Systemic lupus erythematosus in adults: Coronary artery disease

INTRODUCTION — 

Systemic lupus erythematosus (SLE) is associated with several cardiovascular manifestations, including premature and accelerated atherosclerosis and subsequent cardiovascular disease (CVD). CVD, especially coronary artery disease (CAD), is a significant cause of morbidity and premature death in patients with SLE. The greatest increase in relative risk (RR) is among younger female patients, who otherwise have a low risk of CAD; however, the absolute risk of CAD in SLE increases with age, as it does in the general population [1,2].

This topic reviews various aspects of CAD in patients with SLE, including pathogenesis, clinical manifestations, routine evaluation in asymptomatic patients, and management. Other cardiac manifestations of SLE, including pericardial, myocardial, and valvular heart disease, are discussed separately. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults".)

In addition, separate topics provide an overview of the clinical manifestations, diagnosis, and management of SLE. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis" and "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)

EPIDEMIOLOGY — 

The burden of cardiovascular disease (CVD), including coronary artery disease (CAD), is high in patients with systemic lupus erythematosus (SLE) and greater than that in the general population [3-9]. The following studies are illustrative:

●Increased risk of developing CVD – A meta-analysis of 46 studies found that the risks of CVD, myocardial infarction, and stroke among patients with SLE are approximately doubled when compared with people without SLE [3]. While younger patients with SLE had the greatest relative risk (RR) of CVD compared with their healthy counterparts, the absolute risk was also higher in older SLE patients.

●Accelerated progression of existing CVD – Several studies have demonstrated accelerated progression of CVD in patients with SLE compared with control patients [4]. As an example, the risk of atherosclerotic plaque progression in one study was four times higher for patients with SLE compared with healthy controls over a period of seven years (odds ratio [OR] 4.16, 95% CI 1.22-14.19) [5].

●High CVD-related mortality – CVD is a leading cause of death among patients with longstanding SLE [6,7]. As an example, in a cohort of 816 patients with SLE followed over a decade, CVD was the most common cause of death (33 percent) [8]; when compared with the general population, those with SLE were over three times more likely to die of CVD (standardized mortality ratio [SMR] 3.83, 95% CI 2.09-6.42).

Rates of CVD and complications in patients with SLE may vary by certain demographic factors:

●Gender – Male sex is a strong risk factor for incident CVD in SLE, as it is in the general population. In the LUMINA study of 637 patients (including 65 males), male patients had an OR of 3.6 for developing CAD or a related event (eg, myocardial infarction) compared with female patients [10].

●Race and ethnicity – Black patients with SLE often have a higher risk of incident CVD than non-Black patients with SLE, likely due to multiple factors including higher disease activity, higher frequency of lupus nephritis (LN), more traditional risk factors for CVD, and more barriers related to social determinants of health (eg, poorer health care access) [11]. In addition, the risk of death from CVD appears to be even higher in patients with SLE who are Asian or Hispanic [8].

Other risk factors for the development of CVD in patients with SLE are described below. (See 'Risk factors' below.)

PATHOGENESIS — 

The pathogenesis of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) is incompletely understood and likely multifactorial. Acute presentations of coronary artery disease (CAD), such as angina and myocardial infarction, are most commonly due to atherosclerosis in patients with SLE; however, rarely, these may be due to thrombosis in an angiographically normal coronary artery or result from coronary vasculitis or arterial emboli [12]. More information on the pathogenesis of atherosclerosis in the general population is provided separately. (See "Pathogenesis of atherosclerosis" and "Mechanisms of acute coronary syndromes related to atherosclerosis".)

The pathogenesis of SLE and antiphospholipid syndrome is also discussed elsewhere. (See "Systemic lupus erythematosus: Epidemiology and pathogenesis", section on 'Pathogenesis' and "Antiphospholipid syndrome: Pathogenesis".)

RISK FACTORS — 

Patients with systemic lupus erythematosus (SLE) may have an increased risk of cardiovascular disease (CVD) due to traditional risk factors (eg, hypertension) and factors related to SLE, as summarized in the table (table 1). After accounting for traditional risk factors, SLE itself and/or its treatment appear to confer the greatest risk for premature CVD [13-16].

Traditional risk factors — The risk of CVD in patients with SLE is partially determined by traditional risk factors, including diabetes, hyperlipidemia, hypertension, family history of coronary artery disease (CAD), obesity, sedentary lifestyle, and cigarette smoking [10,13,17-24]. In addition, females may have other risk factors for CVD, such as ones related to pregnancy, lactation, and hormonal medications. (See "Overview of established risk factors for cardiovascular disease" and "Overview of atherosclerotic cardiovascular risk factors in females".)

People with SLE commonly have traditional risk factors for CVD. As an example, a study examined such factors for CAD in 250 female patients with SLE in the Toronto Lupus Cohort; when compared with controls, the cohort with SLE had an increased prevalence of hypertension, diabetes, premature menopause, sedentary lifestyle, and at-risk body habitus [25]. Among postmenopausal females, the use of hormone replacement therapy was not a risk factor for the development of CAD [26]. In addition, patients with SLE are also more likely to develop metabolic syndrome [27,28]; the presence of metabolic syndrome among SLE patients has been associated with endothelial damage, arterial stiffness, and atherosclerosis [29,30]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Despite an increasing appreciation of the importance of CAD in SLE, recognition of traditional risk factors has been suboptimal among both patients and providers. As an example, one study found that only 17 percent of patients with SLE believed they had a high risk of developing CAD within five years, when in fact 53 percent had three or more traditional risk factors for CAD [17]. In another study of one academic rheumatology practice, deficits in knowledge and management of cardiac risk factors were observed among both SLE patients and their clinicians [31].

