Peng, Junjie;
Donnes, Pierre;
Ardoin, Stacy;
Schanberg, Laura;
Lewandowski, Laura;
Robinson, George A;
Jury, Elizabeth;
(2023)
Additional Analysis of the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) Trial Identifies Novel Determinants of Patient Heterogeneity and a Distinct Lipid Metabolomic Signature Associated with Atherosclerosis Progression.
SSRN: Amsterdam, Netherlands.
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Abstract
Background: Juvenile-onset systemic lupus erythematosus (JSLE) is associated with chronic inflammation and increased risk of atherosclerosis. The APPLE trial was a randomised, placebo-controlled trial of atorvastatin for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) measurements as primary outcome. Methods: Unsupervised clustering analysis was used to stratify JSLE patients by their baseline CIMT and identify patterns of CIMT progression over 36 months. An additional in-depth metabolomic analysis was performed to identify lipidomic signatures predictive of CIMT progression. Correlation and univariate regression analyses explored associations between patient and disease characteristics and serum biomarkers. Machine learning techniques and ROC analyses were used to identify and validate a serum metabolomic signature of high CIMT progression. Findings: Baseline CIMT measurements stratified JSLE patients into three groups with distinct CIMT progression trajectories irrespective of the treatment allocation. Two distinct CIMT progression rates (high vs. low), characterised by higher total and low-density lipoprotein (LDL) cholesterol levels (P=0.001 and P=0.002, respectively) were found in the placebo group, while patients treated with atorvastatin had three distinct CIMT trajectories (high, intermediate and low progression), not associated with any relevant biomarkers. A robust metabolomic signature predictive of high CIMT progression in the placebo arm was identified (AUC = 80.7%). Interpretation: This complementary analysis of the APPLE trial provides new evidence for the significant heterogeneity of subclinical atherosclerosis in JSLE and its distinct progression trajectories irrespective of treatment allocation. Clinical trial patient stratification using the newly identified metabolomic signature predictive of increased natural atherosclerosis progression rate may improve results. Despite being effective in lowering serum lipids, atorvastatin did not prevent the CIMT progression in many at risk JSLE patients, highlighting the need for personalised therapies to address various molecular mechanism driving atherosclerosis in JSLE.
| Type: | Working / discussion paper |
|---|---|
| Title: | Additional Analysis of the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) Trial Identifies Novel Determinants of Patient Heterogeneity and a Distinct Lipid Metabolomic Signature Associated with Atherosclerosis Progression |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.2139/ssrn.4336159 |
| Publisher version: | https://papers.ssrn.com/sol3/papers.cfm?abstract_i... |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165303 |
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