Isabelle Boccon-Gibod

Disease expression in women with hereditary angioedema

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.

Type III hereditary angio-oedema: clinical and biological features in a French cohort

To cite this article: Vitrat‐Hincky V, Gompel A, Dumestre‐Perard C, Boccon‐Gibod I, Drouet C, Cesbron JY, Lunardi J, Massot C, Bouillet L. Type III hereditary angio‐oedema: clinical and biological features in a French cohort. Allergy 2010; 65: 1331–1336.

BRADYKININ RECEPTOR 2 ANTAGONIST (ICATIBANT) FOR HEREDITARY ANGIOEDEMA TYPE III ATTACKS

In 2000, a new type of hereditary angioedema (HAE) without C1 esterase inhibitor (C1-INH) deficiency, HAE type III, was reported.1,2 It occurred especially in women, and the diagnosis was based on recurrent attacks of subcutaneous or submucosal edema, no chronic relapsing urticaria, familial history, and normal C1INH protein and activity levels. Recent findings3 suggest that bradykinin may play a role in the pathogenesis of angioedema. The morbidity and mortality of HAE are related to abdominal attacks and laryngeal edema. Symptoms seem to be induced or worsened by estrogen.4 In these patients, C1-INH function is normal, and a missense gain-of-function mutation in the F12 gene can be found.5 Treatments for HAE type III are not established, but tranexamic acid seems to be effective for prophylaxis of symptoms. Until recently, the main shortterm treatment for severe HAE attacks was C1-INH concentrate.4 A new therapeutic agent, icatibant, a bradykinin B2 receptor antagonist, is effective for the treatment of HAE with C1-INH deficiency. The efficacy and safety of icatibant in patients with HAE (type I or II) presenting with moderate to severe cutaneous or abdominal attacks were tested in 2 double-blind, randomized, multicenter, phase 3 trials, FAST (For Angioedema Subcutaneous Treatment) 1 and 2.6 We report treatment outcomes in 3 women who fulfilled the diagnosis criteria of HAE type III (Table 1). Patients presented with recurrent severe abdominal attacks, edema of the face, and a family history of angioedema. The C1-INH function was moderately low when the patients took an estrogen-containing contraceptive pill or during pregnancy but was normal after it was discontinued or after delivery. We previously described these data in another patient with HAE type III.7 Levels of C1-INH protein and C4 were normal. All 3 patients had no mutation in the SERPING1 gene. Patient 1 had an identified mutation in the F12 gene. Patient 1 received 1 subcutaneous injection of icatibant, 30 mg, for a severe abdominal attack. Symptom improvement began 30 minutes later, with complete resolution of symptoms by 1 hour after icatibant administration. Patient 2 presented with an unusual severe abdominal attack combined with facial edema. An increase in her dose of tranexamic acid did not improve symptoms. She received an injection of icatibant. Symptoms were relieved within 2 hours. Patient 3 was treated for a severe abdominal attack. After the first injection of icatibant, relief of symptoms occurred within 30 minutes. Symptom recurrence after 6 hours necessitated a second injection of icatibant, which resulted in rapid alleviation of symptoms. For all the patients, icatibant administration was followed by a transient local erythematic reaction at the site of injection. No other adverse reactions to icatibant were noted in the 3 patients. We therefore conclude that icatibant is a safe and effective symptomatic treatment for severe attacks in patients with HAE type III.

Diagnosis and treatment of bradykinin-mediated angioedema: Outcomes from an angioedema expert consensus meeting

Several types of angioedema exist beyond hereditary angioedema (HAE) types I/II; however, the diagnostic and treatment needs of these conditions are not well understood. Noticeably, there are no licensed treatments available for other forms of angioedema beyond HAE types I/II, and similarly they are unresponsive to conventional antihistamine/glucocorticoid treatment. A group of angioedema experts met in Budapest in May 2013 to discuss such issues, presenting their experience, reviewing available literature and identifying unmet diagnostic and treatment needs in three different angioedema types: HAE with normal C1-inhibitor (C1-INH; previously referred to as type III HAE); nonallergic angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (ACEI-AAE), and acquired angioedema due to C1-INH deficiency (C1-INH-AAE). The group identified unmet diagnostic and treatment needs in HAE-nC1-INH, C1-INH-AAE and ACEI-AAE, explored remedies and made recommendations on how to diagnose and treat these forms of angioedema. The group discussed the difficulties associated with using diagnostic markers, such as the level and function of C1-INH, C1q and C4 to reliably diagnose the angioedema type, and considered the use of genetic testing to identify mutations in FXII or XPNPEP2 that have been associated with HAE-nC1-INH and ACEI-AAE, respectively. Due to the lack of approved treatments for HAE-nC1-INH, ACEI-AAE and C1-INH-AAE, the group presented several case studies in which therapies approved for treatment of HAE types I/II, such as icatibant, ecallantide and pasteurized, nanofiltered C1-INH, were successful. It was uniformly agreed that further studies are needed to improve the diagnosis and treatment of angioedema other than HAE types I/II. i 2014 S. Karger AG, Basel

Safety and efficacy of icatibant self‐administration for acute hereditary angioedema

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.

