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Immunologic reactants in the pathogenesis of atherosclerosis in rheumatic diseases

It is increasingly clear that patients suffering from systemic lupus erythematosus and rheumatoid arthritis are at significantly greater risk of developing atherosclerotic cardiovascular disease than otherwise unaffected individuals. Recent studies in our laboratory demonstrate that immunologic reactants such as immune complexes that have fixed C1q and IFN-γ diminish the capacity of macrophages to appropriately metabolize and transport lipoproteins. The effect of these agents on macrophage function suggests a role for these reactants in the premature development of atherosclerotic cardiovascular disease in rheumatic diseases. It was recently observed that methotrexate, unlike any other disease-modifying antirheumatic drugs studied, diminished the risk for development of atherosclerotic cardiovascular disease. Although the explanation for this phenomenon may be that methotrexate is simply a more effective anti-inflammatory agent, recent work in our laboratory suggests an alternative explanation. We have demonstrated that many, if not most, of the anti-inflammatory effects of methotrexate are due its capacity to increase release of adenosine, which interacts with its receptors on the cell surface to modulate inflammation. Adenosine, acting at its receptors on the surface of macrophages, increases the expression of enzymes involved in metabolizing cholesterol and of transporters involved in export of cholesterol from the vessel wall to the liver for elimination. The adenosine receptor-mediated effect on expression of these molecules is associated with diminished foam cell formation in an in vitro assay. These results suggest an explanation for the effect of methotrexate therapy on the development of atherosclerotic cardiovascular disease and, more importantly, indicates a novel target for the development of new anti-atherosclerotic agents.

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Cronstein, B., Reiss, A. Immunologic reactants in the pathogenesis of atherosclerosis in rheumatic diseases. Arthritis Res Ther 5 (Suppl 3), 44 (2003).

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