Risk factors related to systemic lupus erythematosus

Underlying disease — The relationship between SLE and CVD is incompletely understood, especially as the risk of developing CVD is elevated very early in SLE disease course, even prior to SLE diagnosis [32]. However, systemic inflammation in SLE is thought to accelerate atherosclerosis, which is also an inflammatory process with immune cell activation and plaque formation and rupture [3,33,34]. Autoimmune vascular injury in SLE may predispose to atherosclerosis via a number of possible mechanisms, including the following:

●Neutrophil extracellular trap (NET) formation – NET formation is increased in SLE and appears to contribute to endothelial damage and premature cardiovascular disease [34-37].

●Type I interferon (IFN) – Patients who are exposed to high levels of serum type I IFN (ie, induction of IFN-inducible genes or the "interferon signature") appear to have an increased risk of developing CVD. In a study that included 95 patients with SLE without a history of overt CVD, higher levels of type I IFN activity were associated with increased severity of coronary calcification, even after controlling for traditional CVD risk factors [38]. This may be related to the action of type I IFN in stimulating macrophage recruitment to atherosclerotic lesions [39,40].

●Oxidative stress – Excessive oxidative stress enhances inflammation, including apoptotic cell death. Reactive species and free radical production in both SLE and antiphospholipid syndrome are thought to contribute to chronic tissue inflammation, with subsequent dyslipidemia and accelerated atherogenesis. As an example, anti-beta 2-glycoprotein I autoantibodies complex with oxidized low-density lipoprotein (LDL) and accelerate macrophage uptake of oxidized LDL cholesterol [41-43].

●Dysfunctional high-density lipoprotein (HDL) cholesterol – Dysfunctional proinflammatory high-density lipoprotein (HDL) cholesterol, which is commonly present among SLE patients, may accelerate LDL oxidation and atherosclerosis [44,45].

●Antiphospholipid antibodies (apL) – A subset of patients with SLE develop aPL, which may lead to in situ thrombosis, embolization, and acceleration of atherosclerosis [23]. aPL are strong risk factors for acute ischemic stroke and transient ischemic attack among patients with SLE [46]. As an example, in a study of 182 patients with SLE who were followed for a mean of 8.3 years, apL were associated with an over fourfold elevated risk of myocardial infarction, stroke, or peripheral vascular disease [23,47]. (See "Clinical manifestations of antiphospholipid syndrome".)

In addition, studies to identify potential novel biomarkers of CVD in patients with SLE have identified other differences in gene expression and serum proteins (including leptin, homocysteine, plasmalogens, and leukotrienes, among others) in the blood between patients who do and do not have CVD. These tests are not yet clinically available [45,48,49].

In large cohort studies, increasing CAD risks are strongly associated with the overall severity of SLE, in terms of inflammation with multiorgan system involvement necessitating glucocorticoid and immunosuppressant use [50-52]. Other clinical factors associated with CAD in patients with SLE include: higher disease activity [10,16], chronic nephritis, low serum levels of C3 and C4 [53,54], elevated anti-double-stranded deoxyribonucleic acid (dsDNA) antibody levels [53], elevated C-reactive protein (CRP) levels [10,55], aPL [56-59], and increased oxidative stress, the last of which is not a clinically available test [60]. The presence of such risk factors also increases the risk of cerebrovascular disease [52,61].

It should be recognized that SLE patients with nephritis and kidney disease are among those with the highest risks of CAD. This is likely due to a combination of excess traditional risk factors (hypertension, hyperlipidemia), higher doses of glucocorticoids, and higher levels of systemic inflammation [62]. Risk factors for CVD in patients who have received a kidney transplant are discussed in detail elsewhere. (See "Risk factors for cardiovascular disease in the kidney transplant recipient".)

Glucocorticoids — Glucocorticoids can cause or exacerbate traditional risk factors for CVD including hyperlipidemia, diabetes, and obesity. The role of glucocorticoids in promoting atherosclerosis is discussed in more detail elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects'.)

Among patients with SLE, current glucocorticoid use is strongly associated with an increased risk of CAD [16,63]. As an example, in a study that included over 1800 SLE patients followed for a mean of 5.1 years, patients who were currently using glucocorticoids had an increased risk of cardiovascular events, even after controlling for disease activity [16]; specifically, patients actively taking ≥20 mg/day of corticosteroids had 35.4 cardiovascular events per 1000 person-years, compared with 9.9 events in patients not taking corticosteroids, corresponding to a multivariable-adjusted risk of 2.54 (95% CI 1.44-4.48). In another cross-sectional study of 264 SLE patients that adjusted for factors such as age, weight, and antihypertensive drug use, a 10 mg/day increase in prednisone dose was associated on average with a 2.5 kg increase in body weight, a 1.1 mmHg increase in mean arterial blood pressure, and a 7.5 mg/dL (0.19 mmol/L) increase in serum cholesterol [64].

