EPIDEMIOLOGY OF VASCULAR DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus (SLE) is associated with a significant risk of cardiovascular disease (CVD) [1,2]. A recent study suggests that patients with SLE have two-fold higher number of atherosclerotic plaques in the carotid and femoral arteries, comparable with what has been reported in rheumatoid arthritis and diabetes mellitus, two other conditions associated to enhanced CV risk [3▪]. Another recent prospective study reported that during a 5-year follow-up period, 32% of SLE patients developed evidence of carotid atherosclerosis compared with 4% of healthy controls [4▪]. In addition, individuals with SLE have a two-fold increased rate of ischemic stroke or myocardial infarction (MI) compared with the general population [1,5]. In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting a potential link between autoimmune inflammation and atherosclerosis . SLE patients with lupus nephritis display significantly increased risk of MI and CVD mortality than SLE patients without lupus nephritis [7▪]. Furthermore, lupus nephritis is associated with twice as often evidence of carotid atherosclerotic plaques when compared with age-matched nonnephritis SLE patients [even those with positivity for antiphospholipid (aPL) antibodies] and population controls . The prevalence of CV events in SLE also shows racial and ethnic variations. Specifically, the risk of MI was recently reported to be lower among Hispanics and Asians compared with Whites, whereas the risk of stroke was elevated among blacks and Hispanics compared with Whites [9▪].
Traditional Framingham risk factors do not fully explain the increased CVD risk in SLE . A recent study compared the Framingham score with the recently described SLE-specific CVD risk equation (SLE score) and identified that a large proportion of SLE patients could be reclassified as high CVD risk using a formula that incorporates SLE disease-related parameters [11▪]. The authors found that the sex preference in SLE and low BMI in women may lead the traditional Framingham score to underestimate the CV risk in female SLE patients. In contrast, the SLE score may capture those patients as having high risk for CVD [11▪].
Genetic variants can play important roles in both SLE and CVD. A recent study indicates that an interleukin 19 (IL19) risk allele, rs17581834(T) is associated with stroke/MI in SLE by affecting protein binding. SLE patients with that risk allele had increased levels of plasma-IL10 and aPL antibodies . In addition, an SRP54 Antisense RNA 1-AS1 risk allele, rs799454(G) was associated with stroke/transient ischemic attack in SLE . Another recent study shows that apolipoprotein L1 risk variants associate with atherosclerotic disease in African-American SLE patients .
RECENT ADVANCES IN PATHOGENESIS OF PREMATURE ATHEROSCLEROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS
Vascular damage and cardiovascular disease in systemic lupus erythematosus
Endothelial dysfunction is one of the first recognized steps leading to established CVD. A recent study reported a high rate of endothelial dysfunction in individuals with recent onset of SLE (<5 years), even those with mild disease activity and without traditional CVD risk factors . Various soluble adhesion molecules, such as vascular cell adhesion molecule, which are released after endothelial cell damage and have been proposed as markers of endothelial dysfunction, are increased in SLE and correlate with higher coronary calcium scores . Nhek et al. [16▪] recently showed that SLE sera can induce platelet activation leading to endothelial cell activation and synthesis of proinflammatory mediators in an IL-1-dependent manner (Fig. 1). A profound imbalance between endothelial cell damage and repair has been identified in SLE . Thus, patients with SLE have impaired endothelial cell and compromised repair of the damaged endothelial cells, which may promote the development of vascular plaque.
