Sex-specific risk profiles of drug-associated joint stiffness and deformity: a FAERS-based pharmacovigilance study...

Joint stiffness and joint deformity are debilitating musculoskeletal adverse drug reactions, yet their risk profiles and sex-specific differences remain poorly characterised. This study aimed to identify drug-associated safety signals and sex disparities using real-world pharmacovigilance data.

Adverse event reports from the FDA Adverse Event Reporting System (FAERS; Q1 2004-Q2 2025) were analysed. Drug names and events were standardised using RxNorm and MedDRA 27.1. Disproportionality analyses (ROR) with false discovery rate correction were performed overall and by sex. External validation was conducted using the Canadian Vigilance Adverse Reaction Database (CVARDD). Weibull modelling assessed time-to-onset patterns.

We identified 23,763 joint stiffness and 1,414 joint deformity reports, predominantly in females. For joint stiffness, frequently implicated drugs included methotrexate, dupilumab, and fluoroquinolones, alongside 20 newly detected signals (e.g. contrast media, ROR=217.1; gadopentetic acid, ROR=26.14). For joint deformity, alendronic acid, valproic acid, and somatropin showed strong associations, and nine novel signals were identified (e.g. vosoritide, ROR=125.78). Sex-stratified analyses revealed distinct risk profiles: females were more susceptible to bone metabolism and endocrine drugs, whereas males exhibited higher risks with enzyme replacement therapies. Time-to-onset analyses showed an early-failure pattern, with median onset as early as 63 days for methotrexate. Major signals were confirmed by the CVARDD.

This study provides comprehensive real-world evidence of sex-specific differences in drug-associated joint stiffness and deformity, identifies 29 previously unreported signals, and highlights the early-onset nature of these adverse events. These findings support targeted monitoring and personalised risk management, and may inform future updates to drug safety labelling.