CLINICAL MANIFESTATIONS — 

Coronary artery disease (CAD) in patients with systemic lupus erythematosus (SLE) can be asymptomatic or manifest with more traditional symptoms, such as angina. Classically, symptomatic patients with CAD experience chest pain or discomfort, which may radiate into the left arm or jaw and be associated with chest tightness or pressure, dyspnea, diaphoresis, weakness, and anxiety. Less commonly, patients do not have chest pain and instead have "atypical" symptoms such as isolated dyspnea, palpitations, syncope, or nausea and/or vomiting. Patients may also experience an increase in fatigue and generalized weakness. (See "Diagnosis of acute myocardial infarction", section on 'History and physical examination'.)

It is important to note that patients with SLE may not experience classic symptoms of angina, recognizing that CAD can present differently in females and younger patients. As an example, one study looked for evidence of CAD on noninvasive testing (exercise or pharmacologic stress and nuclear imaging studies) in 33 female patients with SLE aged 22 to 45 years who had nonspecific complaints (eg, chest discomfort, dyspnea, and/or occasional palpitations) as well as 28 asymptomatic patients with SLE and 24 healthy controls. Perfusion abnormalities were detected in 27 patients in the symptomatic group (82 percent), 12 patients in the asymptomatic group with SLE (43 percent), and no patients in the healthy control group [65]. More information on the clinical presentation of CAD in females and young people is provided separately. (See "Clinical features and diagnosis of coronary heart disease in women", section on 'Clinical presentation' and "Coronary artery disease and myocardial infarction in young people".)

EVALUATION AND DIAGNOSIS — 

Patients with systemic lupus erythematosus (SLE) who have symptoms suggestive of coronary artery disease (CAD) should have a prompt evaluation for ischemia similar to patients without SLE. Asymptomatic patients should undergo a risk assessment and, if appropriate based on risk, noninvasive testing for CAD [52]. Patients with SLE may benefit from using a lower risk threshold for noninvasive testing since SLE-related risks are not well captured on most general CAD risk calculators.

When to suspect coronary artery disease — A high index of suspicion for CAD is warranted in patients with SLE presenting with any type of chest pain (especially with radiation to the left arm or jaw), chest pressure or tightness, dyspnea, and/or decreased exercise tolerance. We also consider a diagnosis of CAD in patients presenting with palpitations, syncope, and/or a significant increase in fatigue. (See 'Evaluation in symptomatic patients' below.)

Asymptomatic patients with SLE should also undergo evaluation for CAD. (See 'Evaluation in asymptomatic patients' below.)

Evaluation in asymptomatic patients — We suggest reviewing all traditional and SLE-related cardiac risk factors (table 1) and screening patients with SLE who have multiple risk factors, even if they are asymptomatic. In addition, most SLE patients who are at increased risk of cardiovascular disease (CVD) should be referred for CAD screening and consultation with a cardiologist who specializes in CAD prevention. Screening includes performing an atherosclerotic CVD (ASCVD) risk assessment and, in selected cases, progressing to noninvasive stress testing or coronary imaging.

Risk estimation and education for all patients — An ASCVD risk assessment is the initial step in the primary prevention of CAD in adults. It includes determining traditional risk factors and, for most patients, using a risk calculator to estimate the 10-year risk of ASCVD. It is important to recognize that risk calculators will likely underestimate the ASCVD risk in patients with SLE, since having SLE increases ASCVD risk but is not included in standard calculators; SLE is included in some as a potential "risk enhancer." There are exceptions to this, such as the QRISK3 calculator, which includes SLE, and the SLE CRISK calculator, which includes SLE-specific factors such as lupus nephritis (LN), antiphospholipid antibodies (aPL), and complement levels [52,66]. When using calculators that do not adjust for factors related to SLE, we review such risks separately (table 1). ASCVD risk assessment and specific calculators are discussed in detail elsewhere. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

While detailed guidance from professional societies is limited [67], patients with SLE who are not seeing a cardiologist for ASCVD risk assessment need to have their risk factors reviewed and addressed with their rheumatologist and/or primary care provider within six months of diagnosis and repeated at least annually [68]. Assessment should be more frequently when patients are taking prolonged or frequent courses of systemic glucocorticoids and during prolonged periods of active SLE disease activity. Primary care providers often include intermittent ASCVD risk assessment in preventive care visits. (See "Overview of preventive care in adults", section on 'Cardiovascular disease prevention'.)

An individual patient's risk profile may change over time, emphasizing the importance of continued vigilance to identify the emergence of modifiable risk factors for CVD. This was illustrated in a study of an inception cohort of 935 patients with SLE; over three years of follow-up, the prevalence of all Framingham CAD risk factors increased, as did the proportion of patients treated for hypertension and, to a lesser extent, hyperlipidemia [50].

In addition to risk estimation, providers should educate patients with SLE about the increased risk of CAD, preventive measures (eg, avoidance of tobacco, maintaining a healthy diet), and symptoms that should prompt them to contact their provider (eg, chest pain, change in exercise capacity). (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Promoting a healthy lifestyle'.)

Noninvasive testing in selected patients — Various noninvasive screening tests are available for CAD, including coronary artery calcium (CAC) scoring and exercise or pharmacologic stress testing. Such tests are generally not required for asymptomatic patients with SLE since the utility of testing in the absence of symptoms is uncertain. However, noninvasive testing may be indicated in certain scenarios. Screening for CAD in asymptomatic people in the general population with multiple cardiac risk factors is discussed in detail separately and summarized below in the setting of SLE (see "Screening for coronary heart disease"):

●CAC scoring in selected intermediate-risk patients – CAC scoring can detect CACs that suggest subclinical atherosclerosis and allow further risk stratification. The approach to CAC scoring is similar irrespective of whether patients have SLE; specifically, patients who have an intermediate risk of ASCVD may benefit from CAC scoring to further refine the risk estimate and need for preventive therapies. However, it may be appropriate to use a slightly lower risk threshold for obtaining CAC scoring, since SLE increases the risk of ASCVD but is not included in most risk calculators. In addition, it is important to note that CAC reflects chronic and more stable plaque; it is not designed to detect less stable, noncalcified, soft plaques, which may be more likely to acutely rupture. (See "Coronary artery calcium (CAC) scoring: Overview and clinical utilization", section on 'Overview of clinical utility'.)

More research is needed to determine the optimal threshold to obtain CAC scoring in patients with SLE, and to link CAC scores with future cardiac complications in this patient group. Most, but not all, studies of CAC scoring suggest that patients with SLE have an increased prevalence of CACs compared with the general population. As an example, in one study of 65 patients with SLE and 69 controls who underwent computed tomography (CT) evaluation, the prevalence of CAC was significantly higher in those with SLE (31 versus 9 percent) [18]. Similarly, another study of 105 patients with SLE, 105 patients with rheumatoid arthritis (RA), and 105 controls observed CAC in 48 percent of patients with SLE and RA, compared with 35 percent of controls [55]. However, a third study found similar rates of CAC (28 percent) in patients with SLE and control patients [69].

●Stress testing or advanced cardiac imaging in selected higher-risk patients – Selected patients at higher risk for CAD based on traditional and SLE-specific risk factors (table 1) may benefit from screening for CAD, as this may change medical management and surveillance. This includes patients with factors that increase their risk of ASCVD but that are not included in traditional risk calculators, such as a longer duration of active SLE (eg, >5 to 10 years) and higher levels of disease activity (eg, patients taking systemic glucocorticoids in addition to glucocorticoid-sparing immunosuppression) [51,54,70]. Options for screening include CAC scoring or CT coronary angiography, positron emission tomography (PET) with coronary flow reserve (CFR) assessment, or cardiac magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) [71,72]. Evaluation for ischemia with exercise or pharmacologic stress testing can also be considered.

If the patient and provider decide to proceed with noninvasive testing after a discussion of the risks and potential benefits, then we typically obtain exercise electrocardiogram testing. An alternative in patients unable to exercise (eg, due to lung disease or severe arthritis) is pharmacologic cardiac stress testing with radionuclide imaging. (See "Selecting the optimal cardiac stress test" and "Overview of stress radionuclide myocardial perfusion imaging".)

Evidence to support the utility of stress testing in asymptomatic patients with SLE is limited. In one prospective study that performed myocardial perfusion imaging in 122 patients with SLE and no history of CAD, 38 percent of patients had abnormal perfusion scans [70]. Over a mean follow-up of 8.7 years, the incidence of cardiac events was greater in those with abnormal scans than those with no focal defects (15 versus 2 events, respectively). Of the cardiac events observed, 14 were new-onset angina and 1 was a myocardial infarction. Abnormal perfusion imaging was a better predictor of cardiac events than an elevated Framingham risk score (hazard ratios [HRs] of 13 versus 1.8, respectively).

We do not routinely obtain other forms of noninvasive testing for CVD in asymptomatic patients with SLE, such as ankle-brachial index testing and carotid or femoral artery ultrasonography, although these may provide additional information for selected patients. Multiple studies have found a higher proportion of atherosclerotic plaques in the carotid arteries in patients with SLE compared with age- and sex-matched controls and progression based on traditional and SLE-related risk factors [4,13,61,73]. As an example, in a study including 392 females with SLE followed for a mean of eight years, baseline carotid intima-medial thickness on ultrasound and presence of carotid plaque were predictive of any incident cardiovascular events including myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, and cerebrovascular accident, independent of traditional cardiovascular risk factors and medication use [74]. Controlling traditional cardiovascular risk factors was shown to decrease the progression of atherosclerosis on coronary ultrasound in another cohort of patients with SLE [5]. Nevertheless, carotid ultrasonography is not standardly done in asymptomatic patients in the general population, and more specific tests for CAD (eg, CAC scoring) are available. Alternative screening tests for CVD are discussed in more detail separately. (See "Noninvasive diagnosis of upper and lower extremity arterial disease" and "Screening for asymptomatic carotid artery stenosis".)

When to refer — In our practice, we refer most patients with one or more of the following characteristics to a cardiologist specializing in prevention of atherosclerotic CAD for assessment and modification of cardiac risk factors and recommendations for CAD screening and treatment:

●High-risk ASCVD risk profiles

●Moderate to severe SLE or long disease duration

●Other risk factors related to SLE including LN, aPL, and/or long-term glucocorticoid use

While there are no clear guidelines to define precise thresholds, for the purposes of referral we define long-term glucocorticoid use as ≥5 mg/day of prednisone or its equivalent for longer than a short course (eg, a few months).

Future directions — Ongoing research is needed to develop proven screening and monitoring guidelines and prevention strategies for CVD among patients with SLE. Many asymptomatic patients with SLE who are at moderate to high risk of developing CVD likely would benefit from proactive screening and implementation of preventive measures.

There is increasing interest in using cardiac MRI with late gadolinium contrast enhancement (LGE) to detect atherosclerosis in patients with SLE, as this modality can identify areas of myocardial scarring; however, the technique is not yet ready for widespread clinical use [75-77].

There is also ongoing research into using positron emission tomography (PET) scans to assess coronary flow reserve and atherosclerotic lesions in SLE patients. This modality may have promise for early detection of endothelial dysfunction in coronary arteries [72,78].

Finally, there is ongoing research into biomarkers that could help differentiate ASCVD risk [45]; however, such testing is not clinically available and further research is needed into its potential utility.

Evaluation in symptomatic patients — All potential cardiac symptoms should be taken very seriously, even in young patients, as those with SLE are at high risk of CAD compared with patients in the general public [9] (see 'Clinical manifestations' above). The evaluation of symptomatic patients suspected of having CAD includes risk estimation, diagnostic testing (eg, cardiac enzymes, electrocardiogram, chest radiograph, and echocardiography), and, when appropriate, stress testing or other imaging to identify features of CAD. This is discussed in more detail separately:

●(See "Outpatient evaluation of the adult with chest pain".)

●(See "Approach to the adult with nontraumatic chest pain in the emergency department".)

●(See "Diagnosis of acute myocardial infarction".)

●(See "Stress testing for the diagnosis of obstructive coronary artery disease".)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of chest pain or pressure in the patient with systemic lupus erythematosus (SLE) is broad and includes myocarditis, pericarditis, pleuritis, pulmonary embolus, pneumonia, pulmonary hypertension, coronary and aortic vasculitis or other pathology, chest wall pain (eg, costochondritis), and reflux esophagitis. These diagnoses can be distinguished from complications of coronary artery disease (CAD) based on a combination of history, physical examination, and laboratory and diagnostic testing. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Pulmonary manifestations of systemic lupus erythematosus in adults".)

MANAGEMENT — 

Prevention and treatment of coronary artery disease (CAD) in patients with systemic lupus erythematosus (SLE) should be aggressive given the greatly increased risks posed by SLE and lupus nephritis (LN) in particular. Patients with established CAD may require pharmacotherapy and, in some cases, revascularization; we generally adopt a more aggressive approach, as is done for patients with diabetes mellitus. In addition, all patients can benefit from primary and secondary preventive measures by addressing traditional risk factors (eg, achieve goal blood pressure in patients with hypertension) and optimizing treatment of SLE.

Management of established coronary artery disease — The management of established CAD is individualized based on the patient's risk profile and symptoms. We generally treat CAD in patients with SLE more aggressively (eg, stricter goals for blood pressure and lipids, with earlier and higher-dose statin use), as is done for patients with diabetes mellitus, since both disease states are associated with an increased risk of cardiac complications. Management may include the following components:

●Diagnostic testing to establish disease severity – Depending on the approach used to initially diagnose CAD, patients may require additional diagnostic testing to establish disease severity. (See "Chronic coronary syndrome: Overview of care", section on 'Determining disease severity'.)

●Pharmacotherapy – Patients with established CAD typically receive pharmacotherapy to reduce the risk of future events, usually with a high-intensity statin or other low-density lipoprotein (LDL) cholesterol-lowering agent, and often with an antiplatelet agent (usually aspirin). They may also require medications to treat specific symptoms (eg, beta blockers for angina) and comorbid conditions (eg, angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs] for hypertension). (See 'Traditional preventive measures' below.)

●Revascularization in selected patients – Revascularization may be indicated in some patients, including those with high-risk anatomy (eg, three-vessel CAD) and/or persistent symptoms despite medical therapy. Indications for and selection of revascularization procedures, as well as modifications in patients with diabetes, are discussed in detail separately:

•(See "Chronic coronary syndrome: Indications for revascularization".)

•(See "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention".)

•(See "Coronary artery revascularization in stable patients with diabetes mellitus".)

The specific approach to various manifestations of CAD and modifications in patients with diabetes and female patients are described in detail elsewhere:

●ST-elevation myocardial infarction

•(See "Overview of the acute management of ST-elevation myocardial infarction".)

•(See "Overview of the nonacute management of ST-elevation myocardial infarction".)

●Non-ST-elevation acute coronary syndromes

•(See "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

•(See "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)

●Chronic coronary syndrome (see "Chronic coronary syndrome: Overview of care")

●Ischemic cardiomyopathy (see "Treatment of ischemic cardiomyopathy")

●Acute myocardial infarction in patients with diabetes (see "Acute myocardial infarction: Patients with diabetes mellitus")

●CAD in female individuals (see "Management of coronary heart disease in women")

Preventive measures for all patients — Patients with SLE can benefit from preventive measures, including treatment of certain comorbid conditions (eg, hypertension, hyperlipidemia) and optimizing SLE disease activity and management. Our approach is generally consistent with the recommendations for cardiovascular risk management in SLE outlined by the European Alliance of Associations for Rheumatology (EULAR) in 2022 [67].

