Purpose The risk of developing CVD through atherosclerosis in juvenile-onset systemic lupus erythematosus (JSLE) patients is significantly increased. This study aimed to stratify and characterize JSLE patients at elevated CVD risk using patient/disease-related factors and metabolomic data from patients recruited to the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) clinical trial, designed to assess atherosclerosis development.
Methods Unsupervised hierarchical clustering was performed to stratify patients by arterial intima-media thickness (IMT) measurements at baseline (N=151) and carotid (c)IMT progression over 36 months (placebo arm only, N=60). Baseline metabolomic profiles (~250 serum metabolites) were compared between clusters using conventional statistics, univariate logistic regression, sparse Partial Least-Squares Discriminant Analysis (sPLS-DA) and random forest classifier. An independent cohort (UCL-JSLE cohort, N=89) with matching metabolomics, immunophenotyping and proteomics, was used to validate the discovered CVD risk-related signatures from the APPLE cohort.
Results Baseline IMT stratification identified 3 clusters with high, intermediate, and low baseline IMT measurements and progression trajectories over 36 months, each having distinct racial/BMI/household education/income characteristics. Analysis of cIMT progression over 36 months identified 2 patient groups with high and low IMT progression. Unique metabolomic profiles differentiated high and low cIMT progression groups, with good discriminatory ability (0.81 AUC in ROC analysis) using the top 6 metabolites (Total cholesterol esters, Total cholesterol, Phospholipids in small LDL particles, Total cholesterol in small LDL particles, Free cholesterol in medium LDL particles and Total lipids in small LDL particles) selected from the analysis. cIMT progression over 36 months in the placebo group correlated positively with baseline disease activity (SLEDAI), damage score (SLICC), white blood cell count, serum complement C3, blood pressure (both systolic and diastolic) and BMI. Metabolomics signatures discovered from the APPLE cohort were applied to stratify JSLE patients in the validation cohort (UCL-JSLE), where 3 groups were identified with distinct metabolomics profiles indicating JSLE patients with high risk (N= 20), intermediate risk (N= 43) and low risk (N= 26) CVD-risk. Significant differences were observed in the frequency of classical monocytes (p=0.015) and nonclassical monocytes (p=0.005) when comparing high and low CVD risk groups in the UCL-JSLE cohort.
Conclusions Complex analysis of IMT patterns and progression in the APPLE trial cohort identified novel key determinants that could guide further research for CVD-risk stratification in JSLE.
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