Cardiovascular disease (CVD) remains a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Decades of data have established that patients with SLE experience myocardial infarctions and strokes at rates far exceeding those of the general population, often at strikingly young ages.1 The increased prevalence of CVD in younger patients was confirmed in the Manhattan Lupus Surveillance Program, which found the prevalence ratio for cardiovascular events was 6.4 in younger patients with SLE aged 20-49 years and 2.2 in patients with SLE aged 50 years and older, compared with age-stratified national estimates.2 This risk is even greater in patients with a history of lupus nephritis.3 Expert consensus guidelines recommend that high-risk patients with SLE be treated with statins in a manner similar to at-risk general population patients.4 Unfortunately, current screening tools to identify at-risk patients with SLE who need prevention-targeted strategies continue to fall short.
In this issue of The Journal of Rheumatology, the study by Patel et al adds to a growing body of evidence that conventional cardiovascular risk calculators, including the widely used Atherosclerotic CV Disease (ASCVD) Risk Score, are inadequate for patients with SLE.5 Previous studies demonstrated risk calculators that factor an SLE diagnosis into account, such as the QRISK3 or the modified Framingham Risk Score, do not fully capture the increased risk in patients with SLE.6 The recently developed SLE-specific CV risk (SLECRISK; formerly SLE Cardiovascular Risk Equation [SLECRE]) incorporates both general cardiovascular risk factors and SLE-specific risks including disease duration, corticosteroid and hydroxychloroquine use, disease activity, renal involvement, and the presence of antiphospholipid antibodies.7 In the current study, however, even though SLECRISK is an improvement over more traditional tools, it still fails to reliably identify patients with subclinical atherosclerosis.5 The most concerning finding by the authors is that a substantial proportion of patients with SLE categorized as low risk by these tools already demonstrate coronary artery calcification (CAC) on computed tomography (CT),5 which is a powerful predictor of future cardiovascular events in the general population.8
Certainly, patients with SLE who have high scores on conventional risk calculators are truly at increased risk. Patel et al showed a high ASCVD score had a positive predictive value (PPV) of 100% for the presence of coronary artery calcium in subjects with SLE.5 Among SLE patients with CAC, however, the ASCVD score identified only 15% of subjects as high risk, highlighting the poor sensitivity of this traditional tool in SLE-specific CVD. It is also noteworthy that 12% of patients under the age of 40 had evidence of abnormal CAC, yet none were identified as high risk using ASCVD. Similarly, although a high SLECRISK score has a PPV of 75% for the presence of CAC, the sensitivity was still only 30.8% among patients with CAC.5
This disconnect exposes a critical flaw in how cardiovascular risk is conceptualized in SLE. Although traditional risk factors do play an important role, atherosclerotic plaque development in subjects with SLE is multifactorial and likely driven by chronic systemic inflammation and immune dysregulation. Multiple pathways can contribute, including lipid oxidation inflammatory cytokines (including tumor necrosis factor [TNF], interleukin 6, and interferon α), altered immune cell subtypes, and neutrophil extracellular trap activation and release.9 Many aspects of metabolic syndrome are also common in those with SLE, including dysregulation of cytokines and adipokines.9 Finally, cumulative dose and duration of corticosteroid use also independently accelerates atherosclerotic plaque formation, whereas hydroxychloroquine use is thought to decrease overall risk.
Currently, expert panels in both the United States and Europe recommend that patients with SLE should be annually screened for traditional modifiable risk factors for CVD.10,11 However, until optimum SLE risk prediction models are identified, the ideal targets for risk modification are still somewhat unclear. In the future, it is likely that novel SLE-specific risk prediction panels that include both biomarkers and clinical variables will be validated for identification of high-risk patients who should be treated early with therapeutic interventions to prevent future cardiovascular complications. Our group previously developed the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients With SLE (PREDICTS) score, a panel of biomarkers that have been associated with oxidative stress (inflammatory high-density lipoprotein, leptin, homocysteine, and soluble TNF-like weak inducer of apoptosis [sTWEAK]) and 2 traditional cardiac risk factors (age ≥ 48 years and history of diabetes mellitus). SLE patients with high PREDICTS scores had a 3.7-fold increased risk for having a major adverse cardiovascular event (MACE)12; however, panels like PREDICTS that incorporate novel inflammatory biomarkers are not yet widely or commercially available.
One potential solution is to include screening for CAC as part of risk stratification. CAC scoring has repeatedly demonstrated strong predictive value for cardiovascular events in the general population and is increasingly endorsed by cardiology societies as a tool to refine risk assessment. For example, the 2019 American College of Cardiology/American Heart Association guidelines for the primary prevention of CVD recommend assessment of CAC in patients at intermediate risk for CVD (≥ 7.5% to < 20%) using traditional calculators.13 Statin initiation is favored in patients with CAC scores of 1-100 and is strongly recommended in those with a CAC score > 100. Conversely, patients with no CAC have a very low risk of future cardiovascular events; for these patients, statin use would not generally be recommended.13
The data presented by Patel et al5 suggest CAC imaging may be even more valuable in SLE, where traditional scores lack sensitivity and where disease-related risk factors accelerate vascular damage long before clinical cardiovascular events occur. Several previously published observational studies corroborate the current findings that CAC is present at least 2-3 times more frequently in patients with SLE than in controls.14,15 One study of CAC showed the odds of having a significant CAC score were 12.6 times higher in SLE vs controls.15 CAC is known to be associated with an increased risk of MACE both in the general population and in patients with immune-mediated rheumatic diseases, including SLE.16 In a recent study, even rheumatic disease patients with a low level of CAC (1-99) had a 2-fold increased hazard ratio (HR) for MACE, whereas those with higher levels of CAC had over a 3-fold increased HR.16
Unfortunately, it is still unclear how intermediate-risk patients with SLE who could benefit from further risk stratification with CT should be identified, as traditional calculators are still likely to underestimate risk. Most cardiovascular guidelines for the general population do not recommend CAC screening by CT for those under 40 years of age to avoid radiation exposure and cost in those unlikely to have a positive test.16 The current study by Patel et al demonstrates, however, that younger patients with SLE may already demonstrate CAC and therefore are at increased risk for poor future outcomes without preventive interventions.5 Future studies will hopefully help to clarify which patients with SLE, both over and under 40 years of age, are at intermediate risk and may benefit from additional testing to better stratify risk.
Ultimately, however, risk stratification is useful only when preventive strategies are also implemented in higher-risk patients. The findings in the study by Patel et al5 are consistent with numerous other studies in patients with SLE and rheumatic diseases, namely, that initiation of statin use is low even in patients identified as high risk on currently available calculators or on cardiovascular imaging studies.16 There are likely to be numerous contributing factors to this lack of uptake, especially among patients who already have a significant medication burden and a limited amount of time during rheumatology appointments to discuss prevention strategies. Hopefully, the increasing availability of specialty cardiovascular-rheumatology clinics will help to specifically address and implement prevention strategies in the high-risk SLE patient population.
Footnotes
See SLE CVD risk prediction, page 637
FUNDING
The authors declare no funding or support for this work.
COMPETING INTERESTS
The authors declare no conflicts of interest relevant to this article.
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