Arterial stiffness, as a marker of subclinical atherosclerosis, is significantly elevated in patients with SLE. A low level of cardiorespiratory fitness (CRF) has been shown to associate with the risk of CVD in the general population . A recent study examined the association of CRF with arterial stiffness in SLE. CRF was inversely associated with pulse wave velocity (PWV), a marker for arterial stiffness [19,20], suggesting that CRF may attenuate the age-related arterial stiffening in SLE and contribute to primary prevention of CVD in SLE . In contrast, a recent meta-analysis failed to show significant effects of exercise on CVD risk factors and disease activity, but reported that exercise improves cardiorespiratory capacity and reduces fatigue in SLE . By utilizing PWV as a marker of arterial stiffness, Castejon et al.  reported that SLE patients with metabolic syndrome display increased arterial stiffness, which is associated with a decreased percentage of circulating endothelial progenitor cells (EPCs). In contrast, a recent study failed to demonstrate an association between EPC colonies, percentages of circulating EPCs, or SLE disease activity index with PWV . These results indicate that additional longitudinal studies in larger cohorts of SLE patients are needed to conclusively assess the role of various biomarkers in vascular dysfunction in this patient population.
Dysregulation of the innate immune response and systemic lupus erythematosus-related cardiovascular disease
Owing to the central role of type I interferons (IFNs) in SLE, these cytokines have been extensively investigated as a contributing factor to the development of lupus-related CVD. Lupus patients with a high type I IFN signature have decreased endothelial function . Enhanced serum IFN activity has been significantly associated with decreased endothelial function, whereas factors such as serum levels of high-sensitivity CRP, adhesion molecules, and lupus disease activity are not. This suggests that enhanced type I IFN signaling may be particularly important in driving increased CV risk in SLE . Tyden et al.  recently reported that activation of the type I IFN system in SLE may impair endothelial function even in those lupus patients with low disease activity. Diminished activity of endothelial nitric oxide synthase (eNOS) and loss of nitric oxide production are critical in the development of endothelial dysfunction. One of the detrimental effects of IFN-α on endothelial dysfunction was recently reported by Buie et al. [27▪] as this cytokine was reported to inhibit eNOS expression at the mRNA and protein levels and to impair insulin-mediated nitric oxide production in endothelial cells (Fig. 1). In addition, a recent study demonstrated that diet-induced insulin resistance is initiated by a type I IFN response that triggers accumulation of cluster of differentiation (CD)8+ T cells in the liver, resulting in glucose dysregulation and hepatic inflammation [28▪]. The pathogenic role of type I IFNs is also observed in the case of MI. King et al. [29▪▪] recently showed that ischemic cell death and uptake of cell debris by macrophages in the heart fuels a fatal response to MI by activating interferon regulatory factor 3 and type I IFN production through cyclic GMP-AMP synthase-stimulator of IFN genes. Further, treatment of mice with an type I Interferon receptor-neutralizing antibody after MI ablated the IFN response and improved left ventricular dysfunction and survival [29▪▪].
A distinct subset of proinflammatory neutrophils present in lupus patients, called low-density granulocytes (LDGs), have been proposed to play pathogenic roles in lupus CVD by a variety of mechanisms, including their enhanced propensity to form neutrophil extracellular traps (NETs) . A recent publication reported that NETs promote vascular leakage and endothelial-to-mesenchymal transition through the degradation of vascular endothelial cadherin and subsequent activation of β-catenin signaling, and this may promote endothelial dysfunction (Fig. 1) [31▪▪]. Carlucci et al. [32▪▪] recently reported that SLE patients with overall mild-moderate disease activity display a significant increase in aortic wall inflammation, as assessed by [18F]-Fluorodeoxyglucose-PET/computed tomography scan, when compared with healthy controls. This same SLE cohort displayed a significant increase in noncalcified coronary plaque burden (NCB) and endothelial dysfunction. When analyzing the associations of lupus-related factors to these vascular abnormalities, the level of LDGs was independently associated with NCB [32▪▪]. In addition, an LDG gene signature obtained by RNA sequencing showed a significant association with the presence of high vascular inflammation and high NCB in SLE [32▪▪]. These results support the notion that aberrant neutrophil biology contributes to the development of premature vascular disease in SLE.
