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.

Figure 1

Cumulative record of localization of angioedema attacks over time among patients with AAE—general cohort and subgroups according to associated disease. A patient frequently has different localizations along time. χ² test was applied for comparison between lymphoid malignancy, monoclonal gammopathy, and no associated disease subgroups. AAE = acquired angioedema.

Figure 2

Rituximab administration and response of AAE. A response was defined as no attacks or a decrease of attack frequency of >50% during the 6 months following administration or introduction of rituximab. AAE = acquired angioedema, anti-C1INH = anti-C1INH antibody, C1INH = C1-inhibitor, MGUS = monoclonal gammopathy of undetermined significance, n = number of patients, RA = rheumatoid arthritis.

Figure 3

Attack-free survival among patients with acquired angioedema with anti-C1INH antibodies and patients with acquired angioedema without anti-C1INH antibodies. Kaplan–Meier analysis of survival without attacks among 41 patients with acquired angioedema without anti-C1INH antibodies (white circle line) and 40 patients with acquired angioedema with anti-C1INH antibodies (black circle line), for whom data were available; log-rank test P = 0.045. C1INH = C1-inhibitor.