Lupus CVD: Beyond the Lipid Panel Save

Innate immune dysregulation drives premature atherosclerosis in SLE, and it explains much of the cardiovascular risk that Framingham factors and medications do not. The main driver is a self-amplifying loop between type I interferon (IFN) and neutrophil extracellular traps (NETs). That loop injures the endothelium, impairs vascular repair, promotes foam cell formation, and destabilizes plaque. Dysfunctional monocytes and macrophages and complement activation add to the damage.

At ACR Convergence 2026, Dr. Mariana Kaplan presented “Guardians Turned Foes: Innate Immune Players in Cardiovascular Disease,” making a compelling case that cardiovascular risk in systemic lupus erythematosus (SLE) cannot be understood through lipids and blood pressure alone. Traditional risk factors matter, but they do not fully explain the burden of premature vascular disease. The more interesting question is what lupus-specific inflammation is doing to the arterial wall.

One culprit may be low-density granulocytes (LDGs), an inflammatory neutrophil subset prone to releasing neutrophil extracellular traps (NETs). Although NETs are part of host defense, excessive NET formation can injure endothelium, promote thrombosis, and amplify type I interferon signaling.

In a 2018 JCI Insight study, Carlucci and colleagues found that LDG-related measures were associated with vascular inflammation and noncalcified coronary plaque in SLE. I find this particularly compelling because the immune signal correlated with imaging evidence of subclinical vascular disease, rather than circulating biomarkers alone.

Kaplan also highlighted a mechanism that changes how we should think about cholesterol. NET-associated oxidative activity can impair HDL-mediated cholesterol efflux—its ability to remove cholesterol from macrophages. In other words, a seemingly reassuring HDL level may not reflect HDL function in an inflammatory state.

Could targeting these pathways actually reduce cardiovascular risk?

A 2021 study by Casey and colleagues found that anifrolumab, which blocks the type I interferon receptor, improved cholesterol efflux capacity and reduced circulating NET complexes in SLE. The presentation also explored immunometabolic pathways, including itaconate, as potential strategies to restrain vascular inflammation.

While promising, these findings warrant caution. Much of the evidence remains observational or based on surrogate outcomes. Improved vascular biomarkers do not necessarily translate into fewer myocardial infarctions or strokes, and these pathways have not been established as targets for cardiovascular prevention.

My biggest takeaway is that cardiovascular prevention in SLE must address both traditional risk factors and inflammatory disease burden. We need improved cardiovascular risk scoring systems for lupus patients.  And, for now, that means optimizing blood pressure and lipids, maintaining disease control, and minimizing glucocorticoid exposure, consistent with EULAR cardiovascular risk recommendations.

The real question moving forward is whether targeting innate immune dysfunction can prevent cardiovascular events, rather than simply improve laboratory or imaging markers. This research may not change what we prescribe tomorrow, but it should change how we think about cardiovascular disease in lupus.

References 

Primary conference presentation as: Kaplan MJ. Guardians Turned Foes: Innate Immune Players in Cardiovascular Disease. Presented at: American College of Rheumatology Convergence 2026; November 7–11, 2026; Orlando, Florida.

Carlucci et al. Association of low-density granulocytes, vascular inflammation, noncalcified coronary plaque, and impaired HDL cholesterol efflux in SLE.

Casey et al. Anifrolumab-associated improvements in NET complexes and cholesterol efflux capacity. These are surrogate outcomes, not evidence of fewer cardiovascular events.

Drosos et al. EULAR recommendations on cardiovascular risk assessment, managing traditional risk factors, and controlling SLE disease activity.

Casey KA, Smith MA, Sinibaldi D, et al.Arthritis & Rheumatology. 2021. Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.