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Objectives Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in juvenile-onset systemic lupus erythematosus (JSLE). There is an urgent need to identify biomarkers that can predict atherosclerosis progression and therapeutic responses, enabling personalised CVD-risk management in JSLE. This study investigated whether novel autoantibody signatures could predict atherosclerosis progression and atorvastatin response in young people with JSLE.Methods Baseline serum samples were analysed from a sub-cohort of the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) trial, a multi-centre, randomised, double-blind, placebo-controlled study of atorvastatin versus placebo (1:1) across 21 North American sites. Ninety-four JSLE patients (mean [SD] age 15.3 [2.4] years; 78% female) with matched baseline serum and complete 36-month carotid intima-media thickness (CIMT) data were included (45 placebo; 49 atorvastatin). Unsupervised clustering based on CIMT progression identified high and low progression groups within each arm. Baseline differential autoantibody expression was assessed using Empirical Bayes moderated t-tests. Predictive performance was evaluated using logistic regression and ROC analysis, and pathway enrichment performed using Metascape.Results A total of 579 autoantibodies were identified as true signals across the 94 baseline samples. In the placebo arm, six autoantibodies (STK24, RAD23B, HDAC4, STAT4, SEPTIN9 and NFIA) were significantly associated with high versus low CIMT progression over 36 months, achieving a combined area under the curve (AUC) of 0.87 for distinguishing progression patterns ( figure 1). In the atorvastatin arm, a distinct autoantibody profile comprising eight autoantibodies (ABI1, ATP5B, CSNK2A2, NRIP3, PRKAR1A, PDK4, BATF and NUDT2) predicted CIMT progression despite therapy, achieving an exceptional combined AUC of 0.96 (figure 1). Pathway enrichment of the atorvastatin-arm profile revealed lipid-independent mechanisms that may contribute to atherosclerosis progression in statin-treated patients. Based on these distinct profiles, a two-step stratification strategy was proposed to enable precision risk assessment and guide treatment decisions in JSLE.Abstract PT6:03 Figure 1Conclusions This biomarker discovery study identified novel autoantibody signatures as the first JSLE-specific biomarkers predictive of atherosclerosis progression and statin response, suggesting possible autoimmune mechanisms underlying the elevated CVD-risk in JSLE. These findings support the potential application of autoantibody profiling in precision medicine approaches for CVD-risk research and management in JSLE.