Management of cardiovascular disease in patients with systemic lupus erythematosus

Abstract

Introduction

SLE is increasingly recognized as an important risk factor for cardiovascular disease. Premature CAD and several other cardiac manifestations are resulting in significant morbidity and premature death among young and older adults. There is a considerable unmet need for developing specific guidelines towards the primary and secondary prevention of cardiovascular disease in SLE patients.

Areas covered

The authors describe the prevalence of various cardiovascular manifestations, associated with traditional and lupus specific risk factors.They summarize the evidence behind various nonpharmacological and pharmacological options such as cardiac medications, antimalarials, anti-inflammatory and immunosuppressant medications.

Expert opinion

There is considerable literature claiming that the traditional Framingam score used to calculate the risk in the general population would not clearly predict the 10-year risk among SLE patients as they don’t include lupus specific risk factors such as accelerated inflammation, immunometabolic changes, thrombosis, vasospasm, vasculitis and endothelial dysfunction into account. Identifying potential risk factors among SLE patients and treating hyperlipidemia regardless of their risk scores may be the first step in reducing mortality. Blocking lupus-specific inflammatory pathways by targeting validated biomarkers of pathogenesis have great future potential and more studies are needed on their cardiovascular benefits.

1. Introduction

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease, that has been recognized as one of the important risk factors for increased cardiovascular morbidity and mortality, among young and older adults.[1,2] Mortality in SLE follows a bimodal pattern, first peak caused by disease activity, infections and the second peak caused by cardiovascular disease (CVD).[3] A meta-analysis of observational studies done in SLE showed a standardized mortality ratio of 2.72 for CVD related death when compared with the general population.[4] Although the improvement in CVD mortality seen in the general population, a similar trend was not observed among SLE patients.[5] The etiology behind increased CVD in SLE patients is not completely elucidated, however, various pathophysiologic mechanisms like accelerated atherosclerosis, thromboembolism, arteritis, vasospasm, and abnormal coronary flow were proposed in the literature.[6] Understanding the spectrum of CVDs and the associated traditional and novel risk factors will help us to develop more targeted prevention and treatment strategies to reduce the high CVD burden. Accelerated atherosclerosis observed due to chronic inflammation in autoimmune diseases like SLE, RA and psoriasis thus American College of Cardiologists recommended considering SLE as one of the important risk factors in addition to the traditional ones.[7] Various treatment strategies like anti-inflammatory therapy, lipid-lowering therapy, anti-platelet agents were proposed to reduce morbidity from CVD. In this review, we evaluated the studies published over the last three of decades related to the pathogenesis and management of cardiovascular disease in SLE.

2. CVD types and their prevalence in SLE

The prevalence of cardiac diseases in SLE is reported to be higher than 50% of the SLE patients at some point in their life.[8] SLE increases the risk of a wide variety of cardiovascular diseases and is listing the different types below.

1. Coronary artery disease (CAD) - clinical and subclinical forms

2. Infectious and non-infectious endocarditis

3. Myocarditis, cardiomyopathy

4. Pericarditis, Pericardial effusion and tamponade

5. Cardiac arrhythmias (tachyarrhythmias and bradyarrhythmias)

6. Peripheral vascular disease

7. Cerebrovascular accident

8. Venous thromboembolism (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis)

Pericarditis and pericardial effusion related to SLE are reported in nearly a quarter of the patients and the majority of the patients with pericardial effusion are asymptomatic.[9,10] Cardiac tamponade or hemopericardium also reported and very rarely they could be the initial presentation in SLE.[11–15] Autopsy studies done in SLE patients showed myocardial involvement around 40% patients, however, the prevalence of clinical myocarditis seemed to be around 10% or lower^.[16–18] The natural progression of the myocarditis may vary from complete resolution to dilated cardiomyopathy, conduction abnormalities, tachyarrhythmias and heart failure, however majority of them the prognosis is positive.[19] Endocardial and valvular disease in lupus can occur with or without antiphospholipid syndrome (APS).[20,21] Symptomatic coronary artery disease occurs in 6–12 % of the SLE patients and asymptomatic subclinical disease occur in 40% of the patients.[22,23] Bhatt et al demonstrated a 28 % prevalence of PVD in 50 SLE patients they studied.[24] Secondary APS in SLE can also lead to various arterial and venous thromboembolic manifestations. CKD from lupus nephritis, drugs that are not commonly used like cyclosporine could cause hypertension or worsen pre-existing hypertension in SLE patients. SLE patients also suffer from pregnancy-related CVD like early-onset pre-eclampsia and other thrombotic microangiopathies.

