[Hereditary angioedema and its new treatments: An update]. / Mise au point sur les angiœdèmes héréditaires et leurs nouvelles thérapeutiques.

Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.

Fatal hymenoptera venom anaphylaxis by undetected clonal mast cell disorder: A better identification of high risk patients is needed.

Hymenoptera venom anaphylaxis is the most frequent cause of anaphylaxis and responsible for about 20% of all fatal anaphylaxis cases in adults. We report two cases of fatal hymenoptera venom anaphylaxis with undiagnosed underlying mastocytosis and review the risk factors for severe or fatal hymenoptera venom anaphylaxis, as well as the specificities of its association with mastocytosis. As hymenoptera venom allergic patients with underlying clonal mast cell disorder generally lack typical skin lesions of mastocytosis, its diagnosis can easily be missed, underscoring the importance and need for diagnostic strategies in order to correctly identify these patients. Predominant cardiovascular symptoms in the absence of urticaria or angioedema following an insect sting are suggestive of underlying clonal mast cell disorder, and should be distinguished from panic attack or vasovagal syncope. Similarly, an unexplained syncope or an "idiopathic" anaphylaxis might reveal mastocytosis or hereditary alpha-tryptasemia. Acute and basal serum tryptase measurements should always be integrated in the diagnostic work-up of an insect sting reaction or unexplained syncope or shock of any origin.

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment]. / Angiœdèmes par déficit acquis en C1-inhibiteur : recommandations du CREAK pour le diagnostic et la prise en charge.

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

Angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study.

BACKGROUND: Bradykinin-mediated angioedema (AE) is a complication associated with thrombolysis for acute ischemic stroke. Risk factors are unknown and management is discussed. OBJECTIVES: To clarify risk factors associated with bradykinin-mediated AE after thrombolysis for acute ischemic stroke. METHODS: In a case-control study conducted at a French reference centre for bradykinin angiœdema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angiœdema, were compared to controls treated with thrombolysis treatment without angiœdema. RESULTS: Fifty-three thrombolysis-related AE were matched to 106 control subjects. The sites of attacks following thrombolysis for ischemic stroke mainly included tongue (34/53, 64%) and lips (26/53, 49%). The upper airways were involved in 37 (70%) cases. Three patients required mechanical ventilation. Patients with bradykinin-mediated angiœdema were more frequently women [33 (62%) vs. 44 (42%); P = 0.01], had higher frequency of prior ischemic stroke [12 (23%) vs. 9 (8%); P = 0.01], hypertension [46 (87%) vs. 70 (66%); P = 0.005], were more frequently treated with angiotensin-converting enzyme inhibitor [37 (70%) vs. 28 (26%); P < 0.001] and were more frequently hospitalized in intensive care medicine [ICU; 11 (21%) vs. 5 (5%); P = 0.004]. In multivariate analysis, factors associated with thrombolysis-related AE were female sex [odds ratio (OR), 3.04; 95% confident interval (CI), 1.32-7.01; P = 0.009] and treatment with angiotensin-converting enzyme inhibitors [(OR), 6.08; 95% (CI), 2.17-17.07; P < 0.001]. CONCLUSIONS: This case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykinin AE associated with thrombolysis for ischemic stroke.

Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.

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.

Chronic urticaria and hormones: Is there a link?

BACKGROUND: While the role of oestrogens in bradykinin angioedema (AE) has been clearly demonstrated, scarce data are available about the role of sex hormones in chronic urticaria (CU). OBJECTIVES: To gather information from a population of women with various forms of CU [chronic spontaneous urticaria (CSU), including a subtype of isolated histaminic AE and a classic subtype of association of wheals and AE, and exclusive inducible urticaria (IU)] about the impact of sex hormones and reproductive factors on their symptoms. METHODS: This was a cross-sectional study comprising interviews of 200 women consulting for CU at nine centres throughout France between May and July 2013. The dermatologists filled in an online questionnaire on the impact of reproductive factors (puberty, contraception and pregnancy) and hormonal treatments on the course of CU, including CSU and IU, in the presence of the women. RESULTS: Most of the women did not experience CU before puberty and if so, puberty did not influence the course of CU. Only 16 women had experienced a pregnancy during CU which caused a worsening of symptoms in four. Hormonal contraception was associated with aggravation in a minority of women, mostly women with CSU (10%). Women with isolated histaminic AE did not exhibit any female sex hormone dependency. CONCLUSIONS: It would appear that sex hormones act as a trigger in only a small subset of women with CU. Nevertheless, this should be taken into account to improve patient management.

[Angioedema and urticaria]. / Les angiœdèmes dans l'urticaire.

Angiœdema (AE) is the clinical expression of urticaria (U) which occurs when urticaria is located within the subcutis. It is a syndrome characterized by a sudden and limited subcutaneous and/or submucous swelling. The updated classification of urticaria distinguishes acute and chronic urticaria. Chronic urticaria is spontaneous (CSU) or inducible (CIU). Angioedema in chronic urticaria is rarely allergic, but most of the time caused by a non-specific histamine release from activated mast-cell (non IgE mediated reaction). Angioedemas are recurrent, concomitant or not with wheals. They appear skin-coloured, sometimes slightly rosy, non-inflammatory, and more painful than itchy. They are transient, ephemeral, migrant, last most of the time a few hours (< 24 or 48h) and disappear without after-effects. They are considered "deep urticaria" and wheals "superficial urticaria". When AE or wheals last more than 6 weeks (with or without free intermission), it is called chronic urticaria. Angioedema can be elicited or worsened by physical factors (cold urticaria, exercise, heat, solar, vibratory, aquagenic, delayed pressure urticaria…) and /or drugs (as aspirin, nonsteroid anti-inflammatory drugs, morphine, antibiotics…). The treatment of histaminergic angioedemas of chronic urticaria is based on modern second generation antihistamines (anti H1). In allergic acute urticaria only, additional treatment for anaphylaxis can be used if needed (grade 2 to 4). In chronic urticaria, steroids should be avoided : they can make symptoms worse and long-lasting because of corticosteroid dependence.