Traditional preventive measures — We address traditional risk factors for cardiovascular disease (CVD) in patients with SLE who have established CAD (ie, for secondary prevention) or who are at risk of developing CAD (ie, for primary prevention). We adopt a more aggressive approach for preventive measures (eg, weight management, targeting a relatively lower threshold for both blood pressure and LDL cholesterol), since patients with SLE have a greater risk of CVD. While there are little data to guide specific targets, we generally use those for patients with CAD and comorbid diabetes mellitus, as discussed in greater detail below. More information about the approach to primary and secondary prevention of CVD is provided separately:

●(See "Overview of primary prevention of cardiovascular disease in adults".)

●(See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

There is evidence that addressing modifiable cardiovascular risk factors is beneficial for patients with SLE. In a longitudinal study of 115 patients with SLE, the risk of atherosclerotic plaque progression was fourfold higher than that of matched healthy controls over seven years; this increased risk was reduced by approximately 50 percent for each modifiable cardiovascular risk factor (eg, blood pressure, lipids, body weight) that was within the target range (odds ratio [OR] 0.56, 95% CI 0.34-0.93) [5]. Further evidence to support modification of specific risk factors is outlined below.

Controlling blood pressure — Hypertension is an important risk factor for CAD in SLE [17,25]. Information about the importance of addressing hypertension for the primary and secondary prevention of CVD is presented in detail elsewhere and summarized below (see "Overview of primary prevention of cardiovascular disease in adults", section on 'Hypertension' and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Hypertension'):

●Goal blood pressure – We target a goal blood pressure of <130/80 mmHg for all patients with SLE, even those without multiple other risk factors, similar to that recommended for patients without SLE who have diabetes or chronic kidney disease. This target is also supported by the EULAR guidelines [67]. One study compared the incidence of atherosclerotic vascular events (AVEs) in 1532 patients with SLE based on their mean blood pressure over ≥2 years of follow-up; most patients were in the normotensive category (<130/80 mmHg, 69 percent), followed by mildly elevated blood pressure (130 to 139/80 to 89 mmHg, 21 percent), and hypertensive (≥140/90 mmHg) [79]. Compared with the normotensive group, patients in the mildly elevated blood pressure group had an increased risk of AVE (hazard ratio [HR] 1.73, 95% CI 1.1 to 2.7). Additional data to support tighter blood pressure control in patients who are at higher risk of CVD are discussed separately. (See "Goal blood pressure in adults with hypertension", section on 'Intensive goal blood pressure targets for higher-risk patients'.)

●Choice of antihypertensive therapy – For most patients with SLE and comorbid hypertension, we use an ACE inhibitor or an ARB. An alternative in patients with prominent Raynaud phenomenon is using a calcium channel blocker (eg, nifedipine). Treatment of hypertension in patients with comorbid LN is discussed in more detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

The EULAR guidelines favor the use of ACE inhibitors or ARBs for selected patients with LN who also have hypertension and/or significant proteinuria (ie, a urine protein to creatinine ratio >500 mg/g) [67]. Furthermore, in an observational study of 220,168 patients with SLE, antihypertensive drugs that act on the renin-angiotensin system (RAS) were associated with a lower risk of incident cardiovascular disease compared with other antihypertensive treatments (relative risk [RR] 0.80, 95% CI 0.74-0.87) [80]. Use of RAS-modifying therapies increased the probability of remaining free of cardiovascular disease over a five-year period (86.0 versus 78.3 percent).

Reducing low-density lipoprotein cholesterol — Various pharmacologic and nonpharmacologic strategies can help optimize lipid levels, most importantly by reducing the level of low-density lipoprotein (LDL) cholesterol. Most patients with established CVD receive a statin to reduce their level of LDL cholesterol. Statin therapy may also be used for primary prevention in certain patients who have a higher atherosclerotic CVD (ASCVD) risk. It is important to recognize that most CAD prediction models for the general population perform poorly in SLE; development of improved models will help in the tailoring of statin therapy in those at highest risk [54,81]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

When pharmacologic therapy to lower LDL cholesterol is indicated as a primary or secondary prevention strategy in patients with SLE, we typically use statins. For patients who also have significant kidney disease, atorvastatin and fluvastatin may be preferred to other statins, as they do not require dose adjustment in those with a severe reduction in glomerular filtration. (See "Statins: Actions, side effects, and administration", section on 'Chronic kidney disease'.)

Statins have pleiotropic effects including antiinflammatory, antithrombotic, and plaque-stabilizing activities [82]. They are well tolerated and effective in reducing lipid levels in patients with SLE [83]. Observational studies suggest effectiveness of statins in reducing CVD risk among patients with SLE, although clinical trials have not been conclusive or directly measured the impact of statins on outcomes of clinical CAD or mortality [84,85].

Patients who are not candidates for lipid-lowering pharmacotherapy may still benefit from following dietary measures designed to improve lipid profiles [86-92]. (See "Lipid management with diet or dietary supplements".)

