The warning signs appeared long before modern rheumatology could explain them. In 1976, Urowitz and colleagues described a bimodal mortality pattern in lupus patients: early deaths driven by active disease or infection, and late deaths occurring roughly 8.6 years after diagnosis that were overwhelmingly cardiovascular in origin. Post-mortem examination of those late deaths revealed atheromatous occlusion of the coronary arteries, not ongoing lupus activity. Two decades later, Manzi and colleagues quantified the scale of the problem by comparing 498 women with lupus against 2,208 age-matched women from the Framingham Offspring Study. Among women aged 35 to 44 years with lupus, the rate ratio for myocardial infarction reached 52.4, meaning young women with lupus faced more than a 50-fold higher risk of heart attack than their healthy peers. Roughly two-thirds of the 33 cardiovascular events recorded in the lupus cohort occurred in women under 55.

Subsequent large cohorts confirmed the pattern. In the Nurses’ Health Study, which followed 119,332 women over 28 years, the 148 who developed lupus carried a relative risk of 2.26 for cardiovascular events even after adjustment for age, race, hypertension, diabetes, hyperlipidemia, body mass index, smoking, physical activity, and corticosteroid use. A Korean population-based cohort of 8,568 lupus patients and 34,272 controls found a 2.4-fold higher adjusted risk of major adverse cardiovascular events overall, but approximately 12-fold in younger patients, with no sex differences. Meta-analyses have pooled the relative risk of myocardial infarction in lupus at 2.99 and the risk of coronary artery disease at 3.39. The technical conclusion is stark: when Bruce, Urowitz, and colleagues calculated 10-year cardiac risk using standard Framingham variables in 250 lupus patients and 250 matched controls, they found no significant difference between groups, despite coronary heart disease prevalence being up to 8-fold higher in lupus. Esdaile’s team similarly demonstrated a 10.1-fold higher risk of non-fatal myocardial infarction and 7.5-fold higher overall coronary heart disease risk that the Framingham score simply did not predict.

The mechanism behind this accelerated atherosclerosis is now coming into focus, and it is not primarily about cholesterol. Imaging studies tell the story. Roman and colleagues used carotid ultrasonography to detect extracranial plaque in lupus patients and matched controls, finding plaque in 37.1 percent versus 15.2 percent. After multivariate adjustment for traditional risk factors, lupus itself remained a strong independent predictor of plaque with an odds ratio of 4.8. Within the lupus cohort, longer disease duration, higher damage index scores, and absence of cyclophosphamide use predicted plaque, suggesting cumulative inflammatory burden rather than conventional risk factors drives the vascular pathology. A meta-analysis of 80 studies covering 6,085 lupus patients and 4,794 controls confirmed that carotid intima-media thickness and plaque measurement effectively identify patients at increased cardiovascular risk, with age, HDL, triglycerides, disease duration, erythrocyte sedimentation rate, and SLEDAI disease activity score all significantly associated with arterial thickening.

At the cellular level, type I interferon emerges as a central villain. This signaling molecule, produced in excess in lupus, impairs endothelial progenitor cell function, reduces their circulating levels, and promotes endothelial cell apoptosis, shifting the balance from vascular repair toward vascular injury. Interferon signaling also rewires macrophage lipid handling by upregulating Scavenger Receptor class A, enhancing oxidized LDL uptake and foam cell formation. Increased SR-A expression has been documented in peripheral blood mononuclear cells from lupus patients and correlates with heightened interferon signature. Neutrophil extracellular traps, large extracellular structures composed of chromatin, histones, and granular proteins, add another layer of complexity. These NETs promote immune activation and type I interferon production, inflict direct cytotoxic damage on endothelium, and propagate vascular inflammation. Clinical evidence supports the mechanistic story: serum type I interferon activity was independently associated with increased carotid intima-media thickness, reduced vascular repair capacity, and greater coronary calcification severity, even after adjusting for conventional cardiovascular risk factors.

Autoantibodies compound the damage. Anti-beta2 glycoprotein 1 antibodies, a subset of antiphospholipid antibodies, facilitate macrophage uptake of beta2 glycoprotein 1-oxidized LDL complexes, accelerating foam cell and plaque formation. Anti-oxidized LDL and anti-apolipoprotein A-1 antibodies contribute through additional pathways, including vascular smooth muscle cell activation and induction of a prothrombotic state. Meanwhile, chronic inflammation disrupts lipid metabolism itself, promoting formation of dysfunctional HDL with diminished atheroprotective capacity and enhanced pro-inflammatory properties, while simultaneously increasing LDL susceptibility to oxidative modification. Patients with lupus exhibit characteristic lipid abnormalities including increased total cholesterol, LDL, and triglycerides, along with reduced HDL and apolipoprotein A1. Emerging hypotheses implicate gut microbiota dysbiosis as a potential modulator of cardiovascular risk through effects on systemic inflammation, lipid metabolism, and microbial metabolites such as trimethylamine N-oxide, though direct evidence linking dysbiosis to lupus-associated atherosclerosis remains limited.

