John Stone | Johns Hopkins University | Baltimore, MD

Johns Hopkins University | Baltimore,MD

Mayo Clinic College of Medicine | Rochester,MN

University of California, San Francisco | San Francisco,CA

Cleveland Clinic | Cleveland,OH

University of Groningen | Groningen,

Boston University | Boston,MA

University of Alabama, Birmingham | Birmingham,AL

Duke University Medical Center | Durham,NC

Hospital for Special Surgery | New York,NY

Objectives: We will conduct a randomized, double-masked, placebo-controlled trial of rituximab, an anti-CD20 antibody, in ANCA-associated vasculitis (AAV). The trial has two major hypotheses:

1. B cell depletion by rituximab induces stable remissions in AAV by re-establishing B cell tolerance to the ANCA target antigens
2. Rituximab is as effective as the conventional treatment regimen for induction and maintenance of disease remission, and offers substantial advantages over standard therapy by virtue of its superior side-effect profile

Rationale: Activated B cells and autoantibodies to the target antigens proteinase or myeloperoxidase (ANCA) have been implicated in the pathogenesis of AAV. ANCA are produced by B cells and/or plasma cells. Rituximab effectively eliminates B cells for 6-12 months. Without their B cell precursors, short-lived plasma cells disappear after about 2 weeks. Thus, rituximab can be used to suppress antibody production and to disrupt other critical B cell contributions to disease. Treatment of AAV with rituximab should eliminate both the potentially pathogenic B cells and the disease-amplifying ANCA. Our preliminary data indicate rituximab is effective in inducing stable remission of AAV and that B cells returning after such therapy are tolerant to the ANCA target antigens in at least two thirds of patients.

Significance: Rituximab’s narrow spectrum of action provides novel opportunities to study the role of tolerance loss to the ANCA antigens in this disease. In addition, by challenging existing paradigms about conventional treatment (which is both toxic and unsuccessful in restoring tolerance), the proposed trial may may lead to a new standard regimen that is substantially safer.

Relevance to Immune Tolerance: Lessons from this trial and its mechanistic studies will vastly enhance our understanding of the pathogenesis of AAV by determining the conditions under which B cell tolerance can be restored. The findings may have important implications for many other autoimmune diseases.

Protocol summary: To test our hypotheses, we will perform a randomized, multi-center, double-masked, placebo-controlled trial in patients with generalized AAV. We will randomize 197 patients to either: 1) conventional treatment (cyclophosphamide and corticosteroids, followed by azathioprine); or 2) rituximab (plus corticosteroids, initially) for remission induction. The primary clinical comparison will be the ability of rituximab and corticosteroids to induce disease remissions, as measured by the cumulative disease activity at 6 months. Consistent with the standard duration of treatment for AAV, patients in the conventional therapy arm will receive cyclophosphamide for up to 6 months followed by azathioprine, to complete a total length of treatment of 18 months. In order to assess the ability of rituximab to restore B cell tolerance, patients in both arms of the trial will be followed for a total of 18 months.