3. Traditional, and SLE-specific risk factors for CAD

Risk factors associated with CAD in SLE could be broadly classified as traditional and lupus specific risk factors (Tables 1 and 2). The impact of the traditional risk factors for atherosclerosis in SLE patients is not clearly established as it for the general population. The Hopkins lupus cohort reported an 8 % cumulative incidence of CAD and identified an increased prevalence of at least 3 traditional risk factors in 53% of their cohort.[22] A Toronto cohort study of 250 women with SLE also identified an increased prevalence of diabetes, hypertension, hyperlipidemia, and early onset menopause.[25] A study demonstrated nearly 75.4 % of the patients developed hyperlipidemia within 3 years of diagnosis, 40.3% of has sustained elevation in their lipid levels and the best predictors for the sustained elevation of lipids were an age of onset of SLE >35 years, medications such as the presence of steroids, and absence of hydroxychloroquine.[26] CAD-related mortality observed in SLE patients was significantly higher than the prediction from Framingham 10 year prediction model.[27] There are various lupus specific factors that play a role in CAD and the important ones are inflammation with elevated pro-inflammatory cytokines, homocysteinemia, antiphospholipid antibodies, and renal disease and proteinuria increases the risk of atherosclerosis and thrombosis. [28] Arterial dysfunction markers such as increased systemic arterial stiffness diminished regional wall flexibility were demonstrated in SLE patients by showing increased aortic augmentation index, and increased carotid-radial pulse wave velocity.[29]

Table 1.

Traditional risk factors and therapeutic interventions

Classical/Traditional CVD risk factors	Therapeutic interventions	References
Diabetes	Insulin and oral hypoglycemic drugs	[30]
Hypertension	Anti-hypertensives	[31]
Hyperlipidemia	Statins and other lipid lowering drugs	[32]
Obesity	Diet, exercise, FDA approved medications and surgery	[33]
Smoking	Smoking cessation
Family history of CAD	Nothing specific other than controlling risk factors

Table 2.

SLE-specific risk factors and therapeutic interventions.

Lupus specific risk factors	Therapeutic interventions	References
Chronic inflammation with elevated pro-inflammatory cytokines	Hydroxychloroquine, anti-interferon therapy	[34–38]
Antiphospholipid antibodies	Anticoagulation, immunosuppression, hydroxychloroquine	[39]
Immune complex deposition with vasculitis	Immunosuppressants	[40]
Type 1 interferon pathway activation in plasmacytoid dendritic cells, neutrophils, and endothelium	Anti-interferon therapy	[41]
Lupus related renal disease, GN and IN	Immunosuppressants, Renal replacement therapy	[42]
Increased homocysteine and decreased mannose-binding lectin	Although no specific interventions, folic acid and vitamin B12 are beneficial in hyper-homocysteinemia patients	[43]
Drugs used in lupus treatment	Usually the benefits outweigh the risk, avoid when it is not	[44]
Oxidative stress, mTOR pathway activation	Rapamycin, NAC	[45–47]
Arthritis – diminished exercise tolerance due to pain	Treatment of arthritis, symptomatic therapy and physical therapy	[48,49]
Serositis: pericarditis, pleuritis	Immunosuppressants	[50]
Myocarditis, arrhythmia	Immunosuppressants, anti-arrhythmics	[51]

4. Management of coronary artery disease disease in SLE

A combination of pharmacological and non-pharmacological approaches targeting the atherosclerosis, thrombosis and inflammation (Figure 1) with good compliance may contribute to an effective model of cardiovascular disease management in SLE. Few studies have evaluated the diet, exercise, lifestyle modifications, and behavioral modifications such as smoking cessation in SLE patients. To date, various cardiac medications, biologic and non-biologic immunosuppressants, vitamin and supplements are used to treat cardiovascular manifestations of SLE. The majority of the treatment decisions are not made from high-quality randomized control studies (RCT), rather supported by open label studies, case series, and cross-sectional studies. Although the risk of CAD is higher in SLE patients, we do not have any established guidelines that talk about prevention in this population. Management of cardiovascular disease will depend on the various cardiovascular manifestations and underlying pathology driving the disease. We are highlighting the treatment for each type of cardiovascular disease based on available literature.

Figure 1.

