Accelerated atherosclerosis in patients with SLE--mechanisms and management

Abstract

Rapid-onset cardiovascular disease (CVD) is a major concern for many patients with systemic lupus erythematosus (SLE). Cardiovascular events occur more frequently and with earlier onset in patients with SLE compared with healthy individuals. Traditional risk factors, such as altered lipid levels, aging and smoking, do not fully explain this increased risk of CVD, strongly suggesting that autoimmunity contributes to accelerated atherosclerosis. Altered immune system function is recognized as the primary contributor to both the initiation and progression of atherosclerosis. Multiple manifestations of autoimmunity, including changes in cytokine levels and innate immune responses, autoantibodies, adipokines, dysfunctional lipids, and oxidative stress, could heighten atherosclerotic risk. In addition, multiple SLE therapeutics seem to affect the development and progression of atherosclerosis both positively and negatively. SLE-specific cardiovascular risk factors are beginning to be discovered by several groups, and development of a comprehensive, clinically feasible biomarker panel could be invaluable for identification and treatment of patients at risk of developing accelerated atherosclerosis. Here, we discuss the epidemiology of CVD in SLE and the implications of immune system dysfunction on the development and progression, monitoring and treatment of atherosclerosis in individuals with this disease.

Figure 1

Protection from and pathogenesis of atherosclerosis in SLE. A) Protective mechanisms from atherosclerosis: HDL protects LDL from oxidation by reactive oxygen species (ROS) in the arterial intima. In addition, HDL assists with reverse cholesterol transport and prevents the formation of lipid-rich foam cells, the precursor to plaque. Endothelial progenitor cells (EPC) and circulating angiogenic cells (CAC) are able to reseed and repair damaged pockets of arterial endothelial cells to minimize arterial damage. Dashed lines indicate minimized effect and influence of the cells or processes indicated. B) Initiation and progression of atherosclerosis in SLE: Pro-inflammatory HDL (piHDL), present in almost half of SLE patients, augments oxLDL production. EC release inflammatory cytokines after oxLDL stimulation, stimulating monocytes to bind the EC layer and transmigrate into the intima. Monocytes then differentiate into foam cells, assisted by increased piHDL, oxLDL, TNFα, and homocysteine (HCY) found in SLE patients. Elevated HCY also leads to increase ROS and EC damage. Defective, apoptotic and lower overall numbers of EPC/CAC diminish the EC repair system, and all of these processes lead to increased arterial plaque.