APPLE Study Analysis Provides New Insight into Heterogeneity in Pediatric Systemic Lupus Erythematosus

An analysis of the landmark APPLE trial from the European Congress of Rheumatology (EULAR) 2023 annual meeting provides evidence of a significant amount of heterogeneity of subclinical atherosclerosis in pediatric systemic lupus erythematosus.¹

Launched in 2003 and completed in 2009, the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study was launched with the intent of exploring whether the safety and efficacy profile of atorvastatin on development of atherosclerosis in children with systemic lupus erythematosus. The trial enrolled 221 participants and used carotid intima-media thickness (CIMT) measurements as the primary outcome. Study participants were followed for 3 years and took part in 15 study visits.²

Upon completion, the trial missed its primary endpoint, with the difference in mean mean common CIMT failing to reach statistical significance between treatment groups (0.0010 mm/year vs 0.0024 mm/year; P = .24). Results of the study also indicated use of atorvastatin was associated with lower hsCRP (P = 0.04), total cholesterol (P < .001), and low-density lipoprotein (P < .001) levels compared with placebo.²

In the EULAR 2023 study, which was presented by Coziana Ciurtin, PhD, consultant rheumatologist and associate professor at the University College London, investigators had 2 specific intents: evaluate patient stratification strategies to identify responders to a statin in a trial who did not meet the primary outcome and evaluate high-performance biomarkers of atherosclerosis progression in the APPLE trial to establish which pediatric systemic lupus erythematosus patients were at risk for atherosclerosis progression even if they did not respond to statin. With this in mind, investigators designed their study as an in-depth metabolomic analysis to identify lipidomic signatures predictive of CIMT progression in both arms. Additionally, correlation and univariate regression analyses were performed to examine associations between patients, disease characteristics, and serum biomarkers.¹

Upon analysis, investigators identified 2 distinct CIMT progression rates over 36 months in the placebo group of the trial. For the atorvastatin group, investigators identified 3 distinct CIMT progression rates. However, investigators pointed out none of these were able to be predicted by any of the patient and disease determinants, including serum biomarkers, lipid profile, and homocysteine levels collected from participants within the APPLE trial.¹

Investigators highlighted a “robust and novel” metabolic signature predictive of high CIMT progression was identified in the placebo arm of the trial (AUC=80.7%). Investigators also highlighted patients with low rate CIMT progression identified by the CIMT stratification benefitted from treatment with atorvastatin (P = .035), which they suggest provides evidence of patient stratification may have led to the negative results of the APPLE trial.¹

With an interest in learning more about this analysis and how it can inform the care of patients with pediatric systemic lupus erythematosus, our editorial team sat down with Ciurtin while on-site at the EULAR 2023 annual meeting.

Dr. Ciurtin has no relevant disclosures.

References:

1. Ciurtin C, Peng J, Donnes P, et al. Paediatric Systemic Lupus Erythematosus (pSLE) patient stratification and high-performance serum biomarkers identified responders to statin and patients with high cardiovascular risk in the APPLE trial (Atorvastatin for Atherosclerosis Progression in Paediatric Systemic Lupus Erythematosus). Paper presented at: European Congress of Rheumatology (EULAR) 2023. Milan, Italy. May 31 – June 3, 2023.
2. Schanberg LE, Sandborg C, Barnhart HX, et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 2012;64(1):285-296. doi:10.1002/art.30645