Under Crossfire

Thromboembolic Risk in Systemic Lupus Erythematosus

Giuseppe A. Ramirez; Maria Efthymiou; David A. Isenberg; Hannah Cohen

Disclosures

Rheumatology. 2019;58(6):940-952. 

In This Article

Accelerated Atherosclerosis

The rupture of an atherosclerotic plaque is a major cause of thromboembolism and subsequent cardiac, cerebral or limb ischaemia. According to clinical and post-mortem studies,[16,23] atherosclerosis has a high prevalence in patients with SLE. Potential factors accounting for an increased atherosclerotic risk in patients with SLE include inflammation-induced vessel dysfunction and increased prevalence of conventional cardiovascular risk factors (Figure 2).[24,25] Disease-specific inflammatory events probably synergize with traditional drivers of atheroma formation and with the side effects of corticosteroids and other treatments.

Figure 2.

Factors involved in accelerated atherosclerosis in SLE
Deranged immune responses promote endothelial activation and facilitate the extravasation of leucocytes. Monocytes respond to the accumulation of oxidized lipid products within the vessel walls and disrupt the physiological architecture of their inner layers. This process is potentially favoured by unbalanced T cell activation as well as by an IFN-enriched environment and can occur over short periods of time during disease flares. IFN responses also account for impaired endothelial turnover and endothelial dysfunction in patients with SLE. Conventional cardiovascular risk factors further promote the development of atherosclerosis in SLE. aPLs also promote chronic atherosclerotic lesions besides prompting thrombosis.

T cells are major drivers of SLE pathogenesis.[26] Imbalances between effector and regulatory T cell functions can account for disease flares and for accelerated vascular injury.[27] However, growing evidence supports a role of innate immunity in impairing the vascular response to flow-related or metabolic stressors in patients with SLE. IFN-α, in particular, is a hallmark of the antiviral-like inflammatory response that drives disease flares, at least in a subset of patients with SLE.[28,29] IFN-α impairs the maintenance tasks of endothelial progenitor cells and favours the local differentiation of macrophages into foam cells.[30,31] Complement activation may also be associated with endothelial inflammation and subsequent leucocyte recruitment at sites of vascular atherogenic inflammation. Furthermore, complement deposition can be detected in vascular atherosclerotic lesions from patients with SLE.[32]

The significance of traditional cardiovascular risk factors seems to vary among different SLE cohorts, possibly reflecting differences in lifestyles among different populations and/or historical changes in treatment strategies. More consistently, patients with SLE show a higher prevalence of hypertension,[17] which in turn associates with cardiovascular events, pregnancy complications and mortality.[16,33,34] Diabetes and sedentary habits are also more frequent in patients with SLE, although their specific role in SLE as clinical predictors of atherosclerosis is less clear.[16,17] Quantitative data on lipid profiles in SLE are conflicting and do not clearly support a disproportionate prevalence of hyperlipidaemia in patients with SLE.[17,34] In contrast, qualitative data indicate a sinister increase in pro-atherogenic oxidized lipoproteins during active disease,[35–37] pointing to a major role for inflammation-induced oxidative stress in perturbing lipid metabolism and causing subsequent vascular injury in SLE.[38] In accordance with a unique pathophysiological background, patients with SLE show a distinctive pattern of vascular injury characterized by focal, rapidly growing and highly unstable lesions rather than generalized vessel wall thickening.[39–42] Plaque formation in SLE may represent an accelerated misrepair response to a primary vascular injury, possibly favoured by concomitant 'surges' in cellular and humoral inflammatory mediators (perhaps linked to disease flares) as well as in oxidative stress.[27,40,43] In addition, the vascular damage in SLE not only involves large arterial vessels, but also the microcirculation, thus further enhancing the risk of ischemic events.[44]

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