n engl j med 350;21 w ww .n ejm. or g m ay 20, 2004 The new england journal of medicine 2167 review article drug therapy Alastair J.J. Wood, M.D., Editor New Drugs for Rheumatoid Arthritis Nancy J. Olsen, M.D., and C. Michael Stein, M.B., Ch.B. From the Divisions of Rheumatology (N.J.O., C.M.S.) and Clinical Pharmacology (C.M.S.), Departments of Medicine (N.J.O., C.M.S.), Pharmacology (C.M.S.), and Mi- crobiology and Immunology (N.J.O.), Va nderbilt University School of Medicine, Nashville. N Engl J Med 2004;350:2167-79. Copyright © 2004 Massachusetts Medical Society. heumatoid arthritis affects approximately 1 percent of the U.S. population and can cause irreversible joint deformities and functional im- pairment. The cause of this autoimmune disease remains obscure, but greater understanding of the underlying mechanisms has facilitated the development of new drugs and revolutionized treatment. 1 Specific CD4+ T cells are involved in the induction of the immune response in rheu- matoid arthritis, most likely as a response to an unknown exogenous or endogenous antigen. Consequently, recruited monocytes, macrophages, and fibroblasts produce cytokines such as tumor necrosis factor a (TNF- a ) and interleukin-1 within the synovial cavity. These cytokines are central to a damaging cascade, ultimately triggering the pro- duction of matrix metalloproteinases and osteoclasts, which results in irreversible dam- age to soft tissues and bones. The occurrence of B-lymphocyte dysregulation is suggest- ed by the association of erosive disease with the presence of rheumatoid factor, which mediates further damage through complement fixation (Fig. 1). 2 Several new drugs have become available for the treatment of rheumatoid arthritis (Table 1), and in this article, we review their properties. Both the short-term efficacy and the toxic effects of new drugs for rheumatoid arthritis are usually evaluated in clinical trials of 6 to 12 months’ duration. Improvement is most often defined by an outcome measure of the American Co llege of Rheumatology (ACR) called the ACR 20. 3 The ACR 20 is defined as a reduction by 20 percent or more in the number of tender and swollen joints plus similar improvement in at least three of the following five measures: pain, global assessments by the patient and the physician, self-assessed physical disability, and levels of acute-phase react ant. Two other outcome measures that are deemed to be more clinically relevant, the ACR 50 (improvement of 50 percent or more) and the ACR 70 (improvement of 70 percent or more), are also often reported. 4,5 All the drugs we discuss below appear to be more effective than placebo and to slow the progression of disease as measured radiologically. 6-9 These medications are thus classified as disease-modifying antirheumatic drugs. The immunomodulatory drug leflunomide, an isoxazole derivative, is a competitive in- hibitor of dihydroorotate dehydrogenase, the rate-limiting intracellular enzyme re- quired for the de novo synthesis of pyrimidines. 10 Resting lymphocytes can derive pyri- midines from salvage pathways, but activated lymphocytes are dependent on the de novo synthesis of pyrimidines. Therefore, blockade of the pyrimidine-synthesis pathway has antiproliferative effects. In vitro, relatively high concentrations of leflunomide (5 ¡ 10 M) r measuring response to drugs in rheumatoid arthritis leflunomide Downloaded from www.nejm.org on May 3, 2009 . Copyright © 2004 Massachusetts Medical Society. All rights reserved.
