Atherosclerosis progression in the APPLE trial can be predicted in young people with juvenile-onset systemic lupus erythematosus using a novel lipid metabolomic signature.

OBJECTIVES: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the APPLE trial, the largest investigator-led randomised control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as primary outcome.

METHODS: Unsupervised clustering of baseline CIMT and CIMT-progression over 36 months was used to stratify JSLE patients. Disease characteristics, cardio-vascular risk scores and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify/validate a serum metabolomic signature of CIMT progression.

RESULTS: Baseline CIMT stratified JSLE patients (N=151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease-risk based on recommended assessment criteria. In the placebo group (N=60), patients with high vs, low CIMT-progression had higher total (P=0.001) and low-density lipoprotein (LDL) (P=0.002) cholesterol levels, although within the normal range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT-progression was identified in the placebo arm (area under the curve-AUC 80.7%). Patients treated with atorvastatin (N=61) had reduced LDL cholesterol levels after 36 months as expected, however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting non-lipid drivers of atherosclerosis in JSLE with management implications for this subset of patients.

CONCLUSION: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some JSLE patients with relevance for clinical trial stratification.