Mechanisms of Response and Relapse in Rituximab-treated Myositis Patients

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Autoimmune (AI) inflammatory muscle diseases (myositis) include polymyositis (PM), adult dermatomyositis (DM) and juvenile dermatomyositis (JDM). These rare diseases cause significant morbidity and can lead to death. One of the more novel treatments for myositis as well as other autoimmune diseases is B cell depletion (BCD) therapy with a biologic agent, rituximab. We studied rituximab in a recently completed clinical trial in myositis termed the Rituximab in Myositis (RIM) Study. The RIM Study is the first and largest controlled clinical trial ever performed in AI inflammatory muscle disease. The mechanism(s) by which rituximab improves myositis and other AI diseases is unclear and this study proposes to determine rituximab's mechanism of action in myositis. By doing so, we will not only learn how BCD works in myositis, but also the mechanism by which it improves AI disease in general. The studies proposed in this application will be completed using specimens that were prospectively collected from the RIM cohort of 200 myositis patients; the RIM cohort included both adult and pediatric patients with myositis (PM, DM and JDM). In conjunction with the specimens collected, valuable clinical information was also obtained so that the laboratory results from the experiments that are performed can be correlated with accurate, prospectively collected clinical data to provide us with an unmatched dataset in myositis. The immune system is affected in all AI diseases and this study proposes to examine the three major arms of the immune system and how rituximab affects T cell, B cell and innate immune responses. In this way, this proposal will also determine the relevant abnormal immune mechanisms that mediate myositis. PUBLIC HEALTH RELEVANCE (provided by applicant): Inflammatory muscle diseases including polymyositis, adult dermatomyositis and juvenile dermatomyositis cause significant health problems and can lead to death. Recent studies indicate that rituximab is an effective therapy for myositis patients. This application will determine the mechanisms by which rituximab works using samples collected from myositis subjects treated with rituximab in the RIM study.