Assessing the Safety of Biologic Disease Modifying Anti-Rheumatic Drugs in Patients with Rheumatoid ArthritisPatients with rheumatoid arthritis (RA) have shorter life expectancy compared to the generalpopulation and they are at increased risk for serious infections, early cardiovascular disease, insulinresistance and lymphoproliferative neoplasias. Current treatment of RA is based on disease modifying antirheumaticdrugs (DMARDs), including novel biologic antagonists of tumor necrosis factor alpha (TNFa) andinterleukin 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 moresusceptible to infectious agents or abnormal cell proliferation. Whether or not therapy with biologic DMARDsincreases 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 withoutrheumatic diseases. No benefits were shown and paradoxically, high doses of these DMARDs weredeleterious in some patients. Nevertheless, the cardiac effects of biologic DMARDs in patients with RA butwithout preexisting congestive heart failure remain unclear.RA imparts an increased risk for coronary heart disease that is not fully explained by traditional riskfactors. Chronic inflammation is postulated to play an integral role in the pathogenesis of this acceleratedatherosclerosis. Although previous studies suggested that DMARD therapy could reduce the risk ofcardiovascular 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, knownrisk factors for atherosclerosis and highly prevalent conditions among patients with RA. Glucocorticoidtherapy paradoxically improved insulin sensitivity in patients with RA, suggesting that inflammation andinsulin resistance may be closely related. Furthermore, anakinra, the IL-1 receptor antagonist, improvedglucose 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 diabetesin patients with RA is currently unknown.To evaluate the safety of biologic DMARDs in patients with RA, we propose a sequence of studieswith three specific aims: 1) To test the hypothesis that use of biologic DMARDs increases the risk of seriousinfections compared with traditional DMARDs. 2) To test the hypothesis that use of biologic DMARDsincreases the risk of developing lymphoproliferative neoplasias compared with traditional DMARDs. 3) Totest the hypothesis that use of biologic DMARDs increases the risk of congestive heart failure and decreasesthe risk of myocardial infarction and diabetes compared with traditional DMARDs.
Showing the most recent 10 out of 78 publications
