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Rheumatoid Arthritis: Anticytokine Therapies on the Horizon
- William J. Koopman, MD; and
- Larry W. Moreland, MD
- The University of Alabama at Birmingham; Birmingham, AL 35294 Grant Support: In part by National Institutes of Health grant R1AR44384A. Dr. Koopman is a principal investigator for studies sponsored by Sankyo, Inc., and has participated in clinical trials sponsored by Centocor, The Immune Response Corporation, and Immunex. Dr. Moreland is the Director of the Arthritis Clinical Intervention Program at The University of Alabama at Birmingham; has been a principal investigator for clinical trials sponsored by several pharmaceutical companies; and has been a consultant for Alexion Pharmaceuticals, Amgen, Biomatrix, Boehringer Ingelheim, Centocor, Connectics, Glaxo-Wellcome, Immunex, Knoll-BASF, Pharmacia/Upjohn, Schering-Plough Research Institute, Searle, SmithKline Beecham, TAP Holdings, and Wyeth. Requests for Reprints: William J. Koopman, MD, Department of Medicine, The University of Alabama at Birmingham, 402 Diabetes Education and Research Building, 1808 Seventh Avenue South, Birmingham, AL 35294-0012.
The agents currently used to treat aggressive rheumatoid arthritis, the so-called disease-modifying antirheumatic drugs, were generally not developed for that purpose. At best, they reduce the destructive component of the disease modestly and inconsistently.
Although the cause of rheumatoid arthritis remains unknown, recent advances in molecular technology have facilitated the identification of distinct cell subsets, cell surface markers, and cell products that contribute to the inflammatory and destructive components of the disease. This enhanced understanding affords new opportunities to direct specific therapies at relevant disease molecules and cells. In particular, increasing evidence implicates interleukin-1 and tumor necrosis factor-α (TNF-α) as major contributors to the inflammatory and destructive manifestations of rheumatoid arthritis and, therefore, as promising targets for improved therapy.
In this connection, several natural endogenous inhibitors of interleukin-1 and TNF-α have been identified, including interleukin-1 receptor antagonist, soluble interleukin-1 receptors, and soluble TNF-α receptors. These natural inhibitors are present in normal persons. Although increased levels of these inhibitors are found in serum specimens and at sites of inflammation in patients with rheumatoid arthritis, interleukin-1 and TNF-α are present in excess relative to the amounts of their respective inhibitors, a balance that favors the proinflammatory actions of these cytokines. An obvious potential approach to treating rheumatoid arthritis is thus to simply neutralize the cytokines that are suspected of producing the damage.
Studies in animal models of arthritis have provided support for this approach. Interleukin-1 and TNF inhibitors have been shown to alleviate established collagen-induced arthritis [2, 3]. Mice that are transgenic for the human TNF-α gene develop spontaneous chronic inflammatory arthritis, and treating these mice with anti-TNF monoclonal antibody or recombinant soluble TNF receptor fusion proteins abrogates the arthritis [4, 5].
Although interleukin-1 and TNF-α have many overlapping biological properties, each may have distinct roles in the pathogenesis of …
