Editorial: Unraveling the complex interplay of risk factors in SLE-associated cardiovascular disease

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease characterized by persistent systemic inflammation, immune complex deposition, and multi-organ involvement. Although major therapeutic advances have successfully reduced early mortality caused by high disease activity and acute organ damage, cardiovascular disease (CVD) has emerged as a major cause of late morbidity and mortality in these patients. Individuals living with SLE face a 5- to 6-fold increased risk of suffering major adverse cardiovascular events compared to the general population. This phenomenon contributes to a well-known bimodal mortality pattern, where premature coronary artery disease, subclinical atherosclerosis, and myocardial dysfunction significantly reduce overall life expectancy.

Conventional cardiovascular risk scores, such as the Framingham Risk Score, consistently underestimate the true risk burden in SLE patients. This limitation stems from the fact that traditional risk factors, including dyslipidemia, hypertension, obesity, and metabolic syndrome, do not act in isolation. Instead, they interact dynamically with non-traditional, disease-specific mechanisms, including sustained pro-inflammatory cytokine cascades, specific autoantibody profiles, oxidative stress, cumulative drug toxicity (such as prolonged corticosteroid exposure), and underlying genetic or epigenetic variations. This Research Topic was launched to synthesize current evidence and bridge gaps regarding how traditional and non-traditional risk factor drivers converge to shape clinical phenotypes and cardiovascular outcomes in SLE.

This Research Topic compiles contributions ranging from clinical risk prediction to immunometabolic mechanisms, biomarker discovery, and novel pathophysiological pathways: Collectively, these studies demonstrate that cardiovascular risk in SLE cannot be mitigated by addressing traditional risk factors alone. Achieving optimal cardiovascular protection in SLE demands a personalized, multi-targeted approach that integrates tight disease activity control, advanced biomarker assessment, anti-inflammatory strategies, and early lifestyle and pharmacological interventions. We hope this Research Topic serves as a valuable framework for clinicians and researchers striving to untangle the complexities of cardiovascular risk and improve long-term outcomes for SLE patients.

• In a narrative review, Aflaki and Bargman evaluate the clinical utility of emerging risk prediction tools tailored to SLE. They emphasize that overcoming the limitations of standard algorithms requires integrating disease activity indices, damage scores, and therapeutic exposures alongside traditional risk parameters. Furthermore, they highlight the cardiovascular protective properties of antimalarial drugs and explore the potential role of emerging therapies, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, in managing metabolic-cardiovascular risk in SLE. The authors emphasize the need for improved risk stratification strategies that account for both traditional and SLE-specific cardiovascular risk factors.
• Expanding on the molecular crosstalk driving vascular damage, Bilodeau and Tselios discuss the complex interplay between immune dysregulation and dyslipidemia. They illustrate how chronic activation of the type I interferon (IFN-I) axis, dysfunctional high-density lipoproteins (HDL), oxidized low-density lipoproteins (oxLDL), and neutrophil extracellular traps (NETs) interact to promote endothelial dysfunction, foam cell transformation, and atherosclerotic plaque instability, contributing to accelerated atherogenesis in SLE.
• Complementing these mechanistic insights, Phothisane et al. provide novel clinical data regarding oxidative stress and blood pressure regulation. Their study reveals that serum IgG antibodies against isolevuglandins (IsoLGs), highly reactive lipid peroxidation products, are elevated in SLE patients compared to healthy controls. Notably, higher anti-IsoLG antibody levels were inversely correlated with 24-hour ambulatory blood pressure, suggesting a potential protective role for anti-IsoLG antibodies in the clearance of reactive lipid peroxidation products, although the underlying mechanisms remain to be established.
• Finally, applying advanced bioinformatics and machine learning algorithms to translational research, Li et al. identified shared immune-related biomarkers linking SLE to dilated cardiomyopathy. By isolating key genes such as HECT and RLD domain containing E3 ubiquitin protein ligase 6 (HERC6) and interferon induced protein 44 like (IFI44L), both strongly implicated in interferon signaling, the authors constructed a diagnostic nomogram with high predictive accuracy, identifying promising candidate biomarkers for further investigation of the molecular link between SLE and cardiac disease.

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Footnotes

Edited and Reviewed by: Antonio La Cava, University of California, Los Angeles, United States