Pro-inflammatory cytokines in SLE like IFN alpha, IL-1, IL-6 and TNF-alpha promotes formation of foam cells, proliferation, platelet adherence, thrombosis and fibrosis. Smoking, hypertension in SLE results in endothelial injury. Impaired glycemic control, DM in SLE can results in endothelial injury and increased lipids. Obesity, sedentary life style in SLE increases LDL and decreases HDL. Pro-atherogenic lipoprotein particles such as LDL infiltrate into the intima of the arterial wall and undergo oxidative modification. Accumulation of these atherogenic particles attracts macrophages that engulf the cholesterol, causing formation of foam cells and subsequent fatty streaks. This process injures the epithelium of the arterial wall, promoting adherence of platelets, release of PDGF, and development of an advanced fibrocalcific lesion. Anti-atherogenic particles such as HDL and apo-A1 promote reverse cholesterol transport and cholesterol efflux from foam cells. They also help to prevent oxidation of LDL and other atherogenic particles. Targets 1 – 8 are proposed to consider for therapeutic interventions to manage cardiovascular disease in SLE.

1 – Drugs used to control inflammation in SLE like hydroxychloroquine, mycophenolate, azathioprine, rapamycin, belimumab, rituximab, cyclophosphamide, steroids, and methotrexate

2 – Anti cytokine therapy like anakinra, anifrolumab

3 – Smoking cessation

4, 5 – Effective treatment of hypertension, diabetes

6 – Diet, and exercise

7 – Statins

8 – Anti platelets and anticoagulants

Abbreviations : Interleukin (IL), Interferon (IFN), TNF – Tumor necrosis factor (TNF), diabetes mellitus (DM), PDGF – Platelet derived growth factor, LDL – low density lipoprotein, HDL – High density lipo protein, ApoA1 – apo lipoprotein A 1, LCAT – Lecithin cholesterol acyl transferase

5. Non-pharmacological measures in reducing CVD in SLE patients

An RCT evaluated the outcome of the low glycemic diet (n=11) and low-calorie index diet (n=12) in 23 SLE patients for six weeks and both diets resulted in significant initial weight reduction, improvement in fatigue and improved hip and waist circumferences.[52] Another RCT omega 3 polyunsaturated fatty acids supplementation in SLE patients who don’t have traditional CAD risk factors, not on prednisone showed significant improvement in endothelial function (evident by elevation in flow-mediated dilatation (FMD) of the brachial artery), disease activity (BILAG and SLAM-R) and reduction in the oxidative stress (demonstrated by a statistically significant reduction in platelet-8-isoprostanes) in the intervention group compared to the placebo group at 12 and 24 weeks.[53] Prospective non-randomized study with 38 SLE patients on the impact of physical exercise for 16 weeks showed statistically significant improvement in fatigue, aerobic capacity, quality of life without affecting the disease activity in the exercise group (n=18) compared to the control group (n=20).[49] A prospective study evaluating supervised exercise in SLE patients for 16 weeks demonstrated improvement in endothelial dysfunction[54,55] and aerobic capacity[49,55] without affecting the disease activity.[55] Prado et al demonstrated that 3 months of exercise improved cardiorespiratory capacity and autonomic function in SLE patients.[56] O’Neil et al demonstrated 47% of smoking cessation out of 308 patients followed for 3 years by adopting a protocol of risk stratification and counseling in SLE patients.[57]

6. Pharmacological management of clinical and subclinical atherosclerotic cardio vascular disease and thrombotic disease in SLE patients

6.1). Management of acute cardiovascular disease in SLE

The approach to treatement of symptomatic CAD in lupus patients depends on nature of the primary driving pathology. If it is acute coronary syndrome or stable angina related atheroscelerotic heart disease guideline directed therapy as per ACC/AHA guidelines recommended.[58,59] If there is an element of Prinzmetal angina from vasospasm vasodilators are used to treat.[60] If there is any evidence of small, medium or large vessel vasculitis steroids, immunosuppressants will be used to treat according to treatment protocol for the specific type of vascultis.[61] The management of acute stroke(AHA/ASA)[62], acute limb ischemia(AHA/ACC)[63], and acute venous thromboembolism manifestations(CHEST)[64] usually follows the respective society guidelines even if they are related to Lupus. As these guidelines are relatively well defined, reviewing them here will be beyond the scope of this review.

6.2). Primary and secondary prevention of cardiovascular disease in SLE

In the Toronto cohort group of SLE patients, treatment of hypertension, hyperlipidemia were compared among two different time periods. Although 88–96% of hypertensive patients received antihypertensive agents, only 21–28 % of hyperlipidemia patients received lipid-lowering agents.[65] One possible reason could be when risk stratifying for future cardiovascular disease SLE are typically not included by primary care physicians, as the traditional models didn’t include SLE. A study evaluating a randomized control prevention trial in reducing traditional CVD risk factors with aggressive use of preventive medications had difficulty in recruiting and retaining patients and also identified several barriers such as lack of enthusiasm in both patients and clinicians.[66] O’Neill et al evaluated the adaptation of a protocol mandating CVD 10-year risk score calculation in SLE patients in lupus clinic, did not alter the management in 96 % of the patients as these patients were already receiving appropriate treatment. [57]

6.1.1. Statins

Cardiovascular benefits of statins in auto immune diseases like lupus are not only limited to its lipid-lowering effect but also from its anti-inflammatory, anti-thrombotic, immunomodulatory and plaque stabilizing effect.[67] A study evaluated the use of Fluvastatin in renal transplant patients in SLE reduced major cardiac events by 73.4 % and LDL reduction by 29.2%.[68] A nationwide case-control study done at Taiwan evaluating 4095 patients with SLE and hyperlipidemia has shown the potential of statin therapy reducing the mortality in CAD and ESRD patients, furthermore high dose statin reduced the mortality in acute myocardial infarction and stroke.[69] A nonrandomized clinical trial evaluated the effect of 20 mg atorvastatin on 64 SLE patients [ CAD risk factors (n=33), without CAD risk factors (n=31)] by comparing the group without atorvastatin, showed improvement of FMD (primary outcome) from 4% to 7 % only in the treatment arm. [70] One year RCT with 60 patients with 40 mg atorvastatin daily (28 receiving atorvastatin 40 mg and placebo n=32) showed decreased coronary calcium score, lipid levels and CRP in the treatment group compared to placebo.[71]

However, two year-RCT with 200 SLE patients without prior CAD risk factors (atorvastatin 40 mg arm n= 99, placebo = 101) evaluated coronary calcium score (primary outcome) and didn’t find any statistically significant difference despite having a significant reduction in the LDL, Triglycerides (secondary outcome) in the treatment group.[72] A study that compared LDL, total cholesterol reduction with pravastatin on SLE and controls found similar reduction however the patients on corticosteroids, the mean reduction was lower.[73] Routine usage of atorvastatin for 3 years in young SLE patients didn’t show any significant reduction in subclinical atherosclerosis however subgroup analysis suggested a targeted group may have some benefits.[74] Few animal studies evaluated the immunomodulatory effects of atorvastatin, however, no survival benefits were noted.[75] The effect of statins on coronary calcium score is contradicting, and the effect of mortality is not clearly elucidated, further studies need to look in to this in the future. The lipid lowering effect of statin has been clearly demostrated in various studies, and benefits of controlling hyperlipidemia in SLE patients regardless of their risk score needs to be evaluated in future.

6.1.2. Anti-hypertensive medications

The pathogenesis of hypertension in SLE is complex, lupus specific risk factors inflammation, renal dysfunction, immune dysfunction and side effects of drugs may play a role.[76] With each 2 % rise in blood pressure, there is a considerably increased mortality risk for stroke (10%) and ischemic heart disease (7%).[77] Herlitz et al evaluated the effect of captopril in treating hypertension in 14 lupus nephritis patients and excellent blood pressure control (178 +/− 7 / 110 +/− 4 to 145 +/− 5/92 +/− 3 mm Hg) was achieved in at least 11/14 patients over 6 months period with varying degrees of renal dysfunction noted in at least 60 % of them.[78] Bursztyn et al. used nifedipine to treat hypertension in 8 patients and had an effective blood pressure control (151.9 +/− 10/103.7 +/− 8.6 mmHg to a mean of 130 +/− 14.1/87.5 +/− 5 mmHg) without altering renal function and other hematological, immunological indexes. [79] In summary patients with lupus have increased prevalence of hypertension due to higher prevalence of renal disease, arterial dysfunction and controlling their hypertension is an important step in reducing the overall cardiovascular risk.

