Background/Purpose: Cardiovascular disease (CVD) is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE) through atherosclerosis, the build-up of lipids and inflammation in the sub-endothelial intimal layer of medium-sized to large arteries. Our findings in adult-onset SLE link immune cell dysregulation with dyslipidaemia, however, little is known about the immune profile or whether dyslipidaemia contributes to inflammation and atherosclerosis in JSLE.

Methods: Serum NMR metabolomics (130 lipid measures), proteomics (Proximity Extension Assay) and anti-high density lipoprotein(HDL) antibody (ELISA) analysis was performed on a cohort of JSLE patients (n=65, median age 19, 22 active, 43 inactive by SLE Disease Activity Index, SLEDAI) and healthy controls (HCs, n=32, median age=19). Data was analysed using balanced random forest (BRF) machine learning with 10-fold cross-validation and logistic regression (adjusted for demographic characteristics) and linear regression analysis correlating features with measures of disease activity. Flow cytometry evaluated the activation (CD69 and HLA-DR) and inflammatory lipid profile (lipid raft signalling platforms enriched in glycosphingolipids and cholesterol) of immune subsets.

Results: The BRF machine learning model could predict JSLE patients from HCs with a 76% accuracy based on all 130 serum lipid measures with the most important variables being a lower expression of atheroprotective small and medium HDL subsets in JSLE compared to HCs. In support, linear and logistic regression analysis of serum lipids identified atherogenic dyslipidaemia in JSLE patients compared to HCs exacerbated by active disease and altered liver function. Specifically, patients with active disease had significantly increased atherogenic very-low, intermediate and low density lipoproteins (VLDL, IDL and LDL) and decreased atheroprotective HDL compared to patients with low disease activity and HC’s. Strikingly, HDL levels correlated negatively with anti-HDL antibodies (r=-0.49, p=0.012) and atherogenic lipoproteins correlated positively with T-cell and B-cell lipid rafts and activation markers. In addition, lymphocyte culture with serum isolated from JSLE patients with active disease induced a significant increase in cellular cholesterol and activation markers compared to serum isolated from patients with low disease activity and HC’s. Finally, JSLE patients had increased serum levels of ICAM1 (p=0.013), VCAM1 (p=0.007) and lipoprotein lipase (p=0.028) compared to HCs, suggesting increased vascular inflammatory cell recruitment and atherogenic lipoprotein conversion in JSLE respectively.

Conclusion: Multi-omic analysis identified potential early mechanisms of dyslipidaemia in JSLE patients associated with inflammation and atherosclerosis. This could help to inform early lipid targeted therapies in JSLE to improve cardiovascular outcomes and quality of life for patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/metabolomics-identifies-early-mechanisms-of-atherogenic-dyslipidaemia-in-juvenile-sle-patients-associated-with-inflammation/