Assessing the Safety of Biologic Disease Modifying Anti-Rheumatic Drugs in Patients with Rheumatoid Arthritis Patients with rheumatoid arthritis (RA) have shorter life expectancy compared to the general population and they are at increased risk for serious infections, early cardiovascular disease, insulin resistance and lymphoproliferative neoplasias. Current treatment of RA is based on disease modifying antirheumatic drugs (DMARDs), including novel biologic antagonists of tumor necrosis factor alpha (TNFa) and interleukin 1 (IL-1). Through the blockade of key inflammatory mediators, these drugs control RA activity;however, these same mechanisms could also impair immune responses, rendering patients more susceptible to infectious agents or abnormal cell proliferation. Whether or not therapy with biologic DMARDs increases the risk of serious infections and neoplasias among patients with RA remains controversial. TNFa antagonists have been evaluated for the treatment of congestive heart failure in patients without rheumatic diseases. No benefits were shown and paradoxically, high doses of these DMARDs were deleterious in some patients. Nevertheless, the cardiac effects of biologic DMARDs in patients with RA but without preexisting congestive heart failure remain unclear. RA imparts an increased risk for coronary heart disease that is not fully explained by traditional risk factors. Chronic inflammation is postulated to play an integral role in the pathogenesis of this accelerated atherosclerosis. Although previous studies suggested that DMARD therapy could reduce the risk of cardiovascular disease in RA, the effect of specific DMARDs on the risk of myocardial infarction is unknown. Chronic inflammation is also associated with the metabolic syndrome and insulin resistance, known risk factors for atherosclerosis and highly prevalent conditions among patients with RA. Glucocorticoid therapy paradoxically improved insulin sensitivity in patients with RA, suggesting that inflammation and insulin resistance may be closely related. Furthermore, anakinra, the IL-1 receptor antagonist, improved glucose control in patients with diabetes, and infliximab improved insulin resistance in patients with RA. Whether this benefit extends to other DMARDs or whether DMARD therapy can delay the onset of diabetes in patients with RA is currently unknown. To evaluate the safety of biologic DMARDs in patients with RA, we propose a sequence of studies with three specific aims: 1) To test the hypothesis that use of biologic DMARDs increases the risk of serious infections compared with traditional DMARDs. 2) To test the hypothesis that use of biologic DMARDs increases the risk of developing lymphoproliferative neoplasias compared with traditional DMARDs. 3) To test the hypothesis that use of biologic DMARDs increases the risk of congestive heart failure and decreases the risk of myocardial infarction and diabetes compared with traditional DMARDs.
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