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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
24 Pages Posted: 2 Feb 2023
More...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.
Trial Registration: ClinicalTrials.gov Identifier: NCT00065806
Funding: The APPLE study was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases contract N01-AR-2-2265), the Edna and Fred L. Mandel Jr. Center for Hypertension and Atherosclerosis, and Pfizer, which provided atorvastatin and matching placebo. This work was supported by a Versus Arthritis PhD Studentship (22908) and Career Development Fellowship (22856), as well as grants from the National Institute of Heath Research (NIHR) - University College London Hospital (UCLH) Biomedical Research Centre grant, BRC773/III/CC/101350 and Lupus UK and was performed within the Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), UCLH and Great Ormond Street Hospital (GOSH) supported by grants from Versus Arthritis (21593 and 20164), Great Ormond Street Children’s Charity, and the NIHR-Biomedical Research Centres at both GOSH and UCLH. The views expressed are those of the authors and not necessarily those of the National Health System (NHS), the NIHR or the UK Department of Health. Dr Lewandowski was funded by the NIAMS Intramural Program. The APPLE study was funded by the National Institutes of Health (NIAMS N01-AR-2-2265).
Declaration of Interest: The authors declared no relevant conflicts of interest.
Ethics Approval: The study was conducted at 21 Childhood Arthritis and Rheumatology Research Alliance (CARRA) sites in North America. Local institutional review board approval was obtained, and all patients or their guardians gave informed consent and assent following local guidelines.
Keywords: juvenile systemic lupus erythematosus, carotid intima-media thickness, atorvastatin, the APPLE trial, metabolomic signature
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