Background Cardiovascular disease is the leading cause of mortality in patients with Juvenile-onset Systemic Lupus Erythematosus (JSLE) not attributable to lupus flare. This study used a multi-omic approach to investigate cardiovascular risk (CVR) in JSLE patients.

Methods NMR-based serum metabolomic biomarker analysis (including 113 different lipoprotein measures assessing lipoprotein size and lipid content) was performed on a discovery cohort of JSLE patients (n=31, median age 19). Data was analysed using cluster, receiver operating characteristic (ROC) and logistic regression analysis. Results were validated in a second JSLE cohort (n=31, median age 19). Flow cytometry evaluated 28 immune cell subsets and RNAseq assessed gene expression in matched patient samples.

Results Unbiased hierarchical clustering of metabolomic data identified 2 JSLE patient groups, each with a complex and unique lipoprotein profile. Group-1 had decreased high density lipoproteins (HDL) and increased very low and low density lipoproteins (VLDL/LDL) and Group-2 had elevated HDL but reduced VLDL/LDL indicating an association with high and low CVR respectively. These groups were validated in a separate JSLE cohort and Apolipoprotein (Apo) B:A1 ratio was identified as a predictive and longitudinally stable biomarker of CVR (ROC area under the curve>0.99).

The high and low CVR groups were also associated with a unique immune phenotype characterised by altered correlations between T and B-cell subsets and significantly increased CD4+ and reduced CD8+T-cell subsets in high vs low CVR. Transcriptomic analysis of T-cell subsets identified 70 genes upregulated and 62 downregulated in High vs Low CVR patients and pathway analysis identified membrane sphingolipid metabolism and lipid-mediated signalling as the top regulated pathways associated with CVR. Additionally, genes previously related with increased CVR, including IFNG and NLRP2, were significantly increased in the high CVR group.

Conclusion Multiomic analysis identified a putative predictive biomarker (ApoB:A1 ratio) and novel immunopathogenic pathways associated with increased CVR in JSLE.