A Multiomic Analysis to Identify Drivers of Subclinical Vascular Disease in Systemic Lupus Erythematosus

Objective Systemic lupus erythematosus (SLE) increases cardiovascular disease (CVD) risk, and this is not explained by traditional risk factors. Characterization of blood immunologic signatures that associate with subclinical CVD and predict its progression has been challenging and may help identify subgroups at risk. Methods Patients with SLE (n = 77) and healthy controls (HCs) (n = 27) underwent assessments of arterial stiffness, vascular wall inflammation, and coronary atherosclerosis burden with cardio‐ankle vascular index (CAVI); fluorodeoxyglucose–positron emission tomography/computed tomography (CT) (target‐to‐background ratio [TBR]); and coronary CT angiography. Whole blood bulk RNA sequencing was performed in a subset of study participants (HC n = 10, SLE n = 20). In a partially overlapping subset (HC n = 24, SLE n = 64), serum inflammatory protein biomarkers were quantified with an Olink platform. Results CAVI, TBR, and noncalcified coronary plaque burden (NCB) were increased in patients with SLE compared to HCs. When comparing patients with SLE with high CAVI scores to those with low CAVI scores or to HCs, there was a down‐regulation of genes in pathways involved in the cell cycle and differentially regulated pathways related to metabolism. Distinct serum proteins associated with increased CAVI (CCL23, colony‐stimulating factor 1, latency‐activating peptide transforming growth factor β1, interleukin 33 [IL‐33], CD8A, and IL‐12B), NCB (monocyte chemotactic protein 4 and FMS‐like tyrosine kinase 3 ligand [Flt3L]), and TBR (CD5, IL‐1α, AXIN1, cystatin D [CST5], and tumor necrosis factor receptor superfamily 9; P < 0.05). Conclusion Blood gene expression patterns and serum proteins that associate with worse vascular phenotypes suggest dysregulated immune and metabolic pathways linked to premature CVD. Cytokines and chemokines identified in associations with arterial stiffness, inflammation, and NCB in SLE may allow for characterization of new CVD biomarkers in lupus.