Inflammopharmacology · 2026
Bone and growth safety profiles of biologic and conventional DMARDs in juvenile idiopathic arthritis: a 21-year FAERS disproportionality analysis.
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Erdem Fatih, Gürbüz Nida
Аннотация
BACKGROUND: Juvenile idiopathic arthritis (JIA) treatment relies on biologic and conventional disease-modifying anti-rheumatic drugs (b/csDMARDs), but pediatric-specific bone and growth safety remains incompletely characterized. Standard FAERS disproportionality analyses in pediatric polypharmacy may overstate signals through co-medication coding. We aimed to identify drug-specific bone-toxicity (Composite A) and growth/developmental (Composite B) signals and to test whether they survive a Primary-Suspect (PS) restriction designed to isolate reporter-attributed reactions.
METHODS: Pre-specified disproportionality analysis of FAERS Individual Case Safety Reports (2004-2024); pediatric (≤ 17 years) JIA cohort, n = 13,459. Two parallel exposure definitions were applied: PS + SS (Primary or Secondary Suspect, broad) and PS-only (strict). Reporting odds ratios (ROR), proportional reporting ratios with χ2, IC025 and a fixed-prior Bayesian shrinkage estimate were computed; a robust signal required multi-criteria thresholds in both tracks. The PS + SS analysis was independently reproduced in Python and R, with 100% concordance in signal classification.
RESULTS: Of 21 drug × composite signals under broad PS + SS analysis, only 5 met the robust-signal definition after PS-only restriction: methotrexate (both composites; bone ROR 2.4, growth ROR 3.7) and infliximab (4.3), tocilizumab (2.8), and abatacept (3.4) for bone toxicity. Etanercept and adalimumab-the two highest-exposure drugs-showed no PS-only signal despite PS + SS Composite A signals. PS + SS magnitudes attenuated by a median 87% under PS-only restriction.
CONCLUSIONS: Methotrexate was the only drug with robust bone and growth signals, supporting skeletal and growth surveillance during chronic therapy; three biologics showed bone-toxicity signals. In this cohort, conventional PS + SS analysis substantially overstated signal magnitudes, supporting dual-track (PS + SS and PS-only) reporting for pediatric pharmacovigilance.
METHODS: Pre-specified disproportionality analysis of FAERS Individual Case Safety Reports (2004-2024); pediatric (≤ 17 years) JIA cohort, n = 13,459. Two parallel exposure definitions were applied: PS + SS (Primary or Secondary Suspect, broad) and PS-only (strict). Reporting odds ratios (ROR), proportional reporting ratios with χ2, IC025 and a fixed-prior Bayesian shrinkage estimate were computed; a robust signal required multi-criteria thresholds in both tracks. The PS + SS analysis was independently reproduced in Python and R, with 100% concordance in signal classification.
RESULTS: Of 21 drug × composite signals under broad PS + SS analysis, only 5 met the robust-signal definition after PS-only restriction: methotrexate (both composites; bone ROR 2.4, growth ROR 3.7) and infliximab (4.3), tocilizumab (2.8), and abatacept (3.4) for bone toxicity. Etanercept and adalimumab-the two highest-exposure drugs-showed no PS-only signal despite PS + SS Composite A signals. PS + SS magnitudes attenuated by a median 87% under PS-only restriction.
CONCLUSIONS: Methotrexate was the only drug with robust bone and growth signals, supporting skeletal and growth surveillance during chronic therapy; three biologics showed bone-toxicity signals. In this cohort, conventional PS + SS analysis substantially overstated signal magnitudes, supporting dual-track (PS + SS and PS-only) reporting for pediatric pharmacovigilance.