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.

Benefits of progestin contraception in non-allergic angioedema.

BACKGROUND: Hereditary angioedema attacks can be induced or worsened by oral contraceptive containing oestrogens. OBJECTIVES: The purpose of this study was to assess the impact of progestin contraceptives on angioedema attacks. METHODS: We conducted a French retrospective, multi-centre study of progestin contraception in women with non-allergic angioedema, including hereditary angioedema type I, II and III and idiopathic angioedema. Patients were classified into four groups according to frequency of attacks. We evaluated the effects of progestin on the mean number of attacks and compared the number of patients in each group before and under progestin contraception. The influence of hormonal factors on the course of angioedema was also assessed. RESULTS: Fifty-five women were included: mean age was 32.1 years (16-52) and mean follow-up 32.4 months (SD:29). Fourteen women were classified as type I (25.4%), two as type II (3.6%) and 19 as type III (34%) and 20 were idiopathic (36%). Seventeen patients were taking a low dose progestin-only pill (POP), 24 antigonadotropic progestins (AGP) and 14 both successively. Total or partial improvement was observed in 81.8% (45/55) of the patients and more frequently in those on an AGP agent (34 patients, 89.5%) than on POP (19 patients, 61.3%) (P = 0.013). CONCLUSIONS & CLINICAL RELEVANCE: This is the first study evaluating the interest of antigonadotropic progestin contraception in a series of women with non-allergic angioedema. Progestins, especially antigonadotropic progestins, appear to convey a marked benefit in most cases. Antigonadotropic progestins could thus be recommended as adjuvant treatment in childbearing women with non-allergic angioedema.

[Management of angiotensin-converting enzyme inhibitor-related angioedema: recommendations from the French National Center for Angioedema]. / 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.

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.

[Management of bradykinin-mediated angioedema]. / Prise en charge en urgence de l'angiœdème à bradykinine.

OBJECTIVES: Present the clinical signs of bradykinin-mediated angioedema, a disease little known to intensive care anaesthesiologists, and develop their scientific basis with recent data on management in emergency and perioperative care. DATA SOURCES: International recommendations and recent general reviews. Data collection was performed using the Medline database with the keyword: angioedema. STUDY SELECTION AND DATA EXTRACTION: Research studies published during the last 10 years were reviewed. Relevant clinical information was extracted and discussed. DATA SYNTHESIS: Angioedema is a clinical syndrome characterized by episodes of transitory recurrent submucosal and subcutaneous oedema, called attacks. During an attack, the oedema may be localized at the level of the skin and/or ENT and digestive tract mucosa. This syndrome is not due to an allergic reaction. It is related to a C1 complement inhibitor deficiency or an increase in factor XII resulting in the excessive release of bradykinin, which leads to capillary permeability. There are hereditary and acquired forms, notably associated with the use of ACE inhibitors and sartans. This rare disease should be recognized by anaesthesiologists and intensive care and emergency physicians because, in the absence of specific treatment, it can be life-threatening due to the appearance of laryngeal oedema. In addition, there is a risk that the patient may have an attack during the perioperatory period, due to surgical trauma. International recommendations exist, and there are new molecules available in France. For moderate attacks, treatment is based on tranexamic acid. For hereditary forms, according to the localization and gravity of the attacks, emergency treatment is based on the use of Icatibant, a bradykinin B2 receptor inhibitor, and C1 inhibitor concentrate. For pregnant women and acquired forms, C1 inhibitor concentrate is the treatment of reference. Antalgic and perfusion treatments should not be neglected, and should be modified as a function of clinical signs. High-risk situations (perioperatory period, birthing, dental care) should be identified and short-term prophylaxis put in place before any procedure that may trigger an attack. Algorithms are proposed for the diagnosis, treatment and prevention of attacks. Recommendations exist for during childbirth, in which case C1 inhibitor concentrate should be used. CONCLUSION: Bradykinin-mediated angioedema should be evoked in the case of recurrent and transitory oedema. Emergency management has evolved thanks to the commercialization of new molecules. Prevention of attacks during surgery and for during childbirth is important. The availability of C1 inhibitor concentrate in sufficient doses should be verified prior to the procedure. A multi-site reference centre (CREAK) has been created to help clinicians manage this disease. Patients with this disease should be identified in emergency departments. Health establishments, which cannot all have emergency stocks, should set up procedures for rapid provision or the transfer of patients to reference sites.

[Bradykinin mediated angioedema]. / Les angiœdèmes bradykiniques héréditaires ou acquis.

Bradykinin angioedema (AE) are characterized by acute recurrent episodes of localized swelling. They are not associated with pruritus or erythema, and are short-lived (24 to 72 hours), disappearing without any sequelae. Corticosteroids are useless. Skin or mucous membranes (upper respiratory and intestinal) could be affected. Bradykinin AE can be secondary to: (1) AE associated with C1 inhibitor deficiency (hereditary or acquired); (2) drug-induced AE (converting enzyme inhibitors…); (3) type III AE type (oestrogen dependant) without C1 inhibitor deficiency. These type III AE can be associated with a gain of function mutation that markedly increases factor XII activity. Prognosis depends on the laryngeal attacks (resulting in 25 % of death in the absence of specific treatment). In case of severe attacks, icatibant (bradykinin receptor antagonist) or C1 inhibitor concentrate can be used. In case of frequent attacks, long-term therapy with danazol or tranexamic acid is effective.

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

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.