Mechanisms of vascular damage in systemic lupus erythematosus

Epidemiology of vascular damage in systemic lupus erythematosus

Accelerated atherosclerosis leading to cardiovascular (CV) events is a well-established cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). A bimodal mortality pattern in SLE was recognized in the 1970s, and these observations of enhanced mortality late in the course of SLE disease due primarily to CV disease (CVD) have been replicated in several other cohorts. Indeed, enhanced relative risk for vascular disease is well documented in SLE and is particularly enhanced in young women with lupus, who are 50 times more likely to develop a myocardial infarction when compared to women of similar age without SLE. In population-based studies, several risk factors for CV events in women with SLE have been identified, including older age at the time of lupus diagnosis, disease duration, length of corticosteroid use, hypercholesterolemia, and postmenopausal status. However, the rate of CVD in SLE patients is significantly higher than what would be expected based on the Framingham risk equation alone. Furthermore, there is high prevalence of carotid atherosclerosis and noncalcified coronary plaque burden in SLE, as assessed by multidetector computed tomography scans, which may contribute to a higher propensity to develop acute coronary syndrome.

Risk of vascular damage: traditional versus nontraditional factors

While traditional Framingham risk factors for atherosclerosis cannot fully account for the increased risk of CVD in SLE, they likely contribute to vascular complications. Among the traditional risk factors, age, smoking, high body mass index, and high fasting glucose have been associated with CV events in SLE. While hypertension has been reported as an independent predictor of mortality in SLE, the frequent use of antihypertensive medications in patients with lupus nephritis, even in the absence of hypertension, complicates the assessment of the role of this risk factor in CVD.

Patients with SLE frequently present with abnormal lipid profiles, with increased low-density lipoprotein (LDL) and triglycerides and decreased high-density lipoprotein (HDL). The prevalence of metabolic syndrome is close to 10% in SLE, a rate significantly higher than what is reported in age- and gender-matched controls, and it is associated with endothelial injury and coronary atherosclerosis. Overall, it is considered that the presence of any of the Framingham CV risk factors, in association with various nontraditional SLE-specific risk factors for atherosclerosis, may promote additive or synergistic effects on vascular injury.

Several mechanisms unique to SLE have been proposed to contribute to vascular damage and premature atherosclerosis. There is convincing evidence placing atherosclerosis as a chronic inflammatory condition, where a sophisticated interplay of various components of the innate and adaptive arms of the immune system, including cytokines, autoantibodies, T and B lymphocytes, neutrophils, macrophages, and dendritic cells play key roles in contributing to endothelial cell injury. However, several features that characterize SLE are atypical, when considering what is known about promoters of atherogenesis in the general population: (1) young women without SLE are considered protected from plaque formation, whereas young women with lupus are at risk ; (2) the “classical” inflammatory burden associated to atherosclerosis in the general population (i.e., elevated high-sensitivity C-reactive protein) is not traditionally observed in a high proportion of SLE patients ; and (3) while statins lower total and LDL cholesterol levels, it remains unclear what role they play in CVD prevention in SLE. These observations support the notion that immune dysregulation characteristic of SLE plays a key role in the promotion of vascular damage and progression to CV disease in this condition ( Fig. 36.1 ).

Role of cytokines in vascular damage in SLE