Metabolomics in juvenile-onset SLE: identifying new biomarkers to predict cardiovascular risk

ABSTRACTBACKGROUNDJuvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder characterised by immune dysregulation, chronic inflammation and increased cardiovascular risk (CVR). Cardiovascular disease is the leading cause of mortality in JSLE patients not attributable to disease flares. However, it is not possible to predict those patients at greatest risk using traditional CVR factors.METHODSSerum metabolomic analysis was performed using a nuclear magnetic resonance spectroscopy-platform in 31 JSLE patients. Data was analysed using cluster, linear regression and receiver operating characteristic analysis. Results were validated in a second cohort of 31 JSLE patients and using data from a cohort of adult-onset SLE patients with known pre-clinical atherosclerotic plaque.RESULTSUnbiased hierarchical clustering of metabolomic data identified three patient groups. Group-1 had decreased atheroprotective high density lipoproteins (HDL) and increased atherogenic very low and low density lipoproteins (VLDL/LDL); Group-2 had elevated HDL but reduced VLDL/LDL; and Group-3 had low HDL/VLDL/LDL levels. Notably, apolipoprotein(Apo)B1:ApoA1 ratio, a known CVR marker in adult cohorts, was elevated in Group-1 JSLE patients compared to Groups-2/3. The metabolomic signature was validated in a second JSLE cohort and compared with lipid biomarkers previously associated with pre-clinical atherosclerotic plaque in adult SLE patients. Linear regression analysis accounting for demographics, treatment, disease activity, lupus serological markers and body mass index confirmed that a unique metabolomic profile could differentiate between JSLE patients at high and low CVR.CONCLUSIONSPatient stratification using ApoB:ApoA1 ratio and lipoprotein signatures could facilitate tailored lipid modification therapies and/or diet/lifestyle interventions to combat increased CVR in JSLE.Key messagesWhat is already known about the subject?Cardiovascular disease is the leading cause of mortality in juvenile-onset systemic lupus erythematosus (JSLE) not attributable to lupus flares; the cardiovascular risk of JSLE patients is 300 times higher than age matched healthy individuals. It is not possible to predict those patients at greatest risk using traditional risk factors.What does this study add?In depth lipoprotein-based metabolomic analysis identified Apolipoprotein(Apo)B :ApoA1 ratio as a potential biomarker for predicting increased cardiovascular risk in JSLE. This was validated in a second patient cohort and using metabolic signatures associated with pre-clinical atherosclerotic plaque development in adult SLE patients.How might this impact on clinical practice or future developments?Predicting cardiovascular risk in young JSLE patients using ApoB:ApoA1 ratio could help to stratify patients and identify those who would benefit the most from existing lipid targeting therapies. Reducing cardiovascular risk at a young age could improve patient’s life expectancy and quality of life and reduce cardiovascular comorbidity in later life.