Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis A Randomized Trial Pierre Charles, MD; E ´ lodie Perrodeau, MSc; Maxime Samson, MD, PhD; Bernard Bonnotte, MD, PhD; Antoine Ne´ el, MD, PhD; Christian Agard, MD, PhD; Antoine Huart, MD; Alexandre Karras, MD, PhD; Franc¸ ois Lifermann, MD; Pascal Godmer, MD; Pascal Cohen, MD; Catherine Hanrotel-Saliou, MD; Nicolas Martin-Silva, MD; Gre´ gory Pugnet, MD, PhD; Franc¸ ois Maurier, MD; Jean Sibilia, MD, PhD; Pierre-Louis Carron, MD; Pierre Gobert, MD; Nadine Meaux-Ruault, MD; Thomas Le Gallou, MD; Ste´ phane Vinzio, MD; Jean-Franc¸ ois Viallard, MD, PhD; Eric Hachulla, MD, PhD; Christine Vinter, MD; Xavier Pue´ chal, MD, PhD; Benjamin Terrier, MD, PhD; Philippe Ravaud, MD, PhD; Luc Mouthon, MD, PhD; and Loı ¨c Guillevin, MD; for the French Vasculitis Study Group* Background: Biannual rituximab infusions over 18 months ef- fectively maintain remission after a “standard” remission induc- tion regimen for patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Objective: To evaluate the efficacy of prolonged rituximab ther- apy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18- month maintenance regimen. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522) Setting: 39 clinical centers in France. Patients: 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. Intervention: Rituximab or placebo infusion every 6 months for 18 months (4 infusions). Measurements: The primary end point was relapse-free sur- vival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. Results: From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival es- timates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respec- tively, an absolute difference of 22% (CI, 9% to 36%) with a haz- ard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse–free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occur- ring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events devel- oping among 4 patients [9%]). No deaths occurred in either group. Limitation: Potential selection bias based on previous rituximab response and tolerance. Conclusion: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. Primary Funding Source: French Ministry of Health and Hoffmann–La Roche. Ann Intern Med. 2020;173:179-187. doi:10.7326/M19-3827 Annals.org For author, article, and disclosure information, see end of text. This article was published at Annals.org on 2 June 2020. * Other investigators and members of the French Vasculitis Study Group who participated in the study are listed in Supplement 1 (available at Annals.org). T he prognosis of antineutrophil cytoplasmic anti- body (ANCA)-associated vasculitis (AAV) has dra- matically improved with the advent of glucocorticoid treatment and immunosuppressant or rituximab induc- tion therapy (1). Such regimens lead to remission in 53% to 88% of patients with AAV (2, 3), but relapse rates re- main high, making maintenance therapy necessary (4). Prolonged therapy with azathioprine was once rec- ommended to maintain AAV remission, because a ran- domized trial showed lower relapse rates with long-term azathioprine therapy compared with the standard-length regimen (5). In 2014, the MAINRITSAN (Maintenance of Remission Using Rituximab in Systemic ANCA-Associated Vasculitis) trial reported the clear superiority of rituximab over azathioprine in maintaining remission (6), which influ- enced AAV treatment guidelines (7). The therapeutic schedule of 500 mg of rituximab infused on days 0 and 14, then at months 6, 12, and 18, is now recommended by the U.S. Food and Drug Administration and European Medicines Agency to maintain AAV remission. However, the MAINRITSAN trial showed that relapses after discon- tinuation of rituximab treatment were frequent, with a 57.9% relapse-free survival rate 32 months after the last rituximab infusion (8). The MAINRITSAN3 trial was designed to evaluate the efficacy of prolonging the rituximab infusion sched- ule to maintain remission in patients who achieve com- See also: Editorial comment ......................... 235 Summary for Patients ....................... I-18 Web-Only Supplement Annals of Internal Medicine ORIGINAL RESEARCH © 2020 American College of Physicians 179