6.1.3. Anti-platelets and anti-coagulant medications

A meta-analysis evaluating the efficacy of aspirin was published analyzing 11 studies (1 RCT and 10 observational studies) including 1208 patients with positive APL and 139 thrombotic events (460 asymptomatic APL antibodies positive, 440 SLE patients, 308 obstetric APS patients) showed a 50 % reduction (OR: 0.5) in who receive aspirin (n=601) compared to those who don’t (n=607).[80] Subgroup analysis revealed aspirin protects from arterial thrombosis (OR: 0.48 [95%CI: 0.28–0.82]) rather than venous thrombosis (OR: 0.58 [95% CI: 0.32–1.06]) in all groups such as asymptomatic APL positive (OR: 0.50 [0.25–0.99]), SLE (OR: 0.55 [0.31–0.98]) and obstetric APS (OR: 0.25 [0.10–0.62]) patients.[80] Individual patient data meta-analysis including 5 international cohort studies (497 patients and 79 thrombotic events) against showed the protective role against arterial thrombosis (HR: 0.43 [95%CI: 0.20–0.93]) but not against venous thrombosis (HR: 0.49 [95%CI: 0.22–1.11]) in SLE (HR: 0.43 [95%CI: 0.20–0.94]) patients and asymptomatic APL positive patients (HR: 0.43 [95%CI 0.20–0.93]). [81] A open RCT (n = 232) compared low dose aspirin (LDA) against LDA + warfarin in asymptomatic APL positive SLE and/or obstetric morbidity patients found no difference in preventing thrombosis and more episodes of bleeding observed in LDA + warfarin group.[82] A prospective cohort study over 5 years with 272 SLE patients evaluated the effectiveness of primary and secondary prevention of myocardial infarction and stroke. Patients were categorized in to 3 groups; SLE + APS (n=84), SLE + asymptomatic APL careers (n = 81) and SLE without APL antibodies (n= 107). Primary prophylaxis was used in 52 APL positive SLE patients (50 - aspirin, 1 - clopidogrel, 1 – warfarin), 79/84 patients with APS patients (23 - Coumadin, 17- LDA + Coumadin, 37 – LDA, 2 – clopidogrel) At the end of the study, in APL positive group, one patient on LDA and 2 patients without prophylaxis developed strokes and in the APS group, there were 2 myocardial infarction and 5 strokes. [83] In summary benefits of anti platelet therapy have been demonstrated in SLE with or without APL antibodies, however, future studies need to evaluate whether the bleeding risk associate with it would outweigh the overall benefits or not.

6.1.4. Hydroxychloroquine

To date, we have few studies showing the benefit of hydroxychloroquine in improving glycemic control and reducing thrombotic events in SLE patients.[34–38] Penn et al evaluated the relationship with glycemic control of nondiabetic women on hydroxychloroquine in SLE (n = 149) and rheumatoid arthritis (n=177) by using fasting blood glucose and insulin sensitivity as 2 indicators over the period of 16 years. The SLE patients on hydroxychloroquine had better glycemic control (fasting 87.5 mg/dL vs 91.5 mg/dL, p = 0.009) increased insulin resistance by homeostasis model assessment method; HOMA-IR (2.51 vs 2.87, p = 0.046) compared to the control group. Furthermore LDL levels also decreased in the treatment group compared to the control group (102 mg/dL vs 118 mg/dL, p=0.004).[35] A systematic review of English literature between 1982–2007 including 95 articles high-level evidence for increased survival and moderate evidence for protection against thrombosis.[34] Three other individual studies also demonstrated the benefit of antimalarials by showing a significant reduction in thrombotic events in SLE patients.[36–38] In summary the cardiovascular benefit of antimalarials is ovewhelming compared to the small risk of cardiomyopathy.

6.1.5. Belimumab

Belimumab is the first FDA approved biologic agent works by inhibiting B-lymphocyte stimulating protein. Parodis et al. surveyed the patients who received belimumab at a dose of 10 mg/kg in BLISS-52 and BLISS −76 trials and found cardiovascular damage had negative influence (OR: 0.13; 95% CI 0.02, 0.97; P = 0.047) on achieving remission (SLEDAI-2K = 0) along with limited or no steroid use.[84] Belimumab is widely used to treat SLE with mild to moderate SLE; future studies need to evaluate the long-term cardiovascular benefits.

7. Potential new treatments for atherosclerotic and thrombotic cardiovascular diseases in SLE

7.1. mTOR inhibitors.

The mechanistic target of rapamycin (mTOR) pathway is increasingly recognized as one of the key drivers of pro-inflammatory responses in autoimmune diseases like SLE.[85] The mTOR has been shown to be an effective target of therapy both in mice [86] and patients with SLE [87–89]. In cardiac and endothelial cells mTOR pathways are crucial for their growth, regulation of apoptosis and autophagy in oxidative stress, angiogenesis and tissue repair.[90] Chronic activation of mTOR can lead to cardiac and vascular dysfunction.[91] Long-term treatment with mTOR inhibitors has resulted in reduction of vasculopathy and improvement in coronary flow status post cardiac transplant.[92,93] Drug eluted stents that are placed during percutaneous coronary intervention also coated with mTOR inhibitor sirolimus to prevent restenosis.[94] Future trials need to evaluate role of mTOR inhibitors in the management of cardiovascular disease in Lupus. Given the newly uncovered role for mTOR in production of antiphospholipid antibodies outside[46] or within the context of SLE[47], their potential role in reducing thrombotic events also needs to be evaluated in future.

