Atherosclerosis Progression in the APPLE Trial Can Be Predicted in Young People With Juvenile‐Onset Systemic Lupus Erythematosus Using a Novel Lipid Metabolomic Signature

Abstract

ObjectivesPatients 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.MethodsUnsupervised 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.ResultsBaseline 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.ConclusionSignificant 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.image

Investigation of the performance of validated cardiovascular risk scores in a global (UK/US) cohort of young people with childhood-onset systemic lupus erythematosus

“…2 Although very few CYP with cSLE have been stratified as having high CVD-risk by any of the CVD-risk scores used in the APPLE cohort at baseline, we also assessed stratification performance of these scores at the end of the APPLE trial (36 months) in the placebo versus statin arm. As the metabolomic signature of atherosclerosis progression we discovered did not predict the CIMT progression in response to statin, we used the rates of CIMT progression over 36 months in each arm 5 for stratification. As expected, all CVD-risk scores underperformed at the end of the trial as they did at baseline and failed to identify individuals with high CIMT progression rates, irrespective of the treatment arm allocation (online supplemental table).…”

“…4 Although the trial did not meet the primary endpoint, it provided us with the opportunity to discover a novel serum metabolomic signature associated with a high rate of atherosclerosis progression in cSLE. 5 As CIMT measurements on vascular scans are not routinely implemented in clinical practice, we explored the comparative performance of four age-appropriate and validated CVD-risk scores in a global cSLE (UK/ US) cohort to address a key research priority identified by our PPIE activities.…”

“…Demographic data, CVD-risk factors and cSLE characteristics were collected crosssectionally from two cSLE cohorts: a retrospective University College London (UCL) cohort (N=109, UK) and a prospective APPLE trial cohort (N=121), both stratified based on the metabolomic signature of high CIMT progression identified in the APPLE trial. 5 The online supplemental figure depicts the CVD-risk stratification of the UCL cohort based on the metabolomic signature identified in the APPLE cohort.…”