Update on cardiovascular disease in lupus

Abstract

Purpose of Review

Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE) and cannot be fully explained by traditional cardiovascular risk factors. Recent immunologic discoveries have outlined putative pathways in SLE that may also accelerate the development of atherosclerosis.

Recent findings

Aberrant innate and adaptive immune responses implicated in lupus pathogenesis may also contribute to the development of accelerated atherosclerosis in these patients. Defective apoptosis, abnormal lipoprotein function, autoantibodies, aberrant neutrophil responses and a dysregulated type I interferon pathway likely contribute to endothelial dysfunction. SLE macrophages have an inflammatory phenotype that may drive progression of plaque.

Summary

Recent discoveries have placed increase emphasis on the immunology of atherosclerotic cardiovascular disease. Understanding the factors that drive the increase risk for CVD in SLE patients may provide selective therapeutic targets for reducing inflammation and improving outcomes in atherosclerosis.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune syndrome that primarily affects women of childbearing age. Although life expectancy in SLE has improved, estimated mortality rates remain approximately three times that of the general population.(1) Importantly, while deaths due to lupus manifestations have decreased, those due to atherosclerotic cardiovascular disease (CVD) in SLE have not. Indeed, CVD accounts for more than one-third of all deaths in SLE patients.(2, 3) Outcomes of percutaneous coronary intervention are worse in SLE subjects than in matched controls, with regards to the need for repeat vascularization and major adverse cardiac events.(4) Overall, SLE patients have higher incidence of CVD, present with this complication earlier than age- and gender-matched controls,(5) and have an accelerated rate of plaque progression.(6) The risk for myocardial infarction (MI) in SLE patients is 9–50 fold that of the general population, depending on the series.(7) While the Framingham risk equation (8) contributes to vascular risk in SLE, it cannot fully explain it.(9, 10) Indeed, while the absolute risk for CVD increases with age, the highest increment in relative risk for acute MI occurs in young females with SLE.(11) Furthermore, atherosclerosis in SLE is atypical not only because it affects premenopausal women but because it is not associated with the “classical” inflammatory burden characteristic of “idiopathic” atherosclerosis, as such as elevated C-reactive protein (CRP) and elevated levels of plasma low density lipoprotein (LDL).

In SLE, disease duration, higher damage index score and less aggressive immunosuppression are associated with increased CVD burden (12) (13*, 14*), suggesting that the immune dysregulation characteristic of lupus is a crucial player in plaque progression and vascular complications. Similar molecular events that drive autoimmunity have recently been proposed to influence plaque development and progression in SLE. Both the innate and adaptive immune systems contribute to the inflammatory state of lupus, and evidence suggests that similar factors may be implicated in development and progression of CVD.(15)* Furthermore, murine models suggest a synergism between genes that promote atherogenesis with those that promote autoimmunity, although the relationship between enhanced plaque and more profound systemic immune dysregulation requires further elucidation.(16)*

Endothelial Dysfunction and aberrant metabolic pathways in SLE

SLE patients demonstrate endothelial dysfunction, a phenomenon considered to correlate with poor CV outcomes in other populations. A very significant proportion of SLE patients display impaired endothelium-dependent vasorelaxation (17) and enhanced arterial stiffness.(18) The subset of patients affected by lupus nephritis appears to be at a particularly increased risk for arterial stiffness.(19) Cardiac positron-emission tomography (PET) has revealed impaired microvascular blood flow and reduced coronary flow reserve in SLE patients.(20)**

Atherosclerosis occurs in the arterial subendothelial space and is initiated by the interplay between subendothelial lipoprotein retention and endothelial dysfunction that leads to a non-resolving inflammatory response that generates endothelial damage and atherothrombosis.(21) While many atherosclerotic lesions undergo a partial fibrotic protective resolution,(22) some individuals develop “vulnerable plaques” that are more prone to breakdown and subsequent development of acute coronary syndrome. These vulnerable areas are characterized by intimal necrosis, enhanced inflammation and fibrous cap thinning. It has been proposed that plaque necrosis results from a combination of defective clearance of apoptotic cells, and primary necrosis of these cells, quite similar to defects on the immune system observed in other organs from lupus patients.(23–25) However, whether this represents a common mechanism that explains enhanced atherogenesis in SLE and whether lupus patients have increased prevalence of vulnerable plaque, remains to be determined.(26)

