Risk of developing juvenile idiopathic arthritis after quadrivalent HPV vaccination: a retrospective cohort study using the TriNetX U.S. Network.

Introduction: Human papillomavirus (HPV) infection has been implicated in autoimmune processes, yet concerns remain about the potential autoimmune risks of HPV vaccination. Juvenile idiopathic arthritis (JIA) is a chronic autoimmune condition that typically manifests in childhood. The relationship between HPV vaccination and the development of JIA remains uncertain.

Methods: We conducted a retrospective cohort study using data from the TriNetX U.S. Collaborative Network. Females aged 9-13 years were included. Three analyses were performed: (1) comparing HPV4-vaccinated vs. unvaccinated matched cohorts; (2) a stricter comparison excluding subjects with positive ANA; (3) comparing single vs. multiple HPV4 doses. Propensity score matching and Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: In Analysis 1 (n=55,257 pairs) and Analysis 2 (n=53,827 pairs), the HPV4-vaccinated groups showed significantly reduced rates of JIA from 12 to 36 months post-vaccination (HR range: 0.33-0.52). No difference in JIA risk was observed between single and multiple doses in Analysis 3 (n=20,822 pairs). Early-onset JIA (<6 months after HPV4 vaccine) showed inconsistent trends, with only limited protective signals.

Conclusions: Our findings suggest that HPV4 vaccination is not associated with an increased risk of JIA. On the contrary, vaccination may confer a long-term protective effect against new-onset JIA, observable from 6-12 months and lasting for at least 3 years. These findings support the safety and possible immunoregulatory benefit of HPