subcutaneously. In clinical trials, ecallantide appears to be a safe and effective drug useful for the treatment of HAE patients suffering from an acute attack. Ecallantide was found to be superior compared with placebo in relieving symptoms, decreasing the severity of attacks and shortening the duration of attacks. The primary safety concern appears to be related to hypersensitivity reactions. Phase IV postmarketing surveillance studies to monitor the incidence of these reactions will be implemented by the company now that the drug has been US FDA approved. [References: 22].

Available from: tandfonline.com/doi/full/10.1586/eci.09.60

Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, et al. 6/2010 Annals of Allergy, Asthma, and Immunology

BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder resulting from low levels of C1-inhibitor activity that manifests as acute attacks of variable and sometimes life-threatening edema. Ecallantide is a novel potent inhibitor of human plasma kallikrein, a key mediator of the excessive formation of bradykinin associated with the signs and symptoms of an HAE attack.

OBJECTIVE: To evaluate the efficacy and safety of ecallantide in the treatment of acute HAE attacks.

METHODS: In this double-blind, placebo-controlled study, patients with a moderate to severe HAE attack were randomized 1:1 to receive 30 mg of subcutaneous ecallantide or placebo. The primary efficacy end point was change from baseline in mean symptom complex severity score 4 hours after dosing. Additional end points included treatment outcome score 4 hours after dosing and maintenance of significant overall improvement through 24 hours.

RESULTS: Ninety-six patients were enrolled. Mean (SD) change from baseline in mean symptom complex severity score 4 hours after dosing was significantly greater with ecallantide use (-0.8 [0.6]) compared with placebo use (-0.4 [0.8]) (P = .01 comparing distributions). Ecallantide therapy was also associated with a significantly larger mean (SD) treatment outcome score 4 hours after dosing vs placebo use (ecallantide: 53.4 [49.7]; placebo: 8.1 [63.2]; P = .003 comparing distributions). The benefit of ecallantide was apparent within 2 hours after dosing and was maintained through 24 hours after dosing. The safety profile was similar between the treatment groups.

CONCLUSION: Ecallantide appears to be an effective and safe treatment for acute attacks of HAE.

Kaplan AP. 11/2010 Journal of Allergy and Clinical Immunology

A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH.Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Available from: jacionline.org/article/S0091-6749%2810%2901197-8/fulltext

Karen E Binkley 07/2010 Allergy, Asthma & Clinical Immunology

The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/16

Hilary J Longhurst, Henriette Farkas, Timothy Craig, Emel Aygören-Pürsün, Claire Bethune, Janne Bjorkander, Konrad Bork, Laurence Bouillet, Henrik Boysen, Anette Bygum, Teresa Caballero, Marco Cicardi, John Dempster, Mark Gompels, Jimmy Gooi, Sofia Grigoriadou, Ursula Huffer, Wolfhart Kreuz, Marcel M Levi, Janet Long, Inmaculada Martinez-Saguer, Michel Raguet, Avner Reshef, Tom Bowen and Bruce Zuraw 07/2010 Allergy, Asthma & Clinical Immunology

Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks (‘self or assisted administration’) and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/22

Bruce L Zuraw 07/2010 Allergy, Asthma & Clinical Immunology

Advances in understanding the pathophysiology and mechanism of swelling in hereditary angioedema (HAE) has resulted in the development of multiple new drugs for the acute and prophylactic treatment of patients with HAE. This review will recap the past treatment options, review the new current treatment options, and discuss potential future treatment options for patients with HAE.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/23

Tom Bowen 07/2010 Allergy, Asthma & Clinical Immunology

The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was arrived at during the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) second meeting held May 15th/16th, 2010, Toronto, Canada and was cosponsored by CHAEN/RCAH, the Canadian Society of Allergy and Clinical Immunology, and the University of Calgary and was funded through an unrestricted educational grant from CSL Behring. This is the third international consensus and is meant to be a living document requiring continual updating and rethinking. The first consensus conference was scheduled for Toronto, Ontario, Canada in April 2003 but was SARSed out. That conference was rescheduled and held in Toronto in October 2003 and published in 2004. The next consensus was again held in Toronto Canada in 2006 and rediscussed in Budapest in 2007 and published in 2008. This third consensus conference was in danger of being ashed out from the volcanic activity in Iceland making planning of such meetings a challenge.

Rare disorders such as Hereditary Angioedema require international collaboration to push ahead with progress in the management of the disorders. The Hungarian group under Dr. Henriette Farkas and the Italian group under Dr. Marco Cicardi have certainly led the way in organizing these essential get-togethers. Patient Group participation in these discussions has been strongly encouraged and the Consensus Algorithms have been signed off by various National Patient Organizations. The patients should decide how they wish to be treated. I usually bore audiences with my motto: It can be done – It must be done for the sake of our patients. This concept continues in this third consensus algorithm development. We have moved from 2003 from only a few controlled trials in prophylaxis and treatment in HAE-Types I and II to now several clinical trials in various stages of publication. Prophylaxis options have moved from anti-fibrinolytics and androgens to include consideration of plasma-derived C1-inhibitor (pdC1INH) prophylaxis. Therapy options have broadened from pdC1INH to now include bradykinin receptor antagonist Icatibant and kallikrein antagonist Ecallantide and recombinant C1INH under clinical trial. These phase III clinical trials will move this current consensus algorithm approach to evidence-based approach and Dr. Marco Cicardi is moving this along with an important meeting in Italy in September 2010.

Clinical trials in rare disorders are difficult at the best of times but exceptionally difficult in HAE where swelling events are unpredictable and require quick intervention at all hours of day, night, weekends. These clinical trials are difficult for patients and clinic staff alike and it is to the credit of the Patients and the Research Clinics that these studies have moved along and are either now published or in stages of publication. However, phase IV clinical trials and head-to-head evaluation of prophylactic and therapeutic approaches including cost benefit and quality of life are still lacking. To date, the clinical trials have been small and these data may change when larger trials are undertaken. For example, for many years Berinert (Berinert P in the past and now just called Berinert) has been used for therapy at doses of one or two vials (500 to 1000 units; close to 10 units per kg) in thousands of infusions and appear safe and appear to have successfully treated most HAE episodes with second infusions uncommon. However, when the small clinical phase III trial was conducted, results showed benefit from 20 units/kg but not 10 units/kg. Since this was the phase III clinical trial, dose licensing for this drug is 20 units/kg. This recommendation has great economic impact on the therapy of this disorder increasing the cost of treatment by considerable amount. It is essential for national and international networks of clinics to undertake phase IV clinical trials to retest this dose-finding. Plasma derivatives such as pdC1INH are precious resources donated from dedicated blood donors needing conservation when possible and such products are costly for individual patients or treatment programs. The extensive European clinical experience in hundreds of thousands of infusions would indicate a lower dose used early in a swelling event may suffice. With the availability of new non blood product treatments, these treatments need head-to-head comparison with the gold standard pdC1INH and each other so that patients and clinics and payers can make appropriate cost benefit quality of life based analyses to strengthen the evidence based recommendations for management of this disorder.

HAE-Type III has become recognized but whereas the genetic defect and pathophysiology of Types I and II are well worked out, the pathophysiology of Type III is still in its infancy. This group of manuscripts is meant to discuss the differential diagnosis of hereditary versus acquired angioedema, help understand the clinical differences and approaches to the three types of Hereditary Angioedema with nuances in females, pregnancy, pediatrics, and then adults. These manuscripts are from the presenters at the 2010 Consensus Conference held in Toronto Canada and represent some of the background for discussion for the patient and care teams present as they discussed the consensus algorithms. The Consensus Manuscript draft was discussed at the meeting and then circulated to the other international authors including patient groups and treatment team leaders. The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema is the result. We have chosen to publish in an on line open journal to allow wide and timely full free distribution of the consensus. We hope this generates further thoughts and discussions and that Dr. Cicardi will move the consensus forward to evidence-based approach as the various trials become published. This is but an algorithm approach in evolution changing as evidence becomes available. We look forward to the phase IV clinical phase and much larger clinical trials to further investigate the most cost effective approach leading to the best quality of life for all HAE patients.

I would like to congratulate the many Patients who participate in these very difficult clinical trials and further congratulate the clinic teams who undertake these stressful trials requiring 24/7 research team availability in this unpredictable swelling disorder HAE. There is much more work to do! Keep up the good work. I would like to thank the Canadian Society of Allergy and Clinical Immunology and the University of Calgary for taking HAE under their wing and supporting these international consensus meetings.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/13

Laurence Bouillet 07/2010 Allergy, Asthma & Clinical Immunology

Women with hereditary angioedema (HAE) are more likely to be symptomatic that men. Hormonal factors (puberty, contraception, pregnancy,….) play a significant role in the precipitation or worsening of the condition in women. So, combined contraceptive pills are not indicated and progestogen pill must be preferred. During pregnancy, attack rate can increase (38-48% of women). C1Inhibitor concentrate and tranexamic acid can be used during pregnancy. Attenuated androgens for long term prophylaxis are effective but side effects appear more often in female patients. These side effects are dose dependant and can be attenuated by titrating the dose down the lowest effective level.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/17

Maurer M, Magerl M. 9/2010 Journal der Deutschen Dermatologischen Gesellschaft

There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short-term prophylaxis before surgery, and long-term prophylaxis for those with frequent and severe attacks. In Germany, C1-INH concentrate and icatibant are licensed for acute therapy. C1-INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1-INH activity. This therapy, which has been available for decades, is effective and well-tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well-tolerated, even on repeated administration. An additional human C1-inhibitor, a recombinant human C1-inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long- and short-term prophylaxis. Androgen derivatives are established in long-term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1610-0387.2010.07450.x/full

11/2010 Prescrire International

Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.

Deeks ED. 01/2010 Drugs

Icatibant is a selective antagonist of the bradykinin type 2 receptor. In the randomized, double-blind, multicentre, FAST-1 trial, the difference in the median time to the onset of symptom relief (primary endpoint) did not reach statistical significance between a single dose of subcutaneous icatibant 30 mg and placebo in adults with moderate to very severe acute abdominal or cutaneous episodes of hereditary angioedema. However, icatibant was effective with regard to several other endpoints, providing significantly greater reductions from baseline in symptom severity scores 4 and 12 hours after administration, and eliciting significantly shorter times to both first symptom improvement and overall patient improvement than placebo. In the similarly designed, active comparator-controlled, FAST-2 trial, a single dose of subcutaneous icatibant 30 mg was associated with a significantly shorter median time to onset of symptom relief (primary endpoint) than oral tranexamic acid in adults with acute abdominal or cutaneous episodes of hereditary angioedema, and was also more effective than tranexamic acid in terms of most other endpoints. Across both FAST-1 and -2, the efficacy of subcutaneous icatibant 30 mg in the treatment of laryngeal episodes of hereditary angioedema was generally consistent with that seen for abdominal and cutaneous episodes, with a median time to first symptom improvement of 0.6-1.0 hours. Subcutaneous icatibant was generally well tolerated in adult patients with hereditary angioedema in the FAST trials, with the most common adverse events being injection-site reactions that were generally of mild severity, transient in nature and resolved spontaneously without treatment.

Available from: link.springer.com/article/10.2165%2F11204500-000000000-00000

Dubois EA, Cohen AF. 5/2010 British Journal of Clinical Pharmacology

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

Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, et al. 8/2010 New England Journal of Medicine

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.

METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.

RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.

CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.).

Available from: nejm.org/doi/full/10.1056/NEJMoa0906393#t=article

Lunn ML, Santos CB, Craig TJ. 3/2010 Annals of Allergy, Asthma, and Immunology

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency of C1 esterase inhibitor (C1 INH) protein or function. Guidelines do not exist regarding diagnostic criteria or routine testing of family members of patients with HAE. Laboratory data for diagnosis include complement factor 4 level; C1 INH antigenic protein level, which is reduced in approximately 85% of patients with HAE; and C1 INH functional assay, which is considered an unreliable test in the United States secondary to inconsistent standardization of assays.

OBJECTIVES: To assess the shortcomings of diagnosing HAE and to determine whether family members of patients with HAE are being adequately screened.

METHODS: The top physician prescribers of danazol in the United States were screened via an Internet questionnaire focusing on the diagnosis and current management of HAE. To assess the patient perspective on HAE, affected individuals in the United States, the United Kingdom, France, Germany, and The Netherlands participated in the Web-based International Survey of Patient Experience of Hereditary Angioedema.

RESULTS: All 80 physicians who completed the survey were allergist or immunologists with a mean of 7 patients with C1 INH deficiency in their practices. Almost 84% of physician respondents used C1 INH level and function for diagnosis, and 63.8% used complement factor 4 levels. A total of 313 patients with HAE completed the survey. Respondents noted that only 48% of immediate family members and 26% of extended family members had been tested.

CONCLUSION: Guidelines could potentially alleviate delays in diagnosis and incorrect diagnoses and could lead to adequate screening of family members.

Kaplan AP. /2010 Chemical Immunology and Allergy

Anaphylaxis is a term that implies symptoms that are present in many organs, some of which are potentially fatal. The pathogenic process can either be IgE-dependent or non-IgE-dependent; the latter circumstance may be referred to as anaphylactoid. Bradykinin is frequently responsible for the manifestations of IgE-independent reactions. Blood levels may increase because of overproduction; diseases such as the various forms of C1 inhibitor deficiency (hereditary or acquired) or hereditary angioedema with normal C1 inhibitor are examples in this category. Blood levels may also increase because of an abnormality in bradykinin metabolism; the angioedema due to ACE inhibitors is a commonly encountered example. Angioedema due to bradykinin has the potential to cause airway obstruction and asphyxia as well as severe gastrointestinal symptoms simulating an acute abdomen. Formation of bradykinin in plasma is a result of a complex interaction among proteins such as factor XII, prekallikrein, and high molecular weight kininogen (HK) resulting in HK cleavage and liberation of bradykinin. These proteins also assemble along the surface of endothelial cells via zinc-dependent interactions with gC1qR, cytokeratin 1, and u-PAR. Endothelial cell expression (or secretion) of heat-shock protein 90 or prolylcarboxypeptidase can activate the prekallikrein-HK complex to generate bradykinin in the absence of factor XII, however factor XII is then secondarily activated by the kallikrein that results. Bradykinin is destroyed by carboxypeptidase N and angiotensin-converting enzyme. The hypotension associated with IgE-dependent anaphylaxis maybe mediated, in part, by massive proteolytic digestion of HK by kallikreins (tissue or plasma-derived) or other cell-derived kininogenases.Copyright 2010 S. Karger AG, Basel. [References: 102].

Available from: karger.com/Article/Abstract/315938

Longhurst HJ. /2010 Vascular Health and Risk Management

Icatibant (Firazyr()) is a novel subcutaneous treatment recently licensed in the European Union for acute hereditary angioedema. Hereditary angioedema, resulting from inherited partial C1 inhibitor deficiency, is a disabling condition characterized by intermittent episodes of bradykinin-mediated angioedema. Icatibant blocks bradykinin B2 receptors, attenutating the episode. Randomized double-blind, placebo-controlled trials of icatibant, showed significant superiority over oral tranexamic acid in 74 European patients and a trend to improvement in a similar US trial comparing icatibant with placebo in 55 patients. Outcomes for several endpoints did not reach significance in the US trial, perhaps because of low participant numbers and confounding factors: a further trial is planned. Open label studies have shown benefit in multiple treatments for attacks at all sites. Approximately 10% of patients require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial treatment. Its subcutaneous route of administration, good tolerability and novel mode of action make icatibant a promising addition to the limited repertoire of treatments for hereditary angioedema.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC2941790/

Tom Bowen, John Brosz, Kristylea Brosz, Jacques Hebert and Bruce Ritchie 07/2010 Allergy, Asthma & Clinical Immunology

C1-inhibitor (C1-INH) deficiency is a rare blood disorder resulting in angioedema attacks that are debilitating and may be life-threatening. Prophylaxis and therapy of events has changed since our first Canadian Consensus Conference on the diagnosis, therapy and management of HAE. We have formed the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’Angioédème Héréditaire (RCAH) – www.haecanada.com website 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: aacijournal.com/content/6/1/20

Henriette Farkas 07/2010 Allergy, Asthma & Clinical Immunology

Hereditary angioedema is a rare disorder with a genetic background involving mutations in the genes encoding C1-INH and of factor XII. Its etiology is unknown in a proportion of cases. Recurrent edema formation may involve the subcutis and the submucosa – the latter can produce obstruction in the upper airways and thereby lead to life-threatening asphyxia. This is the reason for the high, 30-to 50-per-cent mortality of undiagnosed or improperly managed cases. Airway obstruction can be prevented through early diagnosis, meaningful patient information, timely recognition of initial symptoms, state-of-the-art emergency therapy, and close monitoring of the patient. Prophylaxis can substantially mitigate the risk of upper airway edema and also improve the patients’ quality of life. Notwithstanding the foregoing, any form of upper airway edema should be regarded as a potentially life-threatening condition. None of the currently available prophylactic modalities is capable of preventing UAE with absolute certainty.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/19

Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, et al. 8/2010 New England Journal of Medicine

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening.

METHODS: We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control.

RESULTS: In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling.

CONCLUSIONS: In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.).

Available from: nejm.org/doi/full/10.1056/NEJMoa0805538#t=article

Nagy N, Grattan CE, McGrath JA. 8/2010 Australasian Journal of Dermatology

Hereditary angio-oedema (HAE) is a rare but potentially life-threatening condition. Three types are now recognized. Types I and II HAE involve mutations in the C1NH (SERPING1) gene, encoding the C1 inhibitor protein, whereas type III HAE involves mutations in the F12 gene, encoding coagulation factor XII (Hageman factor). They share a common final pathway leading to increased bradykinin formation. HAE must be distinguished from acquired angio-oedema with C1 esterase inhibitor deficiency, angiotensin-converting enzyme inhibitor-induced angio-oedema and the much more common histaminergic angio-oedema, occurring with or without weals. Understanding the pathogenesis of HAE is leading to the introduction of new therapies that target the bradykinin receptor or inhibit kallikrein activity, innovations that will hopefully reduce morbidity and mortality in this group of severe genetic disease.

Faiyaz-Ul-Haque M, Al-Gazlan S, Abalkhail HA, Al-Abdulatif A, Toulimat M, Peltekova I, et al. 1/2010 International Archives of Allergy and Immunology

BACKGROUND: Autosomal dominant hereditary angioedema (HAE) results in episodes of subcutaneous edema in any body part and/or submucosal edema of the upper respiratory or gastrointestinal tracts. This disorder is caused by mutations in the C1NH gene, many of which have been described primarily in European patients. However, the genetic cause of HAE in Middle Eastern Arab patients has not yet been determined.

METHODS: Four unrelated Arab families, in which 15 patients were diagnosed with HAE, were studied. DNA from 13 patients was analyzed for mutations in the C1NH gene by DNA sequencing.

RESULTS: Three novel and 2 recurrent mutations were identified in the C1NH gene of HAE patients. In family 1, the patient was heterozygous for a novel c.856C>T and a recurrent c.1361T>A missense mutation encoding for p.Arg264Cys and p.Val432Glu, respectively. In patients from family 2, a novel c.509C>T missense mutation encoding for a p.Ser148Phe was identified. In patients from family 3, a novel c.1142delC nonsense mutation encoding for a p.Ala359AlafsX15 was discovered. In family 4, a recurrent c.1397G>A missense mutation encoding for a p.Arg444His was present.

CONCLUSION: This is the first ever report of C1NH gene mutations in Middle Eastern Arab patients. Our study suggests that, despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in HAE patients of non-European origin. We conclude that the spectrum of C1NH gene mutations in HAE patients is wider due to the likely presence of novel and recurrent mutations in patients of other ethnicities.Copyright 2009 S. Karger AG, Basel.

Available from: karger.com/Article/Abstract/236005

Emel Aygören-Pürsün, Inmaculada Martinez-Saguer, Eva Rusicke, Thomas Klingebiel and Wolfhart Kreuz 07/2010 Allergy, Asthma & Clinical Immunology

BACKGROUND: Manifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed.

METHODS: We describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany).

RESULTS: The HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment.

CONCLUSIONS: In conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/21

Henriette Farkas 07/2010 Allergy, Asthma & Clinical Immunology

Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor (C1-INH) is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children) may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/18

Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, von Hentig N, Klingebiel T, Kreuz W. 2/2010 Transfusion

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH).

STUDY DESIGN AND METHODS: This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate.

RESULTS: The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT.

CONCLUSIONS: pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.

Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. 8/2010 Annals of Allergy, Asthma, and Immunology

BACKGROUND: C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available.

OBJECTIVE: To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE.

METHODS: Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model.

RESULTS: The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h).

CONCLUSIONS: The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.Copyright 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Available from: annallergy.org/article/S1081-1206%2810%2900602-2/fulltext

Craig TJ, Wasserman RL, Levy RJ, Bewtra AK, Schneider L, Packer F, et al. 11/2010 Journal of Clinical Immunology

INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema that can be life-threatening if they occur in the laryngeal region. We assessed the efficacy of C1-INH concentrate in the emergency treatment of rarely occurring acute laryngeal HAE attacks in a prospective, open-label clinical study.

METHODS: Acute laryngeal attacks were each treated with C1-INH concentrate (Berinert) at a single dose of 20 U/kg body weight. Efficacy endpoints included time to onset of symptom relief and time to complete resolution of all symptoms, each based on the patient’s assessment.

RESULTS: All 39 laryngeal attacks in 16 patients were treated successfully. The median time to onset of symptom relief was 15 min. The median time to complete resolution of all symptoms was 8.25 h. No treatment-related serious adverse events occurred, and the treatment was well tolerated. The administration of C1-INH concentrate was not associated with any viral infections.

CONCLUSION: C1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC2970824/

Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, Visscher S, et al. 4/2010 Journal of Allergy and Clinical Immunology

BACKGROUND: Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE.

OBJECTIVE: Analysis of pooled study results.

METHODS: Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH.

RESULTS: rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. CONCLUSION: Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Available from: jacionline.org/article/S0091-6749%2810%2901128-0/fulltext

Cicardi M, Zanichelli A. 11/2010 Drugs of Today

Angioedema due to hereditary C1 inhibitor deficiency (HAE) is a highly disabling and potentially lethal disease with an estimated prevalence of 1:50,000 in the general population worldwide. Treatment of this condition by replacing the deficient protein started shortly after discovery of the underlying genetic defect. Along with other therapeutic approaches developed over the years, C1 inhibitor replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Two plasma-derived C1 inhibitors and a recombinant form, produced in transgenic rabbits, have successfully completed controlled trials that reinforced the evidence of the safety and efficacy of this treatment.Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Available from: europepmc.org/abstract/MED/21225025

Riedl M, Campion M, Horn PT, Pullman WE. 12/2010 Annals of Allergy, Asthma, and Immunology

BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, and potentially fatal disease characterized by acute attacks of swelling that can affect the abdomen/gastrointestinal tract, larynx, face, genitals, and extremities. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks.

