BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Background Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti–interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis. Methods In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed. Results A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥ 24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies. Conclusions In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889.)

Background The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is unknown. Methods In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. Results A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide–azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. Conclusions In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

Objective. To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).Methods. Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.Results. We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.Conclusion. This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to the recommendations within this guideline to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient's individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions, and drug formularies or other third-party analyses that cite ACR guidelines should state this. These recommendations cannot adequately convey all uncertainties and nuances of patient care.

Objective. To determine the clinical features and optimal treatment of subglottic stenosis (SGS) in patients with Wegener's granulomatosis (WG). Methods.Review of 43 patients with SGS and treatment of 20 patients with intratracheal dilationglucocorticoid injection therapy.Results. SGS developed in 43 of 189 patients with WG who were followed up at the National Institutes of Health Clinical Center. The diagnosis of SGS occurred in the absence of other features of active WG in 21 of 43 patients (49%). In 21 patients (49%), SGS began while the patient was receiving systemic immunosuppressive therapy for disease activity involving other sites. Tracheostomy was required in 10 of 18 patients (56%) who were treated with systemic immunosuppressive therapy. In 20 patients treated with intratracheal therapy, none required tracheostomy and 6 with previous tracheostomies were decannulated.Conclusion. SGS often occurs independently of other features of active WG and is frequently unresponsive to systemic immunosuppressive therapy. Intratracheal dilation-injection therapy provides a safe and effective treatment for WG-associated SGS and, in the absence of major organ disease activity, should be used