ARTHRITIS & RHEUMATISM Vol. 44, No. 9, September 2001, pp 1977–1983 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc. REVIEW Demyelinating and Neurologic Events Reported in Association With Tumor Necrosis Factor  Antagonism By What Mechanisms Could Tumor Necrosis Factor  Antagonists Improve Rheumatoid Arthritis but Exacerbate Multiple Sclerosis? William H. Robinson, 1 Mark C. Genovese, 1 and Larry W. Moreland 2 Introduction Tumor necrosis factor  (TNF) inhibition is the most significant advancement in the treatment of rheu- matoid arthritis (RA) since the adoption of methotrex- ate in the 1980s (1,2). As TNF antagonists have become increasingly utilized, both as monotherapy and in combination with traditional disease-modifying anti- rheumatic drugs, there have been a number of reports of demyelinating and other central nervous system (CNS) events in patients receiving TNF antagonists (3,4). It is unclear whether these cases represent coincidental events or whether they are side effects of the new therapies. If these events are side effects, then we need to identify the mechanism by which they are occurring. Because these agents are utilized with increasing fre- quency to treat a host of inflammatory and autoimmune diseases, there will undoubtedly be reports of drug associations and side effects. Careful examination of potential treatment-related adverse events is critical and may result in unique insights into the mechanisms of action of these novel therapeutic agents, as well as increase our understanding of the pathophysiology of the diseases currently being treated by these agents. Evidence of association between TNF antagonists and demyelinating and CNS events Recently, neurologic and demyelinating events have been reported in association with the use of TNF antagonists in the treatment of RA and psoriatic arthri- tis. Various CNS events have been reported in patients taking etanercept, a p75 TNF receptor-immunoglobulin fusion protein, although the causal relationship with etanercept therapy remains unclear (3,4). As of Novem- ber 2000 there were at least 9 cases of neurologic or demyelinating events reported in association with the use of etanercept (Siegel JN: personal communication). These adverse events could be broken into 4 general groups: 1) exacerbation/worsening of preexisting multi- ple sclerosis (MS), 2) new-onset MS, 3) acute mental status changes (encephalopathy) in which there was some residual deficit and/or evidence of demyelination on biopsy, and 4) cases in which the findings were consistent with neurologic disease but were not suffi- cient for the diagnosis of MS (such as optic neuritis, dysesthesia, and Lhermitte’s sign) (Siegel JN: personal communication). The clinical presentations of all of these cases varied greatly, and included altered mental status, dys- esthesias, paresthesias, optic neuritis, or motor deficits. Many of the non-MS cases had clinical and/or radio- graphic features consistent with possible MS; it is possi- ble that the primary association with TNF antagonists is that they can cause exacerbation of autoimmune demyelination in patients with early MS (2 exacerba- tions) or established MS. As of January 2001, 2 cases of neurologic events associated with magnetic resonance imaging (MRI) evidence of definite or possible demyeli- nation have been reported in patients with RA in Dr. Robinson’s work was supported by NIH grant 1-K08-AR- 02133-01A1. Dr. Moreland’s work was supported by NIH grants M01-RR-00032 and 5-R01-AR-44384. 1 William H. Robinson, MD, PhD, Mark C. Genovese, MD: Stanford University School of Medicine, Stanford, California; 2 Larry W. Moreland, MD: The University of Alabama at Birmingham. Drs. Genovese and Moreland receive research funding from and have served as consultants for Immunex, Seattle, Washington. Address correspondence and reprint requests to Mark C. Genovese, MD, Division of Immunology and Rheumatology, Stanford University Medical Center, Stanford, CA 94305. Submitted for publication January 26, 2001; accepted in revised form April 27, 2001. 1977