OBJECTIVE: To examine the speed of effect of ecallantide vs placebo.

METHODS: Data were integrated from 2 randomized, double-blind, placebo-controlled phase 3 trials of ecallantide in patients with HAE. Eligible patients presented within 8 hours of onset of a moderate to severe HAE attack for 1:1 randomization to receive a single dose of 30 mg of subcutaneous ecallantide or placebo. End points included time to beginning of improvement, time to sustained overall improvement, and time to significant overall improvement.

RESULTS: A total of 143 participants (70 receiving ecallantide and 73 receiving placebo) were included. The distribution curves for time to beginning of improvement demonstrated a trend in favor of ecallantide vs placebo within 4 hours (P(log rank) = .09). For time to onset of sustained improvement, the difference in the distribution of the curves between the 2 groups reached significance by 2 hours after dosing (P(log rank) = .04). For time to significant overall improvement, the difference in the distribution of the curves reached significance in favor of ecallantide by 90 minutes (P(log rank) = .04). The beneficial effect of ecallantide was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks.

CONCLUSIONS: Ecallantide provides relief of acute HAE attack symptoms, with rapidity of response commensurate with therapeutic needs for HAE attack locations.Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Available from: annallergy.org/article/S1081-1206(10)00815-X/fulltext

Jiang H, Zhang HM, Frank MM. 9/2010 Clinical Immunology

Hereditary angioedema afflicts patients with unpredictable episodes of swelling that can be life threatening. Treatments approved by the Food and Drug Administration for routine prophylaxis include danazol given orally and the nanofiltered human C1 esterase inhibitor, CINRYZE, which is approved for intravenous administration. Approved for the treatment of acute attacks are the C1 esterase inhibitor, Berinert, given intravenously, and the kallikrein inhibitor, KALBITOR, given subcutaneously. C1 inhibitor has generally been non-toxic and neither pro-inflammatory nor pro-fibrotic, suggesting that it may be suitable for subcutaneous infusion. The current study used a swine model to compare blood levels of human C1 inhibitor following intravenous and subcutaneous infusion, and the effect of infusion route on heart and skin pathology. Levels of C1 inhibitor achieved with SC infusion compared favorably with levels achieved after IV infusion and were relatively more stable than those after IV infusion. Neither cardiac nor skin toxicity was observed.Copyright 2010 Elsevier Inc. All rights reserved.

Available from: sciencedirect.com/science/article/pii/S1521661610005784 (small fee)

Krassilnikova S, Craig ET, Craig TJ. 5/2010 Expert Review of Clinical Immunology

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by deficiency of C1 inhibitor (C1-INH) that commonly presents with recurrent swelling affecting different parts of the body. Supplementation with C1-INH is successfully used to treat HAE in selected countries, mostly in Europe. Berinert P (CSL Behring, Marburg, Germany), a human plasma-derived C1-INH, was studied in the International Multicenter Prospective Angioedema C1-inhibitor Trial 1 (IMPACT1) that was completed in 2007. It was the first safety and dose-finding study of C1-INH in patients with acute abdominal and facial angioedema. IMPACT2 was the extension of the first trial to study C1-INH efficacy and safety in multiple treatments of acute HAE attacks in various areas of the body. Berinert P has excellent potential to become a first-line therapy for treating patients with acute HAE attacks in the USA and other countries involved in the IMPACT trials. While final data from the IMPACT2 trial are not yet released, this article reviews currently available data from previous reports and abstract presentations.

Kaplan AP, Joseph K. 3/2010 Annals of Allergy, Asthma, and Immunology

OBJECTIVE: To review the mechanisms by which bradykinin is generated in hereditary angioedema (HAE) (C1 inhibitor deficiency), including the role of human plasma proteins and endothelial cells.

DATA SOURCES: Published articles in reviewed journals that address (1) the fundamentals of bradykinin formation, (2) interactions between kinin-forming proteins and endothelial cells, (3) clinical evidence that bradykinin causes swelling in HAE, and (4) therapeutic options focused on inhibition of the plasma kallikrein-kinin cascade.

STUDY SELECTION: Historical articles that have made fundamental observations. Recent articles that address evolving concepts of disease pathogenesis and treatment.