DYSREGULATION OF ADAPTIVE IMMUNE RESPONSES AND SYSTEMIC LUPUS ERYTHEMATOSUS-RELATED CARDIOVASCULAR DISEASE
As T cells play a critical role in both atherosclerosis and SLE, dysregulated T cells may contribute to SLE-associated CVD and this is also supported by animal models . In patients with SLE, plasmacytoid dendritic cells induce the expansion of CXC chemokine receptor 3+ CD4+ T cells and their migration from the bloodstream into the arterial wall, where they may play proatherogenic roles . The role of IL-17A in atherosclerosis development in SLE is unknown, but low-density lipoprotein receptor knockout mice that receive transfer of CD4+ T cells from SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice develop accelerated atherosclerosis because of an imbalance between IL-17 production and Treg function . In a recent prospective 5-year study, increased levels of CD4+CC chemokine receptor (CCR)5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients [4▪]. In a recent murine atherosclerosis study, CCR5 was reported to be critical for the homing of CD4+ T cells into the atherosclerotic plaque [36▪▪]. These findings support the possibility that increased levels of CD4+CCR5+ T cells in SLE may contribute to atherogenesis.
A recent study suggests that invariant natural killer T (iNKT) cells may promote an atheroprotective effect in SLE patients with asymptomatic atherosclerotic plaques [37▪▪]. The authors found that healthy iNKT cells differentiated in the presence of healthy monocytes and serum from SLE patients with asymptomatic plaque polarized macrophages toward an anti-inflammatory M2 phenotype, whereas SLE patients with clinical CVD had unresponsive iNKT cells and increased proinflammatory monocytes [37▪▪]. Furthermore, the authors demonstrated that the anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes (Fig. 1) [37▪▪].
Autoantibodies and immune complexes
Autoantibodies and immune complexes (ICs) may also contribute to vascular damage and atherosclerosis development in SLE. IgG antioxidized (ox) LDL (oxLDL) ICs are present in both rabbit and human atherosclerotic lesions . In SLE, IgG anti oxLDL Abs are significantly elevated . Stimulation of bone marrow-derived dendritic cells (BMDCs) with oxLDL ICs leads to enhanced secretion of IL-1β, a cytokine important in atherogenesis and inflammasome activation, whereas BMDCs stimulated with free oxLDL promote enhanced Th17 polarization (Fig. 1) [40▪▪].
aPL antibodies, including lupus anticoagulant, anticardiolipin antibodies and antiβ2-glycoprotein I antibodies (aβ2-GPI), are present in 20–30% of SLE patients and have been linked to an increased risk of venous and arterial thrombosis . A significant percentage of SLE patients show a β2-GPI-specific T cell reactivity, which is associated with subclinical atherosclerosis . β2-GPI binds to oxLDL to form oxLDL/β2-GPI complexes  that can increase foam cell formation and proinflammatory cytokine and chemokine expression . Increases in oxLDL/β2-GPI and oxLDL/β2-GPI/aβ2-GPI complexes have been reported in SLE, and correlate with several CVD risk factors (Fig. 1) . In contrast, immunoglobulin M (IgM) antibodies recognizing phosphorylcholine, may exert protective roles in CVD in SLE, at least in part by promoting Treg polarization and reducing the production of IL-17 and tumor necrosis factor (TNF)-α (Fig. 1) [46▪].