7.2. N-acetylcysteine (NAC)

The effectiveness of NAC has been demonstrated in lupus prone mice[95] and patients with SLE[45]. NAC therapy could result in matrix degradation; improve vascular stability in early and late stages of atherosclerosis.[96,97] The potential role of NAC in preventing cardiac myocyte injury in ischemia, reperfusion, preventing thrombosis through antiplatelet activity, activity against vasospasm, the ability to prevent and reverse nitrate tolerance has been demonstrated.[97–99] As there is considerable evidence of several significant benefits of NAC in SLE and cardiovascular disease, future trials need to focus its role in the management of cardiovascular disease in SLE.

7.3. Blockade of interferon signaling

Type 1 interferon plays a major pathogenic role in SLE and increased interferon signature demonstrated in peripheral blood and tissues in SLE patients.[100,101] Recent in-vitro studies have demonstrated the role of interferon alpha in promoting foam cell formation in atherosclerosis[102], increasing thrombosis[103] and may explain the role of interferon alpha in premature CVD associated with SLE. A recent study in a cohort of SLE patients without pre-existing CVD demonstrated that type 1 interferon activity associated with decreased FMD, increased carotid intima media thickness and coronary calcium score in SLE patients.[104] TULIP 1 trial (anifrolumab - anti interferon alpha receptor monoclonal antibody) did not meet its primary end point SRI 4 response, however, TULIP 2 trial met its primary end point BICLA and showed statistically and clinically meaningful increase in BICLA response [41] Future studies need to focus on the role of interferon blockade in managing cardiovascular disease in SLE patients.

7.4. PCSK9 inhibitors

Proprotein convertase subtilisin kexin 9 (PCSK9) is a protein that plays an important role in LDL metabolism by modulating LDL receptor degradation and recycling.[105] In experimental models, shear stress in vascular smooth muscle cells (VSMC) and endothelial cells up-regulated PCSK9 and its pro-inflammatory, pro-atherosclerotic effects were independent of LDL levels.[106,107] Oxidized LDL receptor LOX-1 is increased in VSMC during inflammation. PCSK9 increase LOX-1 transcription and in turn LOX-1 increases PCSK9 levels, resulting in accelerated atherosclerosis during inflammation.[106] In a LDL receptor dependent fashion, PCSK9 also favors the migration of inflammatory monocytes and macrophages.[106] PCSK9 inhibitors such as alirocumab, evolocumab were recently FDA approved to treat hyperlipidemia.[105] Their effect in controlling atherosclerosis in chronic inflammatory diseases needs to be evaluated with human studies.

8. Management of anti-phospholipid syndrome in SLE

Anti-phospholipid syndrome is an acquired pro-atherosclerotic and pro-thrombotic disease, which predisposes to premature CAD, thrombosis and obstetric complications. Following a thrombotic event, life-long anticoagulation is recommended, and the benefits outweigh the bleeding risks.[108] Studies have shown warfarin and enoxaparin are superior to direct anticoagulants.[39] RAPS a randomized, controlled, open label, phase 2/3, non-inferiority trial compared the use of direct oral anticoagulant (DOAC) rivaroxaban with warfarin in patients with thrombotic APS with or without SLE. The primary outcome, endogenous thrombin potential measured on day 42 from randomization with a non-inferiority set at less than 20 % difference from warfarin in mean percentage change, did not meet its non-inferiority threshold for rivaroxaban.[109] However, there was no increased risk of thrombosis or major bleeding observed on 210 days follow up compared to warfarin make us think whether it could be a safe alternative to warfarin.[109] Ordi-Ros J et al compared the rivoraxaban and warfarin in thrombotic APS patients and rivaroxaban didn’t show non-inferiority, in fact, depicted a non-statistically significant increase in recurrent thrombotic events.[110] TRAPS trial reported an increased risk of arterial thrombosis in triple positive APS patients given rivaroxaban compared to warfarin suggesting that DOAC drugs should be avoided in this situation.[111] The trial was stopped prematurely due to the excessive arterial thrombotic events in the rivaroxaban arm.[111] Currently ASTRO-APS trial is comparing apixaban with warfarin for thrombotic APS, and the investigators had to modify their protocol due to increased arterial events in one treatment arm.[112] The current consensus recommends warfarin over DOACs for thrombotic APS; however, emerging evidence may allow the use of DOACs in future in carefully selected individuals, especially lower risk APS group who is not triple positive. LDA and enoxaparin are used in obstetric APS to improve the outcome.[108]

