Nails in the coffin: Increasing evidence for the role of rheumatic disease in the cardiovascular mortality of rheumatoid arthritis

Rheumatologists have naturally concentrated their research and therapeutic efforts on the synovial lesions of rheumatoid arthritis (RA), with major emphasis on the immune inflammation, a process also thought to explain the extraarticular manifestations of systemic RA. While these lesions undoubtedly cause severe morbidity, it is now evident from epidemiologic studies that RA is associated with enhanced mortality. This mortality is largely due to cardiovascular disease (1). At first sight, this mortality fails to fit into the RA paradigm of chronic autoimmune inflammation. Since neither cardiac amyloid nor specific lesions of rheumatoid heart disease appear to be able to account for this cardiovascular mortality, atherosclerosis emerges as the likely culprit. Why should RA patients show an accelerated rate of atheroma deposition? Could this process in any way relate to systemic rheumatic disease? Rheumatologists may be surprised to discover how far vascular biologists have come in thinking of atherosclerosis as an immune disease with low-grade inflammation, reflecting pathogenetic mechanisms similar to those of RA (2). Thus, it is timely to review the role of atherosclerosis in RA and to consider the possible mechanisms in the context of current concepts regarding the development of atherosclerotic lesions and the recent advances in clinical measurements available to study these concepts. Established atheroma takes years to develop, although cellular and molecular studies have shown that this lesion is a dynamic inflammatory process, not an inevitable degenerative disease. The “response to injury” model is a widely accepted paradigm for atherogenesis (3). According to this paradigm, the first step is injury to the endothelial cells (ECs) lining the arterial wall. Methods to study EC function in vivo are now moving from the physiology laboratory into the clinical research arena and have even been used as surrogates for the understanding of coronary atherosclerosis (4).