Prise en charge des angiœdèmes induits par les inhibiteurs de l’enzyme de conversion de l’angiotensine : recommandations du Centre de référence national des angiœdèmes

Angiotensin-converting enzyme (ACE) inhibitor-related angioedema (AE) may be fatal in the absence of specific treatment. No consensus for this side effect currently exists. Also, the French national reference centre for angioedema (CREAK) decided to establish recommendations, developed by an expert group and proposed at a national meeting. A scientific committee conducted a comprehensive literature review and worked out with proposals. These proposals were submitted to a vote to the expert panel of CREAK at a national meeting. Proposals that had received the majority were retained. Diagnosis of ACE inhibitor-related AE is based on clinical events. Regarding the severity of the disease, this diagnosis has to be put forward in any patient currently treated with or who has been treated with ACE inhibitors in the previous 6 months. The diagnosis is important because AE does not respond to usual treatment of histamine-induced AE (antihistamines, corticosteroids, and epinephrine), but only to specific treatment of bradykinin-induced AE, as antagonists of bradykinin or concentrates of C1 inhibitor. The subsequent use of ACE is strictly contra-indicated. A report to pharmacovigilance centres of every case is essential. These recommendations should improve the standardization of the management of ACE inhibitor-related AE.

Tranexamic acid as maintenance treatment for non-histaminergic angioedema: analysis of efficacy and safety in 37 patients.

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.

Current Status of Implementation of Self-Administration Training in Various Regions of Europe, Canada and the USA in the Management of Hereditary Angioedema

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.

A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients.

Abstract Acquired angioedema (AAE) due to C1-inhibitor (C1INH) deficiency is rare. Treatment options for acute attacks are variable and used off-label. Successful treatment of the associated lymphoma with rituximab seems to prevent acute attacks in subjects with AAE. The aim of this study was to describe AAE manifestations, its associated diseases, and patients’ responses to treatments in a representative cohort. A retrospective nationwide study was conducted in France. The inclusion criteria were recurrent angioedema attacks and an acquired decrease in functional C1INH <50% of the reference value. A total of 92 cases were included, with a median age at onset of 62 years. Facial edema and abdominal pain were the most frequent symptoms. Fifteen patients were hospitalized in the intensive care unit because of laryngeal edema, and 1 patient died. Anti-C1INH antibodies were present in 43 patients. The associated diseases were primarily non-Hodgkin lymphoma (n = 44, with 24 splenic marginal zone lymphomas) and monoclonal gammopathy of undetermined significance (n = 24). Three patients had myeloma, 1 had amyloid light-chain (of immunoglobulin) (AL) amyloidosis, 1 patient had a bronchial adenocarcinoma, and 19 patients had no associated disease. Icatibant relieved the symptoms in all treated patients (n = 26), and plasma-derived C1INH concentrate in 19 of 21 treated patients. Six patients experienced thromboembolic events under tranexamic acid prophylaxis. Rituximab prevented angioedema in 27 of 34 patients as a monotherapy or in association with chemotherapy. Splenectomy controlled AAE in 7 patients treated for splenic marginal zone lymphoma. After a median follow-up of 4.2 years, angioedema was on remission in 52 patients. AAE cases are primarily associated with indolent lymphoma—especially splenic marginal zone lymphoma—and monoclonal gammopathy of undetermined significance but not with autoimmune diseases or other conditions. Icatibant and plasma-derived C1INH concentrate control attacks; splenectomy and immunochemotherapy prevent angioedema in lymphoma setting.

Idiopathic histaminergic angioedema without wheals: a case series of 31 patients.

Idiopathic histaminergic acquired angioedema (IH‐AAE) is a common cause of recurrent angioedema without wheals. It is a mast cell‐mediated disease thought to belong to the same clinical entity as chronic urticaria (CU). The objective of this study was to describe the clinical and epidemiological characteristics of IH‐AAE patients. From 2014 to 2015, 534 patients were seen at our national reference centre for angioedema and/or urticaria. Among them, we identified 31 patients with idiopathic histaminergic acquired angioedema without wheals (IH‐AAE). Thirty‐one patients (15 men and 16 women) with a mean age of 50 years met the criteria for IH‐AAE. The average delay in diagnosis was 6·3 years. A history of allergy was found in 12 patients (38·7%), nine suffering from allergic rhinitis. The mean duration of attacks was 28·1 h. The AE attack was located in the upper respiratory tract in 54·8% of cases (17 patients). A lingual location was found in 29% of patients. Men were more likely than women to have an upper airway involvement. No intubations or admissions to intensive care units were reported. The dosage of anti‐histamines to control the symptoms was onefold the recommended dose in 51·6% of patients (16 patients), twofold in 32% (10 patients) and three–fourfold in 16·1% (five patients). IH‐AAE is characterized by an important delay in diagnosis, a frequent involvement of the upper airway and a benign course during attacks. As in CU, a trial of up to fourfold dose of H1‐anti‐histamines may be necessary to control symptoms.