Premature atherosclerosis in patients with Systemic Lupus Erythematosus (SLE) has been recognized for the past 25 years. As much as a 50-fold increase in risk for coronary artery disease has been found in SLE patients compared to controls and an increased risk for thrombotic cerebrovascular disease has also been recognized. In the past decade lipid abnormalities have been recognized in SLE patients that are """"""""proatherogenic"""""""". These include elevated LDL cholesterol, low HDL cholesterol and elevated triglyceride levels that are not due to nephrotic syndrome. Careful clinical studies suggest that conventional risk factors such as age, sex, smoking, hypertension, etc., do not completely account for the prevalence of premature atherosclerosis. Indeed, there appears to be an element of risk conferred by the lupus process itself We postulate that this mechanism of the SLE associated risk lies in autoimmune events that perturb lipid homeostasis in the direction of elevated triglycerides and cholesterol. We further suggest that part of this effect is due to an immune response to lipoprotein lipase which occurs in 50% of SLE patients and promotes hypertriglyceridemia. In addition, autoantibodies to apolipoprotein A-1, Apo B and Apo E may perturb lipid transport and promote decreased HDL cholesterol and increased LDL cholesterol. Our plan is to combine our expertise in autoantibody research with epidemiologic methods. We will conduct a prospective study of SLE patients and their matched controls to evaluate these immune responses on lipid levels, in the presence of conventional risk factors and confounders, and their association with premature atherosclerosis. Recognition of autoimmune mechanisms that promote elevated triglycerides could lead to specific interventions as therapy or even possibly prevention of premature atherosclerosis.
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