Given the failure of conventional prediction tools, researchers have developed alternatives. Urowitz proposed a modified Framingham score, the 2FRS, which doubles the weight of each traditional component, reclassifying 17.3 percent of lupus patients as moderate-to-high risk compared with 2.4 percent using the standard score. QRISK3, developed in the United Kingdom from primary care databases covering 7.89 million people, explicitly incorporates lupus, corticosteroid use, chronic kidney disease, and ethnicity. In lupus cohorts, QRISK3 demonstrated fair discrimination with area under the curve values of 0.76 to 0.77 and reasonable calibration, identifying 45 percent of lupus patients who later experienced cardiovascular events versus 11 percent with Framingham. A French validation cohort of 143 patients identified an optimal risk threshold of 9.4 percent rather than the standard 10 percent. SLECRISK, developed in 2024, goes further by incorporating disease duration, disease activity, autoantibody profile, low C4, and creatinine. At a clinical threshold of 7.5 percent 10-year risk, SLECRISK sensitivity reached 0.74 compared with 0.38 for ACC/AHA and Framingham-based scores, particularly improving detection in younger women with severe lupus and few traditional risk factors. However, in a separate cohort of 128 patients, SLECRISK sensitivity for detecting abnormal coronary artery calcification was only 30.8 percent despite high specificity, indicating it failed to identify a substantial proportion of patients with subclinical atherosclerosis. The adjusted Global Antiphospholipid Syndrome Score outperformed QRISK3 in lupus patients with secondary antiphospholipid syndrome for cerebrovascular and coronary events. The newer PREVENT score, derived from 6.6 million US adults, showed fair discrimination for atherosclerotic cardiovascular disease in lupus with an area under the curve of approximately 0.80, but calibration was poor with a mean observed-to-predicted risk ratio of 2.8, indicating substantial misestimation of absolute risk.

On the therapeutic front, hydroxychloroquine stands out as the most promising existing intervention. A 2024 French cohort study of 52,883 lupus patients found hydroxychloroquine use associated with a composite cardiovascular outcome odds ratio of 0.63, corresponding to approximately 37 percent risk reduction. Remote use, discontinued 91 to 365 days before the cardiovascular event, showed no benefit, underscoring the importance of continuous therapy. The proposed mechanism involves interference with Toll-like receptor signaling, decreasing type I interferon production, reducing pro-inflammatory cytokines including IL-1, IL-6, and TNF-alpha, and inhibiting B cell activation. Chronic use also improves endothelial dysfunction by increasing nitric oxide bioavailability, and hydroxychloroquine stimulates nitric oxide synthase activity in human endothelial cells while preventing endothelial NOS uncoupling. Meta-analyses show modest but significant lipid improvements, with reductions in total cholesterol and LDL and increases in HDL. A systematic review of 13 clinical trials found hydroxychloroquine decreased thromboembolic event risk by 49 percent. Benefit was more pronounced with use exceeding 5 years, showing a hazard ratio of 0.26 for preventing first cardiovascular events, and a recent study associated treatment with reduced progression of atherosclerotic plaque over 3 years.

Corticosteroids present a dual challenge. They suppress inflammation during acute flares, yet long-term exposure at higher doses may accelerate atherosclerosis through metabolic effects. Magder and colleagues demonstrated that current prednisone use exceeding 20 mg daily was associated with a five-fold increase in cardiovascular event risk, while past exposure showed no adverse association. However, disentangling corticosteroid risk from underlying disease activity remains analytically difficult, since disease activity functions as a time-varying confounder and mediator. Statins have shown mixed results. A randomized trial of 200 lupus patients comparing atorvastatin 40 mg daily with placebo found no significant differences in carotid intima-media thickness, plaque burden, or coronary calcium score after two years, though observational data from 4,095 patients with hyperlipidemia associated high-dose statin use with reduced mortality, cardiovascular disease, and end-stage renal disease. Acetylsalicylic acid shows promise in selected populations, particularly those with antiphospholipid antibodies, where EULAR guidelines support low-dose ASA for primary thrombosis prevention in high-risk profiles, though evidence for routine primary prevention of atherosclerotic cardiovascular disease in lupus remains limited.

Emerging therapies offer new hope. Sodium-glucose cotransporter 2 inhibitors, studied primarily in lupus patients with concomitant diabetes, showed reduced heart failure incidence with a hazard ratio of 0.72 in one population-based target trial emulation, though effects on atherosclerotic burden remain unexplored. Glucagon-like peptide-1 receptor agonists demonstrated a 34 percent reduction in major adverse cardiovascular events and a 74 percent reduction in all-cause mortality in lupus patients with type 2 diabetes compared with dipeptidyl peptidase-4 inhibitors. Among biologics, belimumab, which targets soluble BLyS, improved cholesterol efflux and antioxidant capacity of HDL after 6 months in a prospective study of 35 patients with high disease activity. Anifrolumab, a type I interferon receptor blocker, reduced neutrophil extracellular trap formation and improved HDL cholesterol efflux capacity by approximately 17 percent in patients with impaired baseline function, though no trial has yet been powered to demonstrate reduction in adverse cardiovascular events. The review concludes that optimal cardiovascular risk stratification in lupus may ultimately require integration of clinical risk scores with carotid ultrasound imaging, potentially complemented by selected biological markers, alongside aggressive management of both traditional and lupus-related risk factors to reduce the burden of cardiovascular disease in this vulnerable population.

Subject of Research: Cardiovascular risk prediction and prevention in systemic lupus erythematosus

Article Title: Cardiovascular risk in systemic lupus erythematosus: beyond Framingham to emerging risk prediction tools and therapeutic approaches

Article References: Aflaki, M., & Bargman, J. M. (2026). Cardiovascular risk in systemic lupus erythematosus: beyond Framingham to emerging risk prediction tools and therapeutic approaches. Frontiers in Lupus, 4, Article 1725054. https://doi.org/10.3389/flupu.2026.1725054

Image Credits: AI Generated

DOI: 10.3389/flupu.2026.1725054

Keywords: systemic lupus erythematosus, cardiovascular disease, atherosclerosis, Framingham Risk Score, QRISK3, hydroxychloroquine, type I interferon, antiphospholipid antibodies, statins, SGLT2 inhibitors, GLP-1 receptor agonists, inflammation