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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Inflammatory pathways have been implicated in the initiation and progression of cardiovascular diseases. Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases, particularly rheumatoid arthritis, disproportionate to individuals' detectable traditional vascular risk factors. This finding suggests that other pathways associated with inflammation might account for increased vascular risk in such diseases. Highly specific biologic agents can precisely block the activity of cytokines generated during inflammatory cascades; the effects of these inflammatory moieties on vascular physiology and overall risk of cardiovascular events has been directly evaluated. This review summarizes key epidemiologic, physiologic and model data, which together suggest that tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, is directly involved in vascular pathophysiology and that its inhibition might confer an overall advantage to the recipient. Moreover, such data obtained in chronic inflammatory diseases likely have relevance to primary atherosclerosis.

Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c+ DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c+ DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.

blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Annals of the Rheumatic Diseases, 76(11), pp. 1949Diseases, 76(11), pp. -1952 There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/148846/ AbstractObjectives: Patients with rheumatoid arthritis (RA) have reduced serum LDL-cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes.Methods: In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three I.V. infusions of the IL-6R blocker Tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL.