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Atherosclerosis Progression in the APPLE Trial Can Be Predicted in Young People With Juvenile-Onset Systemic Lupus
Junjie Peng1, Pierre Dönnes2, Stacy P Ardoin3
1Centre for Rheumatology Research and Centre for Adolescent Rheumatology Versus Arthritis, University College London, London, United Kingdom.
Insights
Juvenile-onset systemic lupus erythematosus (JSLE) patients show varied atherosclerosis progression. Metabolomic signatures can predict this progression, aiding in clinical trial stratification for better juvenile systemic lupus erythematosus management.
Area of Science:
- Pediatric Rheumatology
- Cardiovascular Research
- Metabolomics
Background:
- Juvenile-onset systemic lupus erythematosus (JSLE) is associated with increased atherosclerosis risk.
- The Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial is the largest randomized control trial investigating atorvastatin for atherosclerosis progression in JSLE.
- Carotid intima-media thickness (CIMT) is a key outcome measure for atherosclerosis in pediatric populations.
Purpose of the Study:
- To identify novel biomarkers for atherosclerosis progression in JSLE patients.
- To investigate the relationship between baseline metabolome and CIMT progression.
- To stratify JSLE patients based on atherosclerosis trajectories.
Main Methods:
- Unsupervised clustering of baseline and 36-month CIMT data to stratify JSLE patients.
- Analysis of disease characteristics, cardiovascular risk scores, and baseline serum metabolome in stratified groups.
- Application of machine learning to identify and validate a serum metabolomic signature for CIMT progression.
Main Results:
- JSLE patients (N=151) stratified into high, intermediate, and low CIMT progression groups, irrespective of treatment.
- In the placebo group, higher CIMT progression correlated with elevated total and LDL cholesterol, even within reference ranges.
- A baseline metabolomic signature predicted high CIMT progression in the placebo arm (AUC 80.7%).
- Atorvastatin reduced LDL but 36% of patients still showed high atherosclerosis progression, suggesting non-lipid drivers.
Conclusions:
- JSLE exhibits significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories.
- Metabolomic signatures demonstrate potential for predicting atherosclerosis progression in JSLE.
- Findings highlight the need for personalized management strategies beyond lipid-lowering therapies in certain JSLE patients.
Objective:
Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator-led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as the primary outcome.
Methods:
Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression.
Results:
Baseline CIMT stratified patients with JSLE (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 versus low CIMT progression had higher total (P = 0.001) and low-density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 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 nonlipid 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 patients with JSLE with relevance for clinical trial stratification.
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