Soluble Mediators as Therapeutic Targets in Systemic Lupus Erythematosus: Cytokines, Immunoglobulin Receptors, and the Complement System Kyriakos A. Kirou, MD, DSc a,b , Jane E. Salmon, MD a,b , Mary K. Crow, MD a,b, * a Weill Medical College of Cornell University, New York, NY, USA b Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY, USA After many years of anticipation, we have entered a period of promise for new lupus therapies, with several clinical trials planned or in progress. The accelerated activity in systemic lupus erythematosus (SLE) therapeutics has been driven by scientific advances. Enhanced understanding of the cells and mediators that drive autoimmunity and tissue damage has led to the identification of rational thera- peutic targets. The conventional immunosuppressive therapies, including cortico- steroids and cyclophosphamide, can be effective but at a high and unacceptable cost of adverse effects. There is high optimism that targeted therapies, including those that are specific for soluble mediators, will allow effective control of dis- ease activity while sparing patients the damaging toxicities that are associated with traditional immunosuppressive agents. Cytokines and soluble mediators of inflammation have been the target of suc- cessful intervention in other chronic autoimmune inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis, and the spondyloarthropathies. In these diseases, it seems that tumor necrosis factor (TNF) plays a central role in pathogenesis by stimulating a proinflammatory cascade that involves other cytokines and mediators. As a result, TNF inhibitors have enabled physicians to 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.rdc.2005.12.001 rheumatic.theclinics.com T Corresponding author. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: crowm@hss.edu (M.K. Crow). Rheum Dis Clin N Am 32 (2006) 103– 119