RESULTS: C1 inhibitor deficiency causes dysregulation of the plasma bradykinin-forming cascade with overproduction of bradykinin due to uninhibited effects of activated factor XII and plasma kallikrein. Swelling in HAE and production of bradykinin are localized (and may then disseminate); activation along the endothelial cell surface involves cell membrane ligands of factor XII and high-molecular-weight kininogen, release of endothelial cell heat shock protein 90, activation of the high-molecular-weight kininogen-prekallikrein complex, and endothelial cell activation at the B2 receptor. Attacks of swelling may be terminated by treatment with a kallikrein inhibitor or B2 receptor blockade. Replenishing C1 inhibitor can abort attacks of swelling and provide prophylaxis with intravenous administration.

CONCLUSIONS: Bradykinin is the mediator of swelling in types I and II HAE and is overproduced because of a deficiency in C1 inhibitor. Inhibition of bradykinin formation by novel agentscan provide targeted therapeutic approaches that address the pathophysiologic abnormalities. [References: 103].

Available from: annallergy.org/article/S1081-1206%2810%2900173-0/fulltext

Zilberberg MD, Jacobsen T, Tillotson G. 11/2010 Allergy and Asthma Proceedings

Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. HAE is frequently confused with angioedema (AE), and little is known about emergency department (ED) or hospital utilization by patients with attacks in the United States. We examined hospitalizations and ED utilization for HAE and AE in two large nationally representative databases. We evaluated annual rate and resource use of HAE (International Classification of Diseases, Version 9, Clinical Modification [ICD-9-CM] code 277.6) and AE (ICD-9-CM code 995.1) hospitalizations within Nationwide Inpatient Sample (NIS), part of the Agency of Healthcare Research and Quality’s Healthcare Costs and Utilization Project (AHRQ-HCUP), for 2007. We also used AHRQ-HCUP’s 2007 Nationwide Emergency Department Sample (NEDS) to study annual rates of ED visits and subsequent hospitalizations with these conditions. There were 1691 hospitalizations with HAE and 22,572 with AE (4.25 HAE and 57.08 AE cases/100,000 hospitalizations). HAE was the principal diagnosis (PD) in 46.0% and AE in 62.5%. In aggregate, HAE and AE PD hospitalizations accrued 35,000 hospital days and hospital costs of $63 million. There were 2282 ED visits with HAE and 112,105 ED visits with AE (1.87 HAE and 91.64 AE cases/100,000 ED visits). HAE occurred as a PD in 51.2% and AE occurred as a PD in 80.0%. Forty-five percent of HAE patients and 18.3% of AE patients required hospitalization. HAE and AE ED use and hospitalization burden are substantial. Because diagnostic uncertainty is likely, HAE-related proportion of patients and resource use are probably underestimated. Clinical validation of current case definition would be useful, because administrative data may present an attractive source for investigating these populations.

Available from: ingentaconnect.com/content/ocean/aap/2010/00000031/00000006/art00014

Farkas H, Czaller I, Csuka D, Vas A, Valentin S, Varga L, et al. 4/2010 The European Journal of Clinical Pharmacology

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients.

METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively.

RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study.

CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

Czaller I, Visy B, Csuka D, Fust G, Toth F, Farkas H. 10/2010 European Journal of Obstetrics, Gynecology, and Reproductive Biology

OBJECTIVE: The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE.

STUDY DESIGN: Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries.

RESULTS: HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed.

CONCLUSIONS: Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Available from: ejog.org/article/S0301-2115(10)00227-7/abstract

Emlen W, Li W, Kirschfink M. 9/2010 Seminars in Thrombosis and Hemostasis

Activation of the complement system significantly contributes to the pathogenesis of various acute and chronic inflammatory diseases. Current strategies to inhibit complement include the replacement or substitution of endogenous soluble complement inhibitors (e.g., C1 inhibitor [C1 inh], recombinant soluble complement receptor 1, TP10), the administration of antibodies to block key proteins of the cascade reaction (e.g., C5) or to neutralize the action of the complement-derived anaphylatoxins, or blockade of complement receptors (e.g., C5aR, CD88). The recent approvals of anti-C5 for the treatment of paroxysmal nocturnal hemoglobinuria as well as of C1 inh for the treatment of hereditary angioedema beyond European countries have provided a resurgence of interest in the potential of complement therapeutics for the treatment of disease.Copyright © Thieme Medical Publishers.

Available from: thieme-connect.com/DOI/DOI?10.1055/s-0030-1262888

Bas M, Greve J, Stelter K, Bier H, Stark T, Hoffmann TK, et al. 9/2010 Annals of Emergency Medicine

STUDY OBJECTIVE: The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema most likely resembles that of hereditary angioedema, ie, it is mainly mediated by bradykinin-induced activation of vascular bradykinin B2 receptors. We hypothesize that the bradykinin B2 receptor antagonist icatibant might be an effective therapy for ACEi-induced angioedema.