Low-dose aspirin — Most patients with established CAD receive low-dose aspirin to reduce the risk of future cardiac events. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

The decision to use low-dose aspirin for primary prevention of CAD in patients with SLE must be individualized and based on the estimated risk of a first cardiovascular event [67]. It is important to note that while low-dose aspirin has been shown to decrease risk of myocardial infarction and ischemic stroke among older adults, it is also associated with a nontrivial risk of gastrointestinal and other bleeding. Furthermore, other medications commonly used in patients with SLE (eg, nonsteroidal antiinflammatory drugs [NSAIDs] and glucocorticoids) may further increase the risk of bleeding. Retrospective studies have found that aspirin use was associated with decreased CAD event risks in SLE patients, but these were not controlled trials [93]. More information about the use of aspirin for primary prevention of CAD is provided separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Other measures — Other interventions that address traditional CVD risk factors may differ slightly when they are being used for primary or secondary prevention of CVD and related complications, and include the following:

●Treatment of comorbid conditions

•Diabetes mellitus – Patients with comorbid diabetes require tight glycemic control. Based on limited observational data, sodium-glucose cotransporter 2 (SGLT2) inhibitors may offer additional benefits beyond dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with SLE. Specifically, in a study of patients with comorbid SLE and type 2 diabetes, 2165 participants initiating SGLT2 inhibitors were matched with 2165 participants starting DPP-4 inhibitors [94]. Over a mean of 753 days, the risks of incident heart failure, kidney disease (acute kidney injury, chronic kidney disease, or end-stage kidney disease), severe sepsis, and emergency department visits were lower in the SGLT2 inhibitor group compared with the DPP-4 inhibitor group; rates of myocardial infarction, stroke, LN, hospitalization, and all-cause mortality were similar. (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Type 2 diabetes mellitus' and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Diabetes mellitus'.)

•Overweight and obesity – Patients with overweight (body mass index [BMI] of 25 to 29.9 kg/m²) or obesity (BMI of ≥30 kg/m²) may benefit from various measures for weight loss. This may include the use of certain weight loss medications (eg, glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 [GLP-1] receptor agonists), which have been associated with some cardiovascular benefits:

-(See "Overview of primary prevention of cardiovascular disease in adults", section on 'Overweight and obesity'.)

-(See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Weight reduction'.)

-(See "Obesity in adults: Drug therapy", section on 'Cardiovascular benefits'.)

•Tobacco use – We counsel patients who use tobacco products about the negative consequences of tobacco use, including increasing the risk of CVD, and different approaches to smoking cessation. More information on tobacco cessation and the importance of addressing this factor in the prevention of CVD is presented separately:

-(See "Overview of smoking cessation management in adults".)

-(See "Overview of primary prevention of cardiovascular disease in adults", section on 'Smoking cessation'.)

-(See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Smoking cessation'.)

●Regular physical activity – Regular physical activity has many potential health benefits, including for patients who have or are at increased risk of developing CAD. Providers should work with patients to develop a safe exercise plan that is appropriate for their overall level of conditioning and specific disease manifestations. As an example, patients with a history of inflammatory arthritis may prefer forms of lower-impact exercise that place less stress on their joints (eg, swimming, elliptical training). Patients who prefer outdoor exercise should also be counseled about using appropriate sun protection. (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Physical activity' and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Physical activity'.)

●Dietary modifications – Patients can implement certain dietary measures, especially in the setting of hypertension and/or dyslipidemia, and minimize alcohol intake. (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Healthy diet' and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Diet'.)

SLE management

Minimizing disease activity — There is increasing consensus that the goal of therapy should be keeping SLE disease activity low without the use of glucocorticoids. This is associated with improved overall prognosis and reduced risk of organ damage, including CAD events. As an example, a reduced risk of CAD in patients with SLE has been associated with targeting a disease measure called Lupus Low Disease Activity State (LLDAS), which incorporates low disease activity and low physician global assessment, as well as limiting glucocorticoids (ie, ≤7.5 mg/day of prednisone or its equivalent) [95]. The EULAR guidelines also emphasize the importance of minimizing disease activity [67].

Using hydroxychloroquine — Hydroxychloroquine is widely used in SLE and offers a wide range of potential benefits, including antithrombotic and anti-atherogenic effects. The use of hydroxychloroquine in patients with SLE is discussed in detail separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Hydroxychloroquine for all patients'.)

Patients with rheumatic diseases who are taking hydroxychloroquine appear to have a lower risk of future cardiovascular events [96,97]. As an example, a study of over 16,500 patients with incident SLE or rheumatoid arthritis (RA) who were started on hydroxychloroquine observed incident cardiovascular events in 13.2 percent of patients over nine years of follow-up. The adjusted HR (aHR) of incident cardiovascular events in patients taking hydroxychloroquine regularly versus those who discontinued it was 0.72 (95% CI 0.64-0.81) [97]. This reduced risk may be related to multiple factors, including decreasing accumulation of SLE-related organ damage and increasing survival, reducing the risk of thrombosis, and possibly improving lipid profiles and lowering the risk of diabetes mellitus [93,96,98-103]. The EULAR guidelines include consideration of using hydroxychloroquine to lower the risk of CAD events [67].

Limiting glucocorticoid and NSAID use — When possible, we minimize the use of both glucocorticoids and NSAIDs in patients with SLE:

●Glucocorticoids – Glucocorticoids contribute to CAD risk factors by worsening hypertension, hyperlipidemia, and diabetes. We therefore reserve glucocorticoid use for life- or organ-threatening manifestations of SLE and use the lowest dose for the shortest duration possible. This is in keeping with the EULAR guidelines [67]. (See "Major adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects'.)

