Accelerated atherosclerosis in autoimmune rheumatic diseases

Atherosclerosis is a multifactorial process that is increasingly considered an immune system–mediated process of the vascular system. Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes. Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit also findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy. Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents. A cellular immune response specifically directed against heat-shock proteins (HSPs), oxidized low-density lipoprotein (oxLDL), and beta2-glycoprotein-I (beta2GPI) has been reported, suggesting a direct involvement of these molecules in atherosclerosis. Several autoantibodies are associated with atherosclerosis and its manifestations in humans. Active immunization of LDL-receptor– deficient mice with anti-cardiolipin (aCL) antibodies resulted in development of high titers of mouse aCL and increased atherosclerosis compared with control subjects. Immunization of mice with beta2GPI resulted in pronounced cellular and humoral responses to beta2GPI, with high titers of anti-beta2GPI antibodies concomitant with larger atherosclerotic lesions that contained abundant CD4+cells. OxLDL is the type of LDL that is more likely to undergo uptake by macrophages, which turn into the foam cells characterizing atherosclerotic lesions. Anti-oxLDL antibodies are present in patients with atherosclerosis, those with AIRDs, and healthy individuals. In multivariate analyses, anti-oxLDL autoantibodies discriminated better between patients with peripheral vascular disease and control subjects than did any of the different lipoprotein analyses. There was also a tendency for higher autoantibody levels in patients with more extensive atherosclerosis.The autoantibodies to ox-LDL were investigated in several AIRD groups, including patients with systemic sclerosis (SSc), systemic vasculitides, and systemic lupus erythematosus (SLE).The antibody levels were higher in those patient groups than in control subjects. This review focuses on the clinical impact and on the specific mechanisms so far identified for accelerated atherosclerosis in rheumatoid arthritis, SLE, antiphospholipid syndrome, systemic sclerosis, systemic vasculitides, and Sjogren’s syndrome.