Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Diagnosis and treatment of upper airway oedema caused by acute angio-oedema in the emergency department: a French consensus statement.

Angio-oedema is a transitory, localized, noninflammatory oedema of subcutaneous tissue or mucous. When the oedema affects the mouth, lips, tongue or larynx, it can result in fatal asphyxiation in the absence of specific treatment. Oedema secondary to plasma extravasation is usually mediated by either histamine or bradykinin. As laboratory tests are not available in an emergency setting, the implicated mediator cannot be readily determined. The challenge for the emergency physician is to determine the aetiological type, evaluate severity and initiate adapted treatment by means of a structured approach. A team of experts from the French Reference Centre for Angio-oedema reached a consensus for recommendations for the diagnostic and therapeutic strategy to be adopted by emergency departments faced with angio-oedema of the upper airways in adults. The experts defined 11 important questions. Responses were rated using a two-round Delphi methodology. The 11 recommendations were related to triage on admission, a step-by-step diagnostic protocol, definition of attack severity, discouragement of instrumental examination, prioritization of treatment for severe attacks according to clinical signs and anticipation of access to specific treatments by the hospital. Angio-oedema of the upper airways can be fatal and requires anticipation by the emergency department. A search for the aetiology, an evaluation of clinical symptoms and the availability of the treatments are challenges justifying these recommendations.

Bradykinin-mediated angioedema: factors associated with admission to an intensive care unit, a multicenter study.

OBJECTIVE: Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life-threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU. PATIENTS AND METHODS: We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission. RESULTS: Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4±5 days). One death was observed by asphyxiation because of laryngeal swelling. CONCLUSION: Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe.

Cutaneous Adverse Drug Reactions with Antimalarials and Allergological Skin Tests.

BACKGROUND: Currently used antimalarial drugs (AM) are hydroxychloroquine and chloroquine, which are prescribed for many autoimmune disorders. The value of skin tests on cutaneous adverse drug reactions (CADR) with AM remains unknown. OBJECTIVE: The main objective of this retrospective study is to know whether skin tests for AM are useful and how to manage the recovery of AM therapy in these patients. METHODS: All patients referred for suspected CADR secondary to AM between 2001 and 2014 in eight French dermatology centers were retrospectively reviewed. RESULTS: We report herein a retrospective series of 20 patients with CADR and AM involvement. Skin tests, performed in 14/20 patients, were negative in all cases. Six patients had an oral provocation test with recurrence of CADR in 1 case. CONCLUSION: We encourage dermatologists to perform oral provocation tests in nonsevere CADR in order to allow AM rechallenge at progressive doses.

Acquired C1-inhibitor deficiency: 7 patients treated with rituximab.

BACKGROUND: Acquired C1-inhibitor deficiency can occur secondary to excessive C1-inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported. METHODS: Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I. RESULTS: Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment. CONCLUSION: Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles.

A three-year-analysis of fixed drug eruptions in hospital settings in France.

Fixed drug eruption (FDE) is one of the most typical cutaneous drug adverse reactions. This localized drug-induced reaction is characterized by its relapse at the same sites. Few large series of FDE are reported. The aim of this study was to retrospectively collect and analyse well informed cases observed in a hospital setting. This study involved 17 academic clinical centers. A French nation-wide retrospective multicentric study was carried out on a 3-year-period from 2005 to 2007 by collecting data in seventeen departments of dermatology in France. Diagnosis of FDE was based essentially on clinical findings, at times confirmed by pathological data and patch-testing. Records were reviewed for demographics, causative drugs, localization, severity, and patch-tests, when available. Fifty nine cases were analysed. Patients were 59-years-old on average, with a female predilection. The most common drug was paracetamol, followed by the non-steroidal anti inflammatory drugs. The time between drug intake and skin symptoms was, on average, two days. Beside these classical characteristics, some original findings were found including, a frequent non pigmentation course and a sex-dependent pattern of distribution. Women often had lesions on the hands and feet, and men on the genitalia. Given the fact that skin pigmentation is an inconstant feature of FDE, its French name (erythème pigmenté fixe) should be reconsidered. The sex-dependent distribution could help our understanding of the pathophysiology of fixed drug eruption.

Polymyositis and pemphigus vulgaris in a patient: successful treatment with rituximab.

Rituximab has been documented to be an effective treatment for autoimmune diseases with contribution of B cells. We report a case of antisynthetase syndrome with a history of EBV-induced lymphoma which developed a pemphigus vulgaris. Rituximab was effective both on polymyositis and on pemphigus. Fifteen months later, the patient died from a septic shock after the first cyclophosphamide infusion for amyloidosis while the B cell population remained depleted. Rituximab may be a good alternative to immunosuppressive drugs in polymyositis and pemphigus especially in lymphoma-risk patients. However, it did not prevent progression to secondary amyloidosis and the fatal infection developed in this patient raises the question of whether a prolonged B cell depletion with rituximab contributes to a greater risk of infection.