Dyslipidemia in systemic lupus erythematosus
Dyslipidemia is a hallmark of atherosclerosis and CVD. In SLE, dyslipidemia is characterized by elevations in total cholesterol, LDL, triglycerides, and apolipoprotein B, and a reduction in high-density lipoprotein (HDL) . This pattern is often observed at the time of lupus diagnosis and correlates to SLE activity . SLE patients display increased levels of oxidized and dysfunctional HDL with impaired cholesterol efflux capacity and in association with atherosclerosis [49–51]. Mechanistically, HDL exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to downregulation of Toll-like receptor (TLR)-induced inflammatory responses . In contrast, a recent study reported that oxidized lupus HDL promotes proinflammatory responses in macrophages [53▪▪]. Indeed, SLE HDL activates nuclear factor (NF)κB, promotes inflammatory cytokine production, and fails to block TLR-induced inflammation. This failure of lupus HDL to block inflammatory responses is because of an impaired ability to promote ATF3 synthesis and its nuclear translocation and this was driven by signaling through the oxidized LDL receptor (Fig. 1) [53▪▪]. Indeed, an HDL mimetic given to lupus-prone mice systemically promoted significant ATF3 induction and decreases in proinflammatory cytokine levels, supporting a putative therapeutic potential [53▪▪]. NETs were previously reported to have the ability to oxidized HDL in a region-specific proatherogenic manner that impairs the cholesterol efflux capacity of HDL . In a recent study, impairments in cholesterol efflux capacity were significantly associated with vascular inflammation and NCB in multivariate analysis, suggesting that therapeutic strategies that improve HDL function may have significant cardioprotective effects in SLE [32▪▪].
Insulin resistance has been shown to contribute to CVD in SLE. A recent study assessed insulin sensitivity in SLE patients in response to a meal tolerance test. SLE patients displayed a bi-hormone metabolic abnormality characterized by increased insulin resistance and hyperglucagonemia despite normal glucose tolerance and preserved ß-cell function and skeletal muscle glucose transporter 4 translocation. The authors thus propose that strategies capable of ameliorating insulin sensitivity may require more than targeting insulin resistance alone .
Screening and assessing cardiovascular disease in systemic lupus erythematosus
Mavrogeni et al.  recently demonstrated that CV magnetic resonance can detect silent heart disease missed by echocardiography. Indeed, CV magnetic resonance detected abnormalities in 27.5% of SLE patients who presented normal echocardiography but had silent/past myocarditis, MI, or vasculitis . Visceral adipose tissue correlates with CV risk factors. A recent study reveals that SLE is associated with increased visceral adipose tissue and altered adiposity distribution. . Furthermore, aortic perivascular adipose tissue density associated with aortic calcification in SLE women, indicating that adipose tissue dysfunction may contribute to CVD in SLE .
Osteoprotegerin and osteopontin (OPN) are involved in vascular calcification and are upregulated in symptomatic human carotid atherosclerosis . A recent study reported that serum OPN levels are significantly increased in SLE compared with healthy controls, particularly in those patients with lupus nephritis. . OPN levels were significantly associated with CV events, indicating that this molecule may contribute to SLE CVD and could potentially serve as a biomarker of CV risk in this patient population . In another study, although SLE patients with higher osteoprotegerin levels had higher measures of coronary artery calcium, carotid intima media thickness, and more carotid plaque, no statistically significant associations were noted after adjustment for age . In addition, a recent study shows that biomarkers reflecting receptor-activated apoptosis and tissue degradation, including Fas, TNF receptor 1, TNF-related apoptosis inducing ligand receptor 2, matrix metalloproteinase-1, and matrix metalloproteinase-7, are significantly elevated in SLE patients with CVD than those without CVD .
Impairment of total antioxidant capacity is associated with subclinical coronary microvascular dysfunction in SLE patients without traditional CV risk factors . Paraoxonase1 (PON1), an enzyme with antioxidant activity that attaches to HDL and can prevent oxidative modifications of LDL , is decreased in SLE and is associated with vascular damage . A recent study evaluated the role of anti-PON1 and anti-HDL antibodies as biomarkers of lupus CVD. They found that anti-HDL antibodies were significantly associated with higher risk of CVD, and anti-PON1 antibodies were significantly associated with carotid intima media thickness in SLE . Thus, those antibodies could be potential early biomarkers of premature atherosclerosis in SLE.
Cardiac troponin T (cTnT) has been proposed as a marker of myocyte necrosis and injury in the early phases of acute MI . High-sensitivity cTnT has shown promising value in predicting CVD in the general population with apparent low CVD risk . In a recent cross-sectional controlled study, Divard et al.  reported that levels of high-sensitivity cTnT were independently associated with subclinical atherosclerosis in asymptomatic SLE patients considered at low risk for CVD based on traditional risk factors.
