ObjectiveWe aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab.Methods192 patients with AAV were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0.Results95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim–sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections.ConclusionsWe found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim–sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections.

This regimen is potentially superior to current standards of care, and controlled studies are warranted to establish the utility of combination drug approaches in the treatment of AAV.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an organ-threatening and life-threatening multi-system autoimmune disease in which B cell-derived ANCAs cause neutrophil activation and endothelial damage, strongly implicating these autoantibodies in the pathogenesis of AAV. B cell depletion with rituximab combined with glucocorticoids is associated with a reduction in ANCA concentrations and with clinical remission in the majority of patients with AAV. However, the safety profile of rituximab is no better than that of conventional therapy with cyclophosphamide, and long-term glucocorticoid treatment is needed to achieve and maintain disease-free remission. A need for new therapies exists to reduce the time to remission, to spare the use of glucocorticoids and to promote long-lasting remission without the risk of relapse. Over the past 20 years, there has been great interest in therapeutically targeting B cell cytokines, such as B cell-activating factor (BAFF), in many autoimmune disease settings. Dual B cell-targeted immunotherapy that combines B cell depletion and BAFF blockade could potentially be more efficacious than targeting either mechanism alone. In this Review, the theoretical background for use of this combination approach in AAV is presented and discussed.

Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.