Efficacy of remission-induction regimens for ANCA-associated vasculitis

Abstract

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.)

Figure 1. Randomization and Follow-up at 6, 12, and 18 Months

Patients were randomly assigned, in a 1:1 ratio, to the receive rituximab or cyclophosphamide–azathioprine. Shown are the numbers of patients who remained in the original treatment groups at 6, 12, and 18 months and the reasons that some patients discontinued the original treatment regimen before each time point. Patients could have had more than one protocol-defined reason for treatment change. Early treatment failure was defined as a lack of improvement or a worsening of disease activity before month 1. Patients crossed over to the opposite treatment group if they had a severe disease flare between month 1 and month 6. Patients were switched to a nonstudy therapy if it was deemed necessary according to best medical judgment. Patients were dropped from the study if they withdrew voluntarily or died. Open-label therapy, which was initiated in the case of a severe relapse, consisted of open-label rituximab and glucocorticoids.

Figure 2. Kaplan–Meier Plots of the Risk of Disease Relapse after Complete Remission

Panel A shows the time to the first disease relapse after complete remission according to treatment group (rituximab [RTX] or cyclophosphamide–azathioprine [CYC–AZA]). Panel B shows the time to the first disease relapse after complete remission according to baseline type of antineutrophil cytoplasmic antibody (ANCA) (proteinase 3–ANCA [PR3] or myeloperoxidase-ANCA [MPO]). Panel C shows the time to the first disease relapse after complete remission according to baseline type of ANCA in each treatment group. Panel D shows the time to the first disease relapse after complete remission among patients with a diagnosis of granulomatosis with polyangiitis (GPA) who were also positive for proteinase 3–ANCA and had a severe relapse at baseline, as compared with all other patients in each treatment group. In Panels C and D, the overall P values are for the comparison of the four patient groups, whereas the other P values are for the comparisons between the two treatment groups within each defined patient subgroup. For additional details, see https://www.itntrialshare.org/RAVE18mos/Fig2.html.