Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterised by immune-dysregulation, chronic inflammation, type-I interferon (IFN) signatures and increased cardiovascular disease (CVD) risk (CVR); CVD is a major cause of morbidity and mortality in SLE. Juvenile-SLE (JSLE) has a more severe disease phenotype and CVR than adult SLE. All patients with SLE should receive careful monitoring and treatment of modifiable CVR factors. However, no guidelines exist for CVR management in SLE and it is not possible to predict the CVR of patients using traditional factors. This study used a multi-omic approach to investigate CVR in JSLE patients.

Methods: NMR-based serum metabolomic biomarker analysis (including 113 lipoprotein measures assessing size/lipid content) was performed on a discovery cohort of JSLE patients (n=31, median age 19). Data were analysed using cluster, receiver operating characteristic (ROC) and logistic regression analysis. Results were validated in a second JSLE cohort (n=31, median age 19). All patients were assessed clinically over 3-6 years of follow up. 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. This pattern was verifed by the measurement of lipid biomarkers associated with pre-clinical atherosclerotic plaque in adult SLE patients. The groups were validated the second JSLE cohort and the Apolipoprotein(Apo)B:A1 ratio was identified as a predictive and longitudinally stable biomarker of CVR (ROC area under the curve >0.99).

Patients with a high ApoB:A1 ratio had significantly increased circulating CD8+ T-cells. Transcriptomic and pathway enrichment analysis of differentially expressed genes (DEGs) from isolated JSLE CD8+ T-cells identified significantly increased interferon (IFN) signaling pathways in high ApoB:A1 ratio patients which overlapped with CD8+ T-cells from human and mouse atherosclerotic plaque. When DEGs associated with disease activity were removed from the analysis, we observed a unique dysregulation of the IFN-stimulated gene factor 3 transcription complex (ISGF3), including significantly increased expression of JAK2, STAT1/2 and IRF9.

Finally, a higher baseline ApoB:A1 ratio predicted an increased average Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over an average of 5 years (p=0.0009), suggesting worsened clinical outcome.

Conclusion: Multi-omic analysis identified a putative predictive biomarker (ApoB:A1 ratio) and novel immunopathogenic pathways, involving CD8+ T-cells and ISGF3 signalling, associated with increased CVR in JSLE. Patient stratification using the measurement of ApoB:A1 may therefore provide an opportunity for tailored disease treatments using lipid modification therapy and/or diet modification to control disease severity and CVR outcome.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/apobapoa1-ratio-could-predict-atherosclerotic-risk-in-juvenile-sle-patients-associated-with-altered-interferon-signalling-in-cd8-t-cells/