RITUXIMAB THERAPY FOR THE INDUCTION REMISSION AND TOLERANCE IN ANCA-ASSOCIATE

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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. The primary objectives of this study are to determine the effect of rituximab on remission induction in patients with ANCA associated vasculitis as compared with conventional therapy and to compare the safety profile of rituximab with conventional therapy. Other aims include to determine if rituximab will induce a lasting effect after remission induction, thereby maintaining remission after rituximab is discontinued (clinical tolerance), and to determine the effect of rituximab on specific immune parameters through a series of detailed mechanistic studies. Wegener's granulomatosis (WG) and microscopic polyangiitis are the two major forms of systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). The incidence of these disorders in the US is about 6,000 new cases per year, with the estimated prevalence at 25 - 30,000. These conditions are termed ANCA-associated vasculitides (AAV) because of their strong associations with these hightly specific autoantibodies. AAV are autoimmune disorders in which tolerance for one of two self-antigens (proteinase 3 (PR3) or myeloperoxidase (MPO), has been lost, leading to the production of PR3-ANCA or MPO-ANCA. Clinical observations indicate that endothelial injury and tissue damage are dependent upon the proinflammatory effects of ANCA that result from the interaction of these specific antibodies with their target antigens on the surface of activated neutrophils and monocytes. There is preliminary evidence that anti-CD20 therapy (rituximab) may reestablish tolerance to the ANCA target antigens. If untreated, the outcome of AAV is death. Conventional therapies are associated with a high percentage of treatment failures, disease relapses and substantial toxicity. The study is a randomized, multicenter, doublemasked, placebo controlled trial. A total of 228 participants will be randomized 1:1 to either the control arm or the experimental arm. Patients in both treatment arms will receive a 3 day intravenous pulse of methylprednisolone followed by prednisone. During the remission induction phase, the control arm will receive weekly rituximab placebo infusions (times 4) and daily cyclophosphamide (CYC) for between 3 and 6 months, followed by azathioprine (AZA) for 12 months in the remission maintenance phase. During the remission induction phase, the experimental arm will receive weekly rituximab infusions (times 4) and daily CYC placebo for 3 - 6 months, followed by AZA placebo for 12 months in the remission maintenance phase. Patients who are defined as treatment failures (within the first 6 months after randomization) will be crossed over to the other treatment arm.