Thirty-five percent of adult SLE patients(27) and 60% of pediatric SLE patients have abnormal lipoprotein profiles at diagnosis(28), and prevalence increases to 60% of adults in a 3-year follow up in the SLICC cohort.(27) In SLE, a described pattern of dyslipidemia is characterized by increased VLDL and triglycerides, and decreased HDL.(29) This pattern is often seen at time of diagnosis and correlates to SLE activity.(30) Oxidized LDL/β2glycoprotein 1 immune complexes have also been described,(31) which bind oxidized LDL (oxLDL) and are phagocytosed by macrophages, promoting foam cell formation.

In addition to the effects of LDL, SLE HDL is dysfunctional and proatherogenic. Indeed, a main antiatherogenic property of HDL is the cholesterol efflux capacity, and this is impaired in SLE with no association to plasma level of the lipoprotein.(32) This proinflammatory nature of lupus HDL appears to be driven by enhanced oxidative modifications triggered, at least in part, by neutrophil extracellular traps (NETs).(33) Apolipoprotein levels and ratios are also disturbed in SLE, possibly due to anti-apolipoprotein antibodies.(34) However, outside of enhanced HDL oxidation and dysfunction, none of the dyslipidemias or apolipoproteins have been found to predict subclinical atherosclerosis or cardioprotection in SLE.(35)

Several studies have described enhanced insulin resistance and metabolic syndrome in SLE, which may be associated with insulin receptor antibody formation, inflammatory cascades or medication use.(36–39) Insulin resistance and metabolic syndrome in SLE patients are associated with increased arterial stiffness and organ damage.(40*, 41, 42*) Whether steroid use leads to insulin resistance in SLE patients is still under debate.(36, 41)

PATHOGENESIS OF PREMATURE ATHEROSCLEROSIS IN SLE

Type I IFNs and atherosclerosis in SLE

Several studies suggest that, in addition to type I IFNs role in lupus pathogenesis, they may be important contributors to premature atherosclerosis in this disease.(43, 44) Type I IFNs promote an imbalance between endothelial damage and vascular repair. Cells that are critical for vasculogenesis, such as endothelial progenitor cells (EPCs), are decreased in number and impaired in function in both adults and children with SLE (Figure 1).(43, 45*) EPC dysfunction is mediated by type I IFNs that promote an antiangiogenic signature and activation of the inflammasome machinery leading to vascular rarefaction through enhanced synthesis of IL-18.(43, 44, 46) Type I IFNs also promote foam cell formation, while blockade of these inflammatory pathways mitigates endothelial dysfunction and atherogenesis in murine systems (Figure 1).(47, 48) Type I IFNs promote platelet activation and enhance a prothrombotic phenotype.(49) Metabolic influences may also promote and enhance the antiangiogenic effects of type I IFNs, as SLE patients with metabolic syndrome have a decreased percentage of circulating EPCs and increased arterial stiffness compared to those without.(42)* Furthermore, recent evidence implicates type I IFNs in impairing maturation of smooth muscle cells that could hypothetically promote plaque rupture.(50)** How the genetic polymorphisms that influence type I IFN pathways impact atherosclerosis risk remains to be clarified and appear to be complex. For example, while IRF5 appears to be implicated in lupus pathogenesis, it appears to have a protective role in lupus-associated atherosclerosis through effects on both immune and nonimmune cells.(16)*

Figure 1.

Potential pathways promoting atherosclerosis in SLE

Endothelial dysfunction (ED) may be induced by an imbalance of vascular damage (triggered by innate and adaptive immune stimuli) and impaired vascular repair induced by a dysfunction of endothelial progenitor cells (EPCs) induced by type I IFNs and metabolic dysfunction. Various proinflammatory pathways in the plaque may induce neutrophils to undergo NETosis and promote further inflammatory cell recruitment, induce endothelial cell death, enhance local type I IFN synthesis, oxidize lipoproteins and promote thrombosis. Type I IFNs and other stimuli may promote enhanced foam cell formation. Decrease in B Regulatory cells (BRegs) may promote loss of natural IgM, impaired apoptosis and increased IFNs at the level of the plaque. Platelet activation may lead to acute coronary syndromes.

