Background

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with systemic lupus erythematosus (SLE).¹ Although overall mortality in SLE has decreased over the previous decades, a similar decrease in magnitude for CVD-related mortality in these patients has not been seen.¹ Compared with the general population, myocardial infarction (MI) and stroke are at least two to three times more prevalent in patients with SLE.¹ The relative risk of an ASCVD event is greater by at least twice and up to 50-fold among those who are young, who have more severe SLE disease activity, and who have lupus nephritis.¹ These risks are attributed to traditional cardiovascular disease (CVD) risk factors such as smoking, diabetes mellitus (DM), and hypertension (HTN), as well as to the inflammatory and immunologic burden of SLE. This complexity makes CVD risk prediction and management in patients with SLE challenging (Table 1).

Table 1: Traditional vs. SLE-Related Risk Factors

BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; HDL = high-density lipoprotein; IFN = interferon; NET = neuroendocrine tumor; SLE = systemic lupus erythematosus.

The high levels of systemic inflammation observed in SLE are known contributors to atherosclerotic plaque formation and progression. Immune dysregulation further exacerbates plaque development via multiple pathways, including lipid oxidation, inflammatory cytokines (e.g., interleukin-6, altered immune cell, and platelet expression), and neutrophil extracellular trap activation and release. Many aspects of metabolic syndrome are also common in those with SLE, including dysregulation of cytokines and adipokines.¹

Glucocorticoid use, often at high doses and for long durations, is common among patients with SLE, which independently accelerates atherosclerotic plaque formation via glucose intolerance, HTN, hypercholesterolemia, and hypertriglyceridemia. Both systemic inflammation and glucocorticoid exposure are significant drivers of ASCVD in the setting of SLE.¹

Existing Screening Tools

Current SLE recommendations for ASCVD risk assessment are outlined in several guidelines. The 2018 British Society for Rheumatology (BRS) Guideline for the Management of SLE in Adults does not specify additional screening measures compared with the general population.² In contrast, the 2022 European Alliance of Associations for Rheumatology (EULAR) Recommendations for Cardiovascular Risk Management in Rheumatic and Musculoskeletal Diseases, Including SLE and Antiphospholipid Syndrome recommends the inclusion of SLE-related risk factors in CVD risk prediction within 6 months of SLE diagnosis, yet does not include specification of risk factors or tools to use.³ SLE and other systemic inflammatory conditions are labeled as risk enhancers in the American College of Cardiology/American Health Association (ACC/AHA) prevention guidelines. However, these guidelines do not provide specific quantitative values when weighing risk estimates.⁴

Subsequent attempts to better contextualize ASCVD risk in SLE by embedding specific risk factors into established models, such as the Framingham Risk Score (FRS) and 2013 ACC/AHA estimated risk score, demonstrate improved performance. However, the predicted risk generated by the modified FRS, doubling the risk estimate for all patients with SLE, is still insensitive and does not capture the variation in excess risk associated with SLE itself.⁵

Other scores incorporate traditional ASCVD risk factors and various aspects specific to SLE, including clinical and research biomarkers (Table 2). The SLECRE (SLE Cardiovascular Risk Equation) incorporates medication class usage and lupus nephritis activity with glomerular filtration rate.⁶ The QRISK®3 (QRESEARCH Cardiovascular Risk Algorithm 3 [University of Nottingham, Nottingham, United Kingdom; EMIS Group Ltd, Leeds, United Kingdom]) includes glucocorticoid use and SLE diagnosis.⁷ The aGAPSS (adjusted Global Antiphospholipid Syndrome Score) is based on laboratory values of lupus anticoagulant, anticardiolipin, and anti-beta 2 glycoprotein 1.⁸ The PREDICTS (Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular disease in PaTients with SLE) model assesses hemoglobin A1c concentration, age, and serum biomarkers implicated in SLE, such as proinflammatory high-density lipoprotein and tumor necrosis factor-like weak inducer of apoptosis.⁹ Although promising in theory, biomarkers captured by these measures may not be the most specific indicators of SLE activity; additionally, several markers are not readily available in clinical practice.

