RITUXIMAB IN SUBJECTS WITH MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS

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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. Hypothesis: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that occurs primarily in women of childbearing age. It is characterized by multi-system involvement and gross immunological abnormality where much of the tissue damage is thought to occur through autoantibody formation and immune complex deposition. The disease is heterogenous in its clinical presentation, course, and prognosis. However, most patients present with joint involvement, skin rashes, mouth ulcers, Raynaud's phenomenon, and/or severe fatigue. Inflammation of pericardial and pleural tissues may also be present. Serious manifestations include central nervous system and renal involvement. Typically, the disease follows a relapsing-remitting course, with a variety of flare rates. Three major patterns of the disease have been reported in longitudinal cohorts: relapsing-remitting, chronic activity, and long quiescence. Medications for the treatment of SLE are limited, and no new medication for lupus has been approved in the past 30 yrs. The mainstay of therapy continues to be corticosteroids for flares of moderate to severe disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids, and other immunosuppressive agents such as Cyclophosphamide, Azathioprine or 6-Mercaptopurine, Methotrexate (MTX), and Mycophenolate Mofetil (MMF) are used alone or in combination for the many manifestations of this disease. This study involves a new therapeutic approach which investigates the role of B-cells in SLE symptomology. B-cells are central to SLE through autoantibody-dependent mechanisms and mechanisms that are common to all manifestations of SLE, including lupus nephritis (LN). Several autoantibodies are correlated with end organ damage. Goals: The primary objective of this study is to assess the efficacy of Rituximab compared with placebo in achieving and maintaining a major clinical response (MCR) or partial clinical response (PCR) in subjects with moderate to severe SLE. The secondary objectives of this study (comparing Rituximab with placebo) will be to evaluate the following: ability of Rituximab to decrease overall SLE disease activity as measured by time-adjusted area under the curve minus baseline (AUCMB) scoring with the British Isles Lupus Assessment Group BILAG assessment over 52 weeks; ability of Rituximab to induce MCRs (excluding PCRs) or PCRs (including MCRs); safety and tolerability of rituximab; ability of Rituximab-treated subjects to achieve a BILAG C or better at week 24; ability of Rituximab to prolong the time to a moderate or severe flare; ability of Rituximab to improve quality of life as measured by SLE Expanded Health Survey (SF-36 index with additional elements specific to lupus); corticosteroid-sparing in subjects receiving Rituximab; and pharmacokinetics of rituximab in subjects with SLE. Experimental Design: This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of Rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe SLE. The primary efficacy endpoint of the trial will be evaluated at 52 weeks. The study will enroll subjects at approximately 55 centers in the United States. Subjects will be randomized in a 2:1 ratio to receive Rituximab + Prednisone or placebo + Prednisone. Randomized subjects will receive intravenous (IV) study drug ¿ 2 separated by 15 days that is repeated at 6 months. In addition, subjects will receive 100 mg IV Solumedrol 30-60 min prior to each study drug (Rituximab or placebo) infusion.