As mentioned previously, LDGs play pathogenic roles in lupus CVD. A recent study demonstrated that LDG levels were significantly associated with NCB severity and lower cholesterol efflux capacity in SLE in an unadjusted linear regression analysis [32▪▪]. Furthermore, the authors found that a neutrophil gene signature was significantly associated with vascular disease in SLE. Indeed, some of the most upregulated genes in the high-NCB SLE groups were the genes previously found to be upregulated in LDGs when compared with normal density neutrophils [32▪▪]. Those findings suggest that the levels of LDGs may serve as a marker for CVD risk in SLE.
A number of studies have indicated that statins may promote autoimmune responses [69,70]. In a recent population-based cohort study assessing the association between statin use and the risk of developing SLE, the authors failed to identify any association between current statin use with the risk of developing SLE among patients 40 years and older [71▪▪]. Instead, they observed a decreased SLE risk among current statin users who continued their therapy for more than 1 year [71▪▪]. Studies on whether statins can prevent CVD in SLE have given inconsistent results. Atorvastatin improved endothelial cell-dependent vasodilation in a short-term (8-week) trial , but failed to exert vasculoprotective effects in a longer (2-year) trial . A recent study indicated that statin therapy might reduce the risk of mortality and CVD in SLE patients with hyperlipidemia . Short-term atorvastatin therapy improved arterial stiffness in middle-aged SLE patients with abnormal PWV. Although these studies suggest that statin may benefit a subset of SLE patients, larger well-controlled, long-term trials are needed to conclude whether current statin regimens are sufficient in decreasing CV risk and what the guidelines for statin use should be in SLE.
Anti-IFN therapies and Janus kinase inhibitors
Targeting the IFN pathway has emerged as a promising therapeutic strategy in SLE [75,76]. Given these promising results and the putative role of IFN in atherogenesis, it will be important to determine whether disrupting this pathway can yield a beneficial therapeutic response in premature atherosclerosis in SLE. A recent study reported that interfering with downstream signaling of this pathway by utilizing the Janus kinase (JAK) inhibitor tofacitinib ameliorates murine lupus and its associated vascular dysfunction [77▪▪]. The role of JAK inhibitors and antitype I IFN therapies in vascular prevention in SLE remains to be determined.
Antimalarials may have cardioprotective effects [78,79]. In a recent study, Fasano et al.  reported that long-term hydroxychloroquine (HCQ) use in conjunction with low-dose aspirin may provide added efficacy in primary CVD prevention in SLE. However, another recent database prospective cohort study failed to demonstrate the protective effect of long-term HCQ in reducing vascular events in SLE . Ruiz-Arruza et al.  recently showed that, those SLE patients that received glucocorticoids later during the course of the disease and at lower doses while receiving more HCQ, displayed significantly decreased incidence of glucocorticoid-related CVD but similar SLE-related damage compared with SLE patients received glucocorticoids earlier and at higher doses. Additional studies are therefore needed to further define the role of antimalarials in CV prevention and the best strategies for treatment (single use versus combination therapy).
A number of SLE-specific mechanisms, such as dysfunctional immune regulation and defective endothelial cell function and vascular repair, contribute to the premature atherosclerosis in SLE. The biological insights in appreciating those complex interplays have progressed significantly, but further understanding of the clinical relevance of targeting those factors in reducing SLE-related CVD is required. In addition, continued efforts to investigate other mechanisms that lead to accelerated CVD in SLE are needed to provide better molecular candidates for therapeutic targeting, and ultimately to improve the CV outcomes.
Financial support and sponsorship
Supported by the Intramural Research Program at NIAMS/NIH ZIA AR041199.
Conflicts of interest
There are no conflicts of interest.
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