Asymptomatic APL careers also have a higher risk of future CAD, thrombosis and obstetric complications compared to general population. In high-risk APL careers, LDA and hydroxychloroquine is recommended, and the benefit of anticoagulation doesn’t usually outweigh the bleeding risks.[82,108] Catastrophic antiphospholipid syndrome is managed with anticoagulation, steroids and plasmapheresis and in resistant cases B-cell depletion (rituximab) and anti-complement therapy (eculizumab) are recommended.[39]

β2-glycoprotein- I (β2GPI) is recognized as the major driving antigen in APS. (Figure 2) It is produced in liver and exists in oxidized and non-oxidized form, studies in mice have shown mTOR dependent mitochondrial dysfunction and oxidative stress increases the oxidized B2GPI production.[47] Oxidized B2GPI with or without oxidized LDL/B2GPI complex binds with APL and increases the atherosclerosis and thrombosis.[113] Rapamycin, an mTOR inhibitor blocked aPL production along with clinical disease in mice; potential cardiovascular athero-thrombotic benefits should be evaluated in humans.[47] NAC helps to restore the reducing environment and controlled trial in SLE patients have shown mTOR blockade with rapamycin and NAC, resulted in reduction of APL antibody levels.[89,114]

Figure 2.

β2GPI is recognized as the primary antigen driving aPL production in APS. It is produced in liver. Only its oxidized form is antigenic. Its oxidization is promoted by mTOR dependent mitochondrial dysfunction. mTOR inhibitors, can be used to reduce the oxidative stress in liver and trials have shown they reduce the aPL production in SLE. Immunosuppressant medications and plasmapheresis are used to reduce the pathogenic antibodies in CAPS. Anticoagulation, and lipid lowering therapy like statin also benefits in thrombosis and atherosclerosis respectively. Abbreviations: aCL – anti cardiolipin, β2GPI – β 2 glycoprotein- I, CAPS – catastrophic anti phospholipid syndrome, mTOR – mammalian target of rapamycin, NAC – N-acetylcysteine, LDL – low density lipoprotein, aPL – Anti phospholipid antibodies, SLE – systemic lupus erythematosus.

9. Management of pericarditis and myocarditis in SLE patients

The first episode of mild to moderate pericarditis is usually treated with oral or parenteral steroids. FLOAT trial randomized 50 SLE patients who presented for mild to moderate SLE flare with pericarditis to receive either intramuscular triamcinolone 100 mg or oral methylprednisolone (Medrol dose-pack) and both groups did equally well at end of month.[115] However, the triamcinolone group had a quicker response compared to the medrol pack group.[115] Patients with recurrent pericarditis usually treated with steroid-sparing disease-modifying anti-rheumatic drugs (DMARDS) like azathioprine, methotrexate, mycophenolate mofetil.[8,116] Colchicine has shown good response in treating recurrent pericarditis especially in subgroups with post-procedural atrial fibrillation and post-pericardiotomy syndrome.[117] Although there are no specific trials in lupus, in general, refractory pericarditis has shown a good response to intravenous immunoglobulin therapy, which could be tried in refractory lupus pericarditis.[118] Anakinra, an interleukin-1 antagonist, has shown promising response in pericarditis in autoimmune/autoinflammatory diseases, however not described lupus, future clinical trials need to evaluate its use in refractory lupus pericarditis.[119–121] Cardiac tamponade or severe pericarditis usually considered as an organ/life-threatening manifestation of lupus and treated with pulse steroid therapy with 1 gram of methylprednisolone.[8] Cardiac tamponade with hemodynamic compromise also should involve cardiology and cardiothoracic surgery for evaluating the necessity for pericardiocentesis, pericardial window or stripping.[8]

Myocarditis is a fatal manifestation of SLE and the majority of the evidence derived from case reports, case-control and cohort studies. The majority of the patients with lupus myocarditis usually respond to treatment with high dose steroids and their cardiac function improves with time.[51,122] Severe cases of myocarditis result in poor cardiac function causing cardiogenic shock and those individual cases are treated with intravenous cyclophosphamide in the past.[123–125] Azathioprine could be used as steroid-sparing maintenance therapy.[126] A 10-year monocentric retrospective cohort study evaluated the use of rituximab in refractory lupus myocarditis in 3 SLE patients and shown improved outcomes in all.[127] There are individual case reports claiming the success of intravenous immunoglobulin therapy in severe lupus myocarditis.[128,129]

