The RAVE trial: Rituximab for ANCA-associated vasculitis [Classics Series]

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1. Rituximab is non-inferior to cyclophosphamide in inducing remission of severe ANCA-associated vasculitis.

2. There were no significant differences between the two groups in the rate of total, serious, or non-disease-related adverse events.

Original Date of Publication: July 15, 2010

Study Rundown: The combination of cyclophosphamide and glucocorticoid has long been the standard of treatment for ANCA-associated vasculitides. The RAVE trial demonstrated that rituximab was non-inferior to cyclophosphamide in inducing remission in severe ANCA-associated vasculitis, when used alongside glucocorticoids. Moreover, there were no significant differences between the two groups in the rates of total, severe, or non-disease-related adverse events. The authors noted that their trial only included patients with severe ANCA-associated vasculitis, thereby limiting its generalizability. Others have also criticized this trial for its short follow-up and point to the paucity of data regarding long-term efficacy and safety. Rituximab subsequently received approval from the Food and Drug Administration for use in treating certain ANCA-associated vasculitides. One group has also recommended the use of rituximab, while cautioning the lack of data regarding long-term effects.

Please click to read study in NEJM

In-Depth [randomized, controlled study]: The RAVE trial, published in 2010 in NEJM, was a randomized, double-blind, double-dummy, non-inferiority trial examining the efficacy of rituximab in inducing remission of severe ANCA-associated vasculitis. Patients were eligible if they had Wegner’s granulomatosis or microscopic polyangitis, positive serum assays for proteinase 3-ANCA or myeloperoxidase-ANCA and a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 3 or more. Both patients with new diagnoses and relapsing disease were eligible for the trial. Eligible participants were randomized to receive either rituximab (375 mg/m² IV weekly for 4 weeks) or cyclophosphamide (2 mg/kg, with adjustments for renal insufficiency) with a subsequent switch to azathioprine if remission was achieved between 3-6 months. Both groups were also treated with glucocorticoids (i.e., 1-3 pulses of methylprednisolone, with subsequent prednisone tapered according to symptomology). The primary endpoint was a BVAS/WG score of 0 and successful completion of prednisone taper at 6 months.

A total of 197 patients with ANCA-associated vasculitis were enrolled in the trial. Approximately 64% of patients in the rituximab group and 53% of the patients in the cyclophosphamide group reached the primary endpoint, and this treatment difference met the criterion for non-inferiority (P<0.001). The difference between the two groups, however, was not statistically significant. There were no significant differences between the groups in the rates of total, severe, or non-disease-related adverse events.

By Adrienne Cheung, Andrew Cheung, M.D.

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