SHORT ANALYTICAL REVIEW B cell depletion therapy in systemic rheumatic diseases: Different strokes for different folks? William Stohl a, * , R. John Looney b a Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, 2011 Zonal Avenue HMR 711, Los Angeles, CA 90033, USA b Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA Received 26 February 2006; accepted with revision 22 March 2006 Available online 11 May 2006 Abstract Autoantibodies have, until recently, been the overriding focus of investigators of autoantibody-associated diseases. Increasing attention is now being paid to B cells, which not only are the producers of autoantibodies but also contribute to autoimmune disease via autoantibody-independent mechanisms. Therapeutic measures that target B cells for depletion are gaining in popularity. In this review, we will focus on two distinct approaches of depleting B cells; one employing a direct-kill approach by engagement of B cell surface CD20 with an anti- CD20 monoclonal antibody (rituximab), and the other employing an indirect starvation approach by neutralization of B lymphocyte stimulator (BLyS), a potent B cell survival factor. Among the systemic immune-based rheumatic disorders, we will focus on rheumatoid arthritis and systemic lupus erythematosus, two disorders for which therapeutic B cell targeting is being intensely investigated. D 2006 Elsevier Inc. All rights reserved. Introduction It has long been appreciated that many disease states are associated with circulating autoantibodies. In several of them (e.g., myasthenia gravis, Graves’ disease, Goodpas- ture’s syndrome), the autoantibodies are unequivocally pathogenic. However, as our global understanding of auto- immune diseases expands, it has become increasingly clear that not all autoantibodies are created equal. Although the presence of a circulating autoantibody characteristic of a given disorder may indicate pathogenicity of that autoanti- body, the presence of a circulating autoantibody does not ipso facto prove the autoantibody’s pathogenicity. A striking example of this is rheumatoid factor (RF). Whereas circu- lating RFs were widely felt 40 years ago to be central to development of rheumatoid arthritis (RA), it subsequently became as widely felt that RFs were strictly epiphenomena (albeit useful clinical markers) with essentially no direct role in disease pathogenesis. Of note, interest in a 1521-6616/$ — see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2006.03.010 * Corresponding author. Fax: +1 323 442 2874. E-mail address: stohl@usc.edu (W. Stohl). KEYWORDS B cells; B lymphocyte stimulator (BLyS); Rheumatoid arthritis; Rituximab; Systemic lupus erythematosus Clinical Immunology (2006) 121, 1—12 available at www.sciencedirect.com www.elsevier.com/locate/yclim