RAVE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are the two major forms of systemic vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA); collectively they are termed ANCA-associated vasculitis (AAV). Conventional therapy for AAV (cyclophosphamide and glucocorticoids for remission induction, then azathioprine for remission maintenance) is associated with a high percentage of treatment failures, disease relapses and toxicity. An underlying mechanism for AAV is thought to be pathogenic B cells that express the CD20 antigen. The destruction of these B cells with rituximab, a monoclonal antibody specific for CD20, (plus glucocorticoids) may restore tolerance to ANCA antigens and ameliorate disease. This is a multi-center, double-blind, placebo controlled trial to determine the efficacy and safety of rituximab (plus glucocorticoids) compared with conventional treatment for severe AAV. Two hundred participants will be randomized in a 1:1 ratio to the experimental arm or the control arm. The common closing date will be 18 months after the last participant is enrolled. Taking into account the recruitment period of 30 months, the total duration of the treatment phase of the trial will be 48 months. The primary objective is to determine the efficacy of rituximab (375 mg/m2, four weekly infusions) and glucocorticoids in the induction of remission. Other objectives include comparing the safety profiles, remission durations, and other differences between treatment groups, to demonstrate superiority of the experimental arm, to determine if patients who received the experimental therapy achieved clinical tolerance, and to determine the effect of rituximab on markers of inflammation and specific immune parameters.