METHODS: Eight patients with acute ACEi-induced angioedema were treated with a single subcutaneous injection of icatibant. The outcome was assessed by the time to first improvement of symptoms, complete symptom relief, and drug safety. In addition, we retrospectively assessed the clinical course of 47 consecutive patients of our clinic with ACEi-induced angioedema.

RESULTS: First symptom improvement after icatibant injection occurred at a mean time of 50.6 minutes (standard deviation [SD] 21 minutes) and complete relief of symptoms at 4.4 hours (SD 0.8 hours). No patient received tracheal intubation, other drug treatment, tracheotomy, or a second icatibant injection. There were no adverse effects except erythema occurring at the injection site. In the historical comparison group treated with methylprednisolone and clemastine, the mean time to complete relief of symptoms was 33 hours (SD 19.4 hours). Some of these patients received a tracheotomy (3/47), were intubated (2/47), or received a second dose of methylprednisolone (12/47).

CONCLUSION: Although sample size limits the external validity of our results, the substantial decrease of time to complete symptom relief suggests that this new treatment is likely effective as a pharmacotherapeutic approach to treat ACEi-induced angioedema.Copyright (c) 2009 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

Available from: annemergmed.com/article/S0196-0644%2810%2900279-9/fulltext

Callie Dagen, Timothy J Craig 05/2010 Allergy, Asthma & Clinical Immunology

BACKGROUND: Hereditary Angioedema (HAE) is a rare, autosomal dominant (AD) disorder caused by a C1 esterase inhibitor (C1-inh) deficiency or qualitative defect. Treatment of HAE in many parts of the world fall short and certain items need to be addressed in future guidelines.

OBJECTIVE: To identify those individuals who should be on long-term prophylaxis for HAE. Additionally, to determine if prodromal symptoms are sensitive and specific enough to start treatment with C-1 INH and possibly other newly approved therapies. Also, to discuss who is appropriate to self-administer medications at home and to discuss training of such patients.

METHODS: A literature review (PubMed and Google) was performed and articles published in peer-reviewed journals, which addressed HAE prophylaxis, current HAE treatments, prodromal symptoms of HAE and self-administration of injected home medications were selected, reviewed and summarized.

RESULTS: Individuals whom have a significant decrease in QOL or have frequent or severe attacks and who fail or are intolerant to androgens should be considered for long-term prophylaxis with C1INH. Prodromal symptoms are sensitive, but non-specific, and precede acute HAE attacks in the majority of patients. Although the treatment of prodromal symptoms could lead to occasional overtreatment, it could be a viable option for those patients able to adequately predict their attacks. Finally, self-administration, has been shown to be feasible, safe and effective for patients who require IV therapy for multiple other diseases to include, but not limited to, hemophilia.

CONCLUSIONS: Prophylactic therapy, treatment at the time of prodromal symptoms and self-administration at home all should allow a reduction in morbidity and mortality associated with HAE.

The electronic version of this article is the complete one and can be found online at: aacijournal.com/content/6/1/11

Vitrat-Hincky V, Gompel A, Dumestre-Perard C, Boccon-Gibod I, Drouet C, Cesbron JY, et al. 10/2010 Allergy

BACKGROUND: Hereditary angio-oedema (HAE) has been associated with C1inhibitor deficiency. The first cases of type III HAE were described in patients with normal C1Inh antigenic protein level and function and normal C4 levels in 2000. This finding has been reported mostly in women with a family history and may be influenced by exogenous oestrogen exposure.

OBJECTIVES: The purpose of this article is to describe the clinical, biological and genetic characteristics of a French population suffering from type III HAE.

PATIENTS AND METHODS: We conducted a retrospective analysis of angio-oedema (AE) cases seen in the National Reference Centre of AE between 2000 and 2009.

RESULTS: We found 26 patients (from 15 unrelated families) with type III HAE. All but four were women and presented with typical AE attacks, exacerbated by pregnancy or oral contraceptives containing oestrogens (OC). We also found that 54.5% of women were worsened with oestrogen and 23% were oestrogen dependent. All patients improved on long-term prophylactic tranexamic acid treatment; some acute attacks improved with C1Inh concentrate infusion. All of the patients had normal C1Inh and C4 levels. C1Inh function was also normal, except in women receiving OC or during a pregnancy: transient, moderately low levels (32-74% of the normal range) were found in 18 patients tested (67%). No SERPING1 gene mutation was found. Six patients from three unrelated families were heterozygous for an F12 gene variant.

CONCLUSION: Diagnosis of type III HAE should be based on clinical (typical attacks, often hormonally influenced), laboratory (normal C1Inh antigenic protein) and genetic (F12 gene mutation) evidence.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2010.02368.x/full