A nationwide study of acquired C1-inhibitor deficiency in France

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.

Case report presenting the diagnostic challenges in a patient with recurrent acquired angioedema, antiphospholipid antibodies and undetectable C2 levels

“…AAE is uncommon. However, recently series have reported the presentation, associations and responses to treatment in large cohorts of patients with AAE [2, 7, 12]. This patient, in addition to having AAE, met the Sapporo Criteria for the diagnosis of Antiphospholipid Syndrome [13].…”

“…The failure to detect an IgG anti-C1 inhibitor is not surprising since 30% of patients with acquired C1 inhibitor deficiency have undetectable anti-C1 inhibitor antibodies [15]. A limitation of our case presentation is that we were not able to check for IgA or IgM anti-C1 inhibitor antibodies, which can be present in AAE [7]. …”

“…The most common lymphoma associated with cases of AAE, is splenic marginal zone lymphoma [7, 12]. However, the most frequent type of lymphomas associated with C1 inhibitor deficiency, symptomatic or not, in a case series of patients with lymphoma was diffuse large B cell lymphoma [16].…”

“…The prevalence of AAE has been estimated to be around 1: 600,000 [2]. The association of AAE with APS has been reported rarely [3–6], though its association preceding or following MGUS (monoclonal gammopathy of undetermined significance) and lymphomas is a common one [7]. Low serum C2 and C4 levels have been frequently found in AAE since the disease was first reported in the literature [8].…”

The Lung in Dysregulated States of Humoral Immunity

“…By contrast, shortened survival was reported in patients with IgM-related systemic amyloidosis as a complication of cardiac or renal involvement [169,171,172]. These observations justify comprehensive evaluation to distinguish peritumoral amyloidosis from systemic AL, as the therapeutic approach is different [175]. …”