Systemic lupus erythematosis is a multi-system autoimmune disease characterized by numerous autoantibodies. These autoantibodies may be responsible for most, and possibly all, of the disease manifestations. While numerous defects and abnormalities of the immune system both, innate and acquired, and endogenous and exogenous, have been described the final common denominator is aberrant antibody production by B lymphocytes. There are compelling arguments to support interventions aimed at reducing B lymphocyte function and/or number. Observations that support this concept are that cyclophosphamide is a is a B cell predominant chemotherapeutic agent that is highly effective in SLE, that intravenous immunoglobulin is effective therapeutically for SLE and down regulates B lymphocyte activity, that both HIV disease and anti- CD4 reduce lupus activity, and that when patients with SLE develop common variable immunodeficiency their SLE is improved. A therapeutic approach that selectively diminished B lymphocyte function or number might be a useful intervention to treat patients with SLE. Because immunoglobulin deficiency is easily reversed by pooled immunoglobulin which is not toxic (and might be somewhat therapeutic) targeted B cell therapy might be moth effective and well tolerated. Current efforts in this same direction using antibodies to the CD40 ligand are underway in a multi-center trial sponsored by Biogen and a second trial at University of San Francisco sponsored by IDEC. The CD40/GP 39 is a co-stimulatory interaction necessary for an immune response. Bon contrast, the anti-CD20 antibody is directed at a pan B cell marker and a directly inhibitory to B cells in part by antibody dependent cellular cytotoxicity. In both in vitro and in vivo studies the anti-CD20 is more effective than CD40 antibody in B cell lymphoma and should be a more effective inhibitor of B cell function. We plan an open label phase 2 trial of rituximab a chimeric anti-CD20 antibody (IDEC-C2B8) in the treatment of severe but not life threatening systemic lupus erythematosis. Patents will have failed conservative management and be candidates for cytotoxic and chemotherapeutic intervention. We will monitor disease activity by convention indices (SLEDAI and SLAM), immunologic markers of disease activity such as complement components and acute phase reactants, hematological parameters and renal function. These outcome measures will permit us to make an initial assessment of the safety and efficacy of this agent for the treatment of systemic lupus erythematosis. With these finding we will be able to plan a randomized double blind placebo controlled trial of anti- CD20 therapy for SLE.