Objectives: To develop evidence-based EULAR

Abstract-There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Key Words: immune system Ⅲ risk factors Ⅲ atherosclerosis C onsiderable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease (CHD). 1 Seventeen of 21 relevant observational studies show an increased standardized morality ratio in RA and that life expectancy is shortened by 3 to 18 years. Pooled analysis of these studies suggests a 70% increase in risk of death in RA patients. Life expectancy is especially shortened in RA patients treated in specialist referral centers, where the prognosis is comparable to that of triple-vessel CHD or stage 4 Hodgkin's disease. 1 Cardiovascular disease accounts for 35% to 50% of excess mortality in RA patients, with cerebrovascular disease being the second leading cause of death. Intriguingly, most evidence suggests that classic risk factors do not explain excess vascular disease in RA. In an 8-year follow-up of 236 RA patients, a 3.96-fold (95% CI 1.86 to 8.43) higher incidence of cardiovascular events relative to a community-dwelling cohort was noted. 2 However, this risk ratio was only minimally attenuated (to 3.17 [95% CI 1.33 to 6.36]) by adjustment for conventional risk factors. These clinical epidemiological observations strongly suggest that mechanisms other than classic risk factors promote accelerated atherogenesis in RA, and responsible candidate pathways are explored in this review. Inflammation as a Candidate Pathway for CHDIt is firmly established that systemic markers of inflammation, albeit at considerably lower levels than those apparent in RA, independently predict CHD events in men and women with or without existing heart disease. 3,4 The levels of cytokines and other inflammatory mediators detected in CHD are such that high-sensitivity assays rather than conventional assays are required. This concept of inflammatory-driven atherogenesis is consistent with the plaque composition of unstable coronary lesions, with an abundance of inflammatory molecules and immune cells at the shoulder region that act to erode the collagen cap that separates the atheromatous material of the plaque from blood. 4 This appearance is similar to that of inflammatory synovitis in RA. 5 However, whereas in RA, C-reactive protein (CRP) is a powerful measure of synovial infla...

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

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