10. Expert opinion

There is considerable literature claiming that the traditional Framingham score used to calculate the risk in the general population would not clearly predict the 10-year risk among SLE patients as they don’t include lupus specific risk factors such as accelerated inflammation, thrombosis, vasospasm, vasculitis and endothelial dysfunction into account. Few studies have clearly demonstrated the benefits of diet, exercise and behavioural modifications in improving the cardiovascular health of lupus patients. Identifying potential risk factors such as hypertension, hyperlipidemia, smoking among SLE patients and treating hyperlipidemia regardless of their risk scores may be the first step in reducing mortality. Chronic kidney disease with or without lupus nephritis needs to be aggressively managed as preventing the progression of kidney disease will improve the cardiovascular morbidity and mortality in SLE patients.

Several studies have shown that statin therapy results in lowering lipids, contradicting effect on coronary calcium score and their overall benefit in cardiovascular mortality in SLE patients need to be studied further. The use of anti-platelet and anti-coagulants are beneficial in the primary prevention of thrombotic events in SLE with or without antiphospholipid syndrome. Steroids and other immuno-suppressants are mainstay in the management of lupus myocarditis and pericarditis and treatment tailored according to the severity of the disease. The cardiovascular benefit of hydroxychloroquine is overwhelming compared to the small risk of cardiomyopathy. NAC, mTOR inhibitors, anti-interferon therapy, PCSK 9 inhibitors have great future potential, albeit more studies needed with a clear focus on cardiovascular outcomes. Both the rheumatologists and primary care physicians should know the importance in assessing the cardiovascular risk in SLE patients and further management depends on their risk stratification.

Article Highlights.

• SLE is increasingly recognized as an important risk factor for cardiovascular disease young and older adults.

• SLE increases the risk of a wide variety of cardiovascular diseases, traditional models don’t include lupus specific risk factors.

• Management of cardiovascular disease will depend on the various cardiovascular manifestations and underlying pathology driving the disease.

• Todate, various pharmacological and non pharmacological methods were studied in atherosclerotic heart disease in SLE and we are reviewing evidence behind each in detail.

• Although anti-platelet agents and statins are very effective secondary prevention of CAD, their effectiveness in primary prevention in SLE patients is controversial due to mixed results in past studies.

• Hydroxychloroquine is effective in preventing in artherosclerotic heart disease and manifestations in anti-phospholipid syndrome. The effect of other anti-inflammatory therapies like mTOR inhibitors, belimumab and interferon blockade needs to be explored.

• Warfarin is generally preferred over DOACs in antiphospholipid syndrome with or without SLE, however emerging evidence may favor their use in carefully selected individuals who in low risk group.

Abbreviations

ACC

American College of Cardiology

aCL

anti cardiolipin

AHA

American Heart Association

ApoA1

apolipoprotein A1

aP

anti-phospholipid antibodies

APS

anti phospholipid syndrome

ASA

American Stroke Association

β2GPI

β2 glycoprotein –I

BILAG

British isles lupus assessment group

BLISS

Belimumab in Subjects in SLE

CAD

coronary artery disease

CAPS

catastrophic APS

CIMT

carotid intimal medial thickness

CKD

chronic kidney disease

CVD

cardiovascular disease

CI

confidence interval

DM

diabetes mellitus

DMARDS

Disease modifying anti rheumatic drugs

ESRD

end stage renal disease

FDA

Food and Drug Administration

FMD

Flow mediated dilatation

FLOAT

Flares in lupus; outcome assessment trial

HDL

high-density lipoprotein

HOMA

homeostasis model assessment

HR

hazard ratio

IL

interleukin

IFN

interferon

LDL

low density lipoprotein

LCAT

lecithin cholesterol acyl transferase

LDA

low dose aspirin

LOX 1

oxidized LDL receptor 1

mTOR

mechanistic target of rapamycin

NAC

N-acetylcysteine

OR

odds ratio

PCSK9

proprotein convertase subtilisin kexin 9

PDGF

platelet-derived growth factor

PVD

peripheral vascular disease

RA

rheumatoid arthritis

RCT

randomized control trial

SLE

systemic lupus erythematosus

SLAM R

systemic lupus activity measure revised

TNF

tumor necrosis factor (TNF)

TULIP

treatment of uncontrolled lupus via interferon pathway trial, VSMC – vascular smooth muscle cells