●NSAIDs – NSAIDs are associated with potential adverse cardiac effects including myocardial infarction and hypertension. In addition, if patients are using aspirin as a preventive strategy for CVD, concomitant use of a nonselective NSAID may interfere with the beneficial effects of aspirin (see "NSAIDs: Adverse cardiovascular effects", section on 'Patients using aspirin and other antithrombotic agents'). We therefore avoid using them in patients with established CAD and minimize their use in patients who are at risk of CAD. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

PROGNOSIS — 

While data are limited, the outcomes for patients who experience myocardial infarction appear to be similar regardless of whether the patient has SLE. One study compared over 3200 hospitalizations for patients with SLE with propensity score-matched hospitalizations for patients without SLE [104]. While the odds of undergoing coronary artery bypass grafting (CABG) during the myocardial infarction hospitalization was 29 percent lower in the SLE group compared with the control group, in-hospital mortality, length of stay, and total cost were similar in the two groups. When analyzing hospitalizations for non-ST-elevation myocardial infarction (NSTEMI), SLE was associated with 20 percent higher odds of undergoing percutaneous coronary intervention (PCI) during the hospitalization and 37 percent lower odds of undergoing CABG; this may reflect that patients with SLE are more likely to experience acute thrombosis in a limited coronary artery distribution, while those without SLE are more likely to have extensive atherosclerosis.

More information on the prognosis of SLE, including morbidity and mortality related to CAD, is provided separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – The risk of coronary artery disease (CAD) is greatly increased in patients with systemic lupus erythematosus (SLE) compared with an age- and sex-matched segment of the general population. Patients with SLE have an increased prevalence of traditional risk factors for CAD, plus additional risk related to moderate to severe SLE, longstanding disease, lupus nephritis (LN), antiphospholipid antibodies (aPL), and glucocorticoid use (table 1). Patients with high disease activity, LN, and aPL are among those at highest risk. (See 'Epidemiology' above and 'Risk factors' above.)

●Evaluation and diagnosis

•When to suspect CAD – A high index of suspicion for CAD is warranted in patients with SLE. Patients with significant CAD may be asymptomatic or present with classic symptoms (eg, exertional chest pain or pressure) or atypical, nonspecific complaints (eg, isolated exertional dyspnea, palpitations, decreased exercise tolerance). (See 'Clinical manifestations' above and 'When to suspect coronary artery disease' above.)

•Evaluation in asymptomatic patients

-Risk estimation in all patients – Risk estimation involves asking about traditional risk factors and, for most patients, using a risk calculator to estimate the 10-year risk of atherosclerotic cardiovascular disease (ASCVD). Most traditional risk calculators underestimate risk in patients with SLE as they do not incorporate SLE-specific factors. (See 'Risk estimation and education for all patients' above.)

-Noninvasive testing in selected patients – While noninvasive stress testing for CAD is not indicated for most asymptomatic patients with SLE who lack other risk factors for CAD, coronary artery calcium (CAC) scoring may be useful in selected intermediate-risk patients to allow for further risk stratification. In addition, selected higher-risk patients may benefit from intermittent screening for CAD with stress testing or advanced cardiac imaging. (See 'Noninvasive testing in selected patients' above.)

-When to refer – We refer most patients with moderate to severe SLE, and those with high-risk ASCVD profiles, to a CAD specialist or preventive cardiologist for further screening and management. (See 'When to refer' above.)

•Evaluation in symptomatic patients – Evaluation includes risk estimation, standard diagnostic testing (eg, cardiac enzymes, electrocardiogram, chest radiograph, and echocardiography), and, when appropriate, stress testing and other types of cardiac imaging. (See 'Evaluation in symptomatic patients' above.)

●Differential diagnosis – The differential diagnosis of chest pain in patients with SLE is broad, including myocarditis, pericarditis, pleuritis, pulmonary embolus, pneumonia, pulmonary hypertension, coronary and aortic vasculitis or other pathology, chest wall pain, and reflux esophagitis. (See 'Differential diagnosis' above.)

●Management

•Management of established CAD – We generally adopt a more aggressive approach to pharmacotherapy in patients with SLE and, when needed, revascularization, as is done for patients with diabetes mellitus. (See 'Management of established coronary artery disease' above.)

•Preventive measures for all patients – We address risk factors in patients with SLE who have established CAD (ie, for secondary prevention) or who are at risk of developing CAD (ie, for primary prevention). (See 'Preventive measures for all patients' above.)

-Controlling blood pressure – We target a goal blood pressure of <130/80 mmHg, similar to the approach for other high-risk patient groups. For most patients with hypertension, we use an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) rather than other antihypertensives (Grade 2C). An alternative in patients with prominent Raynaud phenomenon is a calcium channel blocker. (See 'Controlling blood pressure' above and "Goal blood pressure in adults with hypertension", section on 'Intensive goal blood pressure targets for higher-risk patients'.)

-Reducing LDL cholesterol – Pharmacotherapy to reduce low-density lipoprotein (LDL) cholesterol, typically with a statin, is indicated for secondary prevention in most patients with established CAD and for primary prevention in certain patients who have a higher ASCVD risk. (See 'Reducing low-density lipoprotein cholesterol' above.)

•SLE management – We aim to minimize disease activity and ensure regular use of hydroxychloroquine. We also limit the use of glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs). (See 'SLE management' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.