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Objectives Type I-III interferons (IFNs) are key mediators in systemic lupus erythematosus (SLE) and have been proposed to contribute to cardiovascular disease (CVD). This study examined the association between biologically active IFN, disease activity, and a spectrum of cardiovascular outcomes, including broad cardiovascular disease (CVD), atherosclerotic CVD (ASCVD), and hard endpoints cerebrovascular (CVI) and coronary artery disease (CAD) in patients with SLE.Methods This multicenter, retrospective analysis included 378 patients from the Swiss Systemic Lupus Erythematosus Cohort Study (SSCS). IFN activity was quantified using a validated reporter cell line-based assay detecting type I–III IFNs. To comprehensively evaluate cardiovascular risk, two complementary models were employed: logistic regression to assess associations between IFN activity and prevalent CVD, and Cox proportional hazards regression to evaluate incident cardiovascular events during a mean follow-up of 4.3 years. All models were adjusted for traditional and SLE-related cardiovascular risk factors.Results High IFN activity was observed in 27.8% of patients and was strongly associated with disease activity scores and an interferon gene signature (IFNGS). While IFN activity showed inverse associations with prevalent CVD and ASCVD in univariable models, these relationships were not retained after adjustment for risk factors. In Cox analyses, IFN activity did not predict incident CVD, ASCVD, CVI, or CAD. Significant predictors of new cardiovascular events included higher SELENA-SLEDAI, antiphospholipid antibodies, CKD, corticosteroid use, hypertension, hyperlipidemia, and previous CVD.Conclusions Type I-III IFN activity reflects disease activity in SLE but does not independently predict cardiovascular outcomes across modeling approaches. Traditional and SLE-related risk factors remain the primary determinants of cardiovascular risk in SLE.