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Trials treating human rheumatic diseases with biologic agents and drugs that selectively affect B cells will be reviewed. Rituximab, an anti-CD20 monoclonal mouse/human antibody, will be the primary focus of the review because it has been widely used in several autoimmune and rheumatic conditions, but the limited studies on other reagents such as anti-BlyS, anti-CD154, and B cell tolerogens will also be covered.The single most important recent development was the completion of a randomized, double-blind, placebo-controlled trial of rituximab in methotrexate-resistant rheumatoid arthritis. In this trial, B cell depletion with rituximab led to a sustained clinical response with an impressive improvement in America College of Rheumatology 50% response (ACR 50) at both 24 and 48 weeks. Additional open studies of rituximab showing clinical benefit in systemic lupus erythematosus, cryoglobulinemia, antineutrophil cytoplasmic antibodies+ vasculitis, and dermatomyositis are noteworthy but must be interpreted with caution until randomized control trials are available. Two well-designed studies of anti-CD154 antibodies in systemic lupus erythematosus were reported. Unfortunately, one was halted because of unexpected vascular complications, and the other failed to show any beneficial clinical effect. A phase I study using anti-BlyS in SLE demonstrated a selective effect on B cells and no overt toxicity, but in this very short-term study no effect on serology or clinical activity was seen. Two B cell tolerogens have been used in human trials. The first tolerogen, directed at anti-dsDNA responses in SLE, did significantly decrease titers of high-affinity anti-dsDNA antibodies but had no clinically beneficial effect overall. A phase I trial of a tolerogen directed at anti-β2-glycoprotein I antibodies demonstrated a decrease in antibody titers after a single injection.Several therapeutic agents targeting B cells have now been tested or are being tested in human trials. The success of rituximab in a well-controlled trial confirms previous preliminary reports indicating that B cell depletion can treat established autoimmune disease.