Impact of Immune Activation on Cardiovascular and Immune Health in RA

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Untreated rheumatoid arthritis (RA) carries high morbidity, including musculoskeletal disability and cardiovascular disease. Fortunately, in the past 15 years we have been able to control rheumatoid arthritis very well by offering methotrexate alone, leflunomide alone, TNF blocker therapy, rituximab, or a combination of methotrexate and a biologic (genetically-engineered proteins derived from human genes) therapy. At the same time, it is known that biologic agents contribute to an increased incidence of serious infections, impaired host response to vaccines, and a modest increase in risk for cancer. For certain, these agents block both pathogenic autoimmune disease activity pathways as well as the beneficial host response and host defense pathways. Furthermore, rheumatoid arthritis itself is associated with increased systemic immune activation and risk for cardiovascular disease. Our data, and that of others, indicate that chronic immune activation likely contributes to immune dysfunction, as measured by host response to neo-antigen and recall antigen immunization, and that immune activation predicts cardiovascular disease in the setting of chronic infection. We propose here to investigate determinants of immune health in the setting of auto immune disease by testing the hypothesis that in rheumatoid arthritis chronic immune activation (elevated sCD14, sCD163, TNFR2, TNF, autotaxin, and CD8/DC/monocyte activation) predicts immune dysfunction, as manifest by impaired host response to vaccine, and cardiac disease. This relationship is interrupted by TNF blockade. Aim 1: Determine whether immune activation, as reflected by elevated levels of sCD14, sCD163, autotaxin, TNFR2, IL6, CRP, dendritic cell activation and monocyte activation, predict immune health, as measured by host response to neo-antigen and recall antigen vaccine in treated RA, and whether TNF blocking treatment modifies this relationship. Aim 2: Determine the relation between immune activation, endothelial function, coronary atherosclerosis in RA, and whether TNF blockade improves both immune activation and cardiovascular surrogates.