Myeloid cells and atherosclerosis in SLE

Neutrophils

A role for neutrophils in atherogenesis and plaque destabilization has recently been proposed. High-fat diet exposure can induce neutrophil recruitment into arterial walls and complement activation.(51)** Low density granulocytes (LDGs) are a distinct subset of proinflammatory neutrophils present in SLE patients(52) that may play important roles in vascular damage and atherogenesis in this disease through multiple mechanisms. For example, LDGs have an enhanced capacity to synthesize type I IFNs, propagating a vicious cycle of vascular damage, abnormal endothelial repair and atherothrombosis.(53) LDGs can activate a cell death program in endothelial cells through their enhanced capacity to form NETs.(52) NETs have been identified in atherosclerotic plaques in humans and mice(54) and matrix metalloproteinase-9 (MMP-9), found on NET surfaces,(55)** damages endothelial cells (Figure 1). Recently, it has been shown that oxidized mitochondrial DNA and mitochondrial ROS synthesis is increased in NETs, and these molecules drive enhanced IFN synthesis in target myeloid cells, thereby exacerbating potential for inflammatory responses systemically and in the vascular plaque.(56)**

NET formation induced by cholesterol crystals in atherosclerotic plaques primes macrophages for IL-1β production, leading to an IL-1β/IL-17 loop that promotes inflammation.(57)* OxLDL can stimulate NETosis (58), while NETs have a pronounced effect on HDL oxidation and may impair the anti-atherogenic roles of this lipoprotein.(33) Thrombus NET burden correlates positively with infarct size and negatively with ST-segment resolution.(59)** NETs are also prothrombotic and may play important roles in the development of acute coronary syndromes(60**, 61) Therefore, NETs seems to play a role in many crucial aspects of vascular health, and may contribute to the risk left unexplained by traditional factors.

Macrophages

Macrophages are central to the pathogenesis of atherosclerosis(62), and many SLE related factors influence macrophage behavior. SLE monocytes are more prone to oxidative damage (63)* and there is evidence for increases in macrophage proinflammatory subsets M1 and M2b, and decreases in the anti-inflammatory M2a and M2c populations in SLE, which may contribute to inflammation.(64) IFNs drive macrophages to engulf lipids,(48) and enhanced monocyte migration to plaque site increases foam cell production. FcRyIIB is an inhibitory member of the family of Fc receptors (FcR). FcRyIIB knockout mice were found to have lower lipid levels yet had larger atherosclerotic plaques.(15)* Lack of FcRyIIB promotes both autoantibody production in SLE and promotes atherosclerosis in mice.(65, 66)

Adaptive immunity

B cells and Autoantibodies

Subpopulations of B cells may alter risk for CV events, as B1 cells have been described as protective in CVD, whereas B2 cells appear to be pathogenic. B1 cells produce natural antibodies to oxidized LDLs, thus conferring potential cardioprotection (Figure 1).(67) Patients with SLE have decreased levels of protective IgM antibodies against the apoB-100 antigens p45 and p210, and these are further reduced in SLE patients with CVD.(68) Recently, a dysfunctional feedback loop between regulatory B cells and pDCs has been implicated in the pathogenesis of SLE.(69)* Interestingly, B cell depletion restores normal regulatory feedback in SLE and also reduces atherosclerosis.(70)

Immune complexes are identified in atherosclerotic plaques, but evidence remains conflicting over whether they drive plaque formation or vascular damage. Recent evidence suggests that they may amplify endothelial damage through cytolysis and interruption of phagocytosis and autophagy, causing inflammation and increase in plaque.(15)* Antiphospholipid (aPL) antibodies (found in 30–40% of SLE patients) increase risk for thrombosis, may enhance expression of adhesion molecules on endothelial cells and increase monocyte adhesion, increasing mortality in SLE patients. In SLE patients, anticardiolipin titers predict atherosclerosis and thrombus.(71*–73) Anti-β2GP1 antibodies in patient sera predisposes to an increase in NETs and thrombin production.(74)* These prothrombotic factors may add to SLE CV risk.