Table 2: CVD Risk Scores Incorporating SLE-Related Factors

^aThe QRISK®3 is jointly registered by the University of Nottingham (Nottingham, United Kingdom) and EMIS Group Ltd (Leeds, United Kingdom)
ACC = American College of Cardiology; AF = atrial fibrillation; aGAPSS = adjusted Global Antiphospholipid Syndrome Score; AHA = American Heart Association; anti-dsDNA = anti-double-stranded DNA; anti-RNP = anti-ribonucleoprotein; aPLs = antiphospholipid antibodies; BMI = body mass index; CAD = coronary artery disease; CHD = coronary heart disease; CHF = congestive heart failure; CKD = chronic kidney disease; Cr = creatinine; CVA = cerebrovascular accident; CVD = cardiovascular disease; DBP = diastolic blood pressure; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; FRS = Framingham Risk Score; HDL-C = high-density lipoprotein cholesterol; HF = heart failure; HLD = hyperlipidemia; HTN = hypertension; LDL-C = low-density lipoprotein cholesterol; MACE = major adverse cardiovascular event; mFRS = modified Framingham Risk Score; MI = myocardial infarction; PREDICTS = Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular disease in PaTients with SLE; QRISK®3 = QRESEARCH Cardiovascular Risk Algorithm 3; RA = rheumatoid arthritis; SBP = systolic blood pressure; SELENA-SLEDAI = Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index; SLE = systemic lupus erythematosus; SLECRE = SLE Cardiovascular Risk Equation; TC = total cholesterol; TIA = transient ischemic attack; TNF = tumor necrosis factor-like.

The authors' group recently published the SLECRISK calculator, based on a large SLE cohort of over 1,200 patients. Risk modeling for the SLECRISK uses the 2013 ACC/AHA 10-year risk prediction score as the base model.¹⁰ To the base model, the following SLE-related variables were added: SLE activity (remission/mild vs. moderate/severe), disease duration, serum creatinine level, anti–double-stranded DNA, anti-ribonucleoprotein, lupus anticoagulant, anti-Ro positivity, and complement component level. Compared with other models, SLECRISK predicted 3.4-fold more patients at moderate/high risk, many of whom were young female patients with active SLE otherwise lacking traditional CVD risk factors. External validation of the tool is underway in more diverse SLE cohorts and with high ASCVD event rates; this study cohort had few ASCVD events, likely because of well-controlled SLE. A user-friendly application or online calculator for SLECRISK is being developed for point-of-care use.

Clinical Implications

Stratifying patients into low-risk, moderate-risk, and high-risk subgroups on the basis of thresholds indicated by each model impacts how clinicians discuss and counsel patients on CVD prevention therapies and lifestyle modifications. Initiation of statin therapy and/or further testing with cardiovascular imaging are potential next steps to be considered on the basis of predicted CVD risk.¹⁰

One challenge is that these risk models consider different thresholds as low risk versus moderate risk versus high risk. For instance, the threshold considered low risk on the basis of the ACC/AHA score is at 5% compared with 7.5% as low risk in the SLECRISK.¹⁰ The recommendation for moderate risk would be statin initiation and/or a discussion of further testing such as cardiac computed tomography for coronary artery calcium (CAC) assessment when the risk decision is uncertain. As uncalcified plaque is not yet quantified by CAC assessment, it may be more prevalent and dangerous in patients with SLE, with the risk of provoking thrombosis.^1,11,12 Beyond lipid-lowering therapy, additional testing with CAC has the potential to further guide decision-making on aspirin initiation, which is another relevant discussion in SLE given thrombotic risk and antiphospholipid antibody assessment. The SLECRISK can further guide more targeted control of the SLE disease activity. The heterogeneity of SLE itself and the variation in the risk of CVD observed in SLE require usage of a score tailored to the individual and their SLE-related risk factors. Adoption of a single SLE CVD risk assessment method would not only streamline clinical practice, but also facilitate comparison of outcomes across randomized controlled trials.

Conclusion

CVD remains a common cause of morbidity and mortality in patients with SLE. CVD risk prediction tools tailored to SLE are essential in the management of SLE and CVD risk to enhance patient and provider understanding to guide shared decision-making, inform preventive therapy, and ultimately reduce adverse outcomes. Stratifying patients by risk can lead to better targeted and timed therapeutic initiation with the overarching goal of efficient preventive health care delivery.

References

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