Premature cardiovascular disease is a major cause of mortality in rheumatoid arthritis (RA). The mechanisms underlying accelerated atherosclerosis and its relationship to inflammation in RA are poorly understood. Recent studies indicate that inflammation through the effects of inflammatory cytokines, and oxidative stress, through lipid peroxidation, are important in the pathogenesis of atherosclerosis. We postulate that accelerated, inflammation-promoted atherosclerosis occurs in RA. Thus, we propose to test the hypotheses: 1) that structural and functional vascular damage is more frequent and more severe in patients with established RA than matched controls and is related to cumulative disease severity; 2) that this impairment of vascular integrity is associated with clinical and laboratory markers of inflammation, plasma homocysteine concentrations, and oxidative stress. To address these two hypotheses the relationship between longstanding inflammation and vascular integrity will be determined in a cross-sectional study of 75 patients with established RA in whom prospectively obtained clinical data are available for 15 years, and 75 matched non-RA controls. Endothelium-dependent, flow-mediated dilation of the brachial artery measured by ultrasound, and coronary calcium volume measured by electron beam computed tomography (EBCT) will provide functional and structural measures of vascular integrity, respectively. F2-isoprostane excretion, a reliable index of lipid peroxidation in vivo, homocysteine and lipid concentrations will be measured. Vascular integrity, oxidative stress, lipids and homocysteine will be compared in controls and RA patients. In the RA patients the relationship between RA activity and damage indices obtained over 15 years and vascular function and damage measures will be determined. Using the same techniques we will address hypothesis 3) that the rate of progression of vascular disease in patients with early RA can be altered by control of inflammation. In a prospective cohort of 100 patients with early RA receiving usual clinical care and 100 matched non-RA controls followed over 24 months the relationship between clinical and biochemical measures of inflammation and vascular integrity will be determined by comparing """"""""responders"""""""" and """"""""non-responders"""""""". These proposed studies will provide a basic understanding of the interrelationship between inflammation, lipids, oxidative stress and vascular damage, and will suggest strategies for reversing or preventing such damage in RA and, potentially, other diseases.
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