T cells

Activated T cells are expanded in SLE patients (33), while Treg cells are decreased in number and function; this may contribute to autoimmunity and inflammation.(75) Tregs may protect against atherosclerosis, as they improve endothelial function, inhibit B cell activation and the production of inflammatory cytokines. Proatherogenic ApoE−/− mice have significantly lower number of Tregs compared with wild type,(76) and Treg deficient mice show increased atherosclerotic lesions and plaque vulnerability.(77) Whether this Treg imbalance is implicated in atherogenesis in SLE remains to be determined.

Screening

Risk factors

As traditional risk factors contribute to CV risk in SLE, it is imperative that smoking cessation, healthy weight, and exercise are encouraged. Recently published adult guidelines recommend the following: initial risk assessment of lipid profile, blood pressure and fasting glucose assessment, tobacco exposure, and plasma homocysteine evaluation; hsCRP and SLE monitoring labs at each visit, and yearly assessment of aPL antibodies.(78)** CIMT monitoring is recommended for patients with > 1 risk factor or renal disease but their utility needs to be further validated. In childhood-onset SLE, no imaging has yet proven robust for surrogate of atherosclerosis and screening guidelines remain to be developed.(13) It is unclear if these modifications will mitigate CV risk in subsets of SLE patients. Other non-invasive markers of reversible endothelial dysfunction, such as flow mediated vasodilation (FMD), and reactive hyperemia- peripheral arterial tonometry (RH-PAT) have been reported to be increased in SLE patients, but require further validation in large studies.(79, 80)

Biomarkers are needed to serve as reliable surrogates for atherosclerotic disease in SLE. Novel methods able to determine which SLE patients are at increased risk for CVD are also of interest. Recently, the PREDICTS model that uses a combination of inflammatory and metabolic markers (inflammatory HDL, leptin, TWEAK, and homocysteine, age, and diabetes status) demonstrated good predictive capacity for development of atherosclerosis in female SLE patients in short term follow up.(81) As neutrophils may play important roles involved in both SLE and atherosclerosis pathogenesis, the proteins S100A8, A9, A8/9, and A12 (secreted by activated neutrophils and associated to inflammation and atherosclerosis)(82)** have been proposed as putative biomarkers but remain to be validated. Indeed, in the general population, elevation of these proteins predicts future CV events,(83) and use of these alarmins as CVD biomarkers warrants investigation in SLE. Carotid ultrasound and CT for coronary calcification assessment have been used to predict subclinical atherosclerosis in SLE in research studies, but may only identify a small subset of individuals with damage and at risk for CV events. It is not only the quantity of plaque, but its quality, that needs to be further examined in these individuals. Assessments of vascular inflammation, unstable plaque and microvascular disease should be studied for risk stratification in SLE.¹⁸F-flouride PET/CT or MRI may identify patients with vulnerable plaque;(84)* further studies are needed to determine if it can identify SLE patients at risk for CV event (Table 1).

Table I.

Potential Imaging and Vascular Function Screening tools for CVD in SLE

Tool	Measures	Abnormal in SLE
US for CIMT and carotid plaque (78) (85)	Carotid artery intima media thickness, subclinical atherosclerosis; association with coronary atherosclerosis	x
Flow mediated vasodilation (FMD) (79, 80)	Non-invasive method to evaluate endothelial dysfunction in conduit vessels	x
Reactive hyperemia- peripheral arterial tonometry (RH-PAT) (79, 80)	Non-invasive method to evaluate endothelial dysfunction in microvessels. Associates with coronary involvement	?
(18)FDG PET CT or MRI(84)	Quantifies uptake by inflammatory cells in the aortic tree.	?
Pulse wave velocity (PWV)(42, 86)	Non invasive measure of arterial stiffness, but depends on blood pressure; associates with CV risk.	x
Cardio-ankle vascular index (CAVI)(87)	Non-invasive measure of arterial stiffness, independent of blood pressure; associates with coronary abnormalities.	?

Therapeutic targets

Statins

Statins are a cornerstone of treatment in atherosclerosis through pleiotropic metabolic and anti-inflammatory effects.(88–90) Previous studies on the use of statins in SLE have been overall small in size and not shown improvement in outcomes, despite improved lipoprotein profiles.(91) More recently, specific statins were shown to modulate distinct inflammatory pathways.(92) Simvastatin lowers small LDL-IgG-immune complex levels more effectively than levels of LDL-cholesterol and LDL-apoB levels in individuals with atherosclerosis.(93)* Atorvastatin decreases IL-6 and IL-10 and this could have implications for SLE.(86) Fluvastatin had anti-inflammatory effects on SLE macrophages, lowering ROS production.(63)* A recent study suggested that statin therapy in Taiwanese SLE patients with hyperlipidemia may reduce the risk of mortality, CVD and end-stage renal disease.(94)** As we learn more about the shared pathogenesis of these inflammatory conditions, perhaps specific statin and patient selection will yield greater improvement in CV risk for SLE patients.

Antimalarials

Antimalarials are standard of care in SLE and they improve lipid profiles and may have vasculoprotecive effects.(95) Hydroxychloroquine has been shown to inhibit IFN production by pDCS, which may account for the reduced risk.(96) In murine models of SLE, hydroxychloroquine decreased reactive oxygen species production via NADPH, improving nitric oxide availability and preventing endothelial dysfunction. (97)** Antimalarials also inhibit NET formation in vitro and this could have a putative vasculoprotective role.(98)

Insulin resistance

Insulin resistance in SLE is associated with traditional CV risk factors as well as higher levels of oxLDL and end organ damage. (41, 99) Therapy aimed at improving insulin resistance therefore holds promise for ameliorating some of the excess CV risk of SLE. Metformin downregulates NET formation and IFN generation, and was shown to decrease SLE flares in a recent pilot study.(100) However, whether metformin will be efficacious is reducing CV risk in SLE requires further investigation. PPAR-y is a transcription factor involved in lipid metabolism, inflammation, insulin resistance, and vascular health, by inhibiting leukocyte and endothelial cell interaction in endothelial cells.(101)** PPAR-y-treated mice showed significant decreases in immune complex deposition, renal inflammation, improvement in insulin resistance, adipokine, and lipid profile and reduced SLE associated atherosclerosis,(102–104) making this an interesting prospect of therapy for CVD in SLE.(105) Indeed, a recent pilot study performed in subjects with rheumatoid arthritis who received the PPAR agonist pioglitazone indicated a significant modulatory effect on vascular function and inflammation, suggesting that this class of drugs could be investigated in SLE.

Vitamin D

Vitamin D deficiency is common in patients with SLE, and has been associated with CVD in the general population.(106) SLE patients with low vitamin D are at higher risk for CV events,(107, 108) and have increased aortic stiffness.(109, 107**) Treatment with Vitamin D improved myeloid angiogenic cell numbers and function, possibly through downregulation of IP10(110) and regulation of nitric oxide in endothelial cells.(111) A small study suggests Vitamin D repletion may benefit endothelial function in SLE,(112) but large prospective studies are needed to determine the role of Vitamin D supplementation in cardioprotection for SLE.

Biologics

Other anti-inflammatory therapies, such as anti-IL6(113) and TNF inhibitors(114) are currently in clinical trials to decrease CV risk in patients with rheumatoid arthritis. In SLE, targeting B cells through anti-BLys(67) or anti-CD20(67) may have the potential to reduce endothelial dysfunction but this remains to be further investigated. Given recent positive results with anti-type I IFN receptor trials for SLE disease activity(115) and the putative role that these cytokines play in atherogenesis in SLE, it will be important to determine their role in CV health in this disease.

SUMMARY AND CONCLUSION

CV disease is not only an important comorbidity of SLE, but similar proinflammatory and dysregulated immune pathways may lead to shared pathogenesis of these two conditions. Prospective studies are needed to determine ideal monitoring for subclinical disease (Table I), prevention of atherosclerosis, and aggressive treatment of ongoing CVD to reduce the excessive risk for SLE patients.

Key Points.

• Cardiovascular disease confers significant risk for SLE patients, which cannot be accounted for by traditional risk factors.

• Dysregulation of the innate and adaptive immune system in SLE likely contributes to premature CVD.

• Novel imaging methods and biomarkers for identifying subclinical vascular inflammation and patients at high risk for poor CV outcomes are needed

• Decreasing oxidative damage caused by neutrophils and interrupting the proinflammatory loop perpetuated by type I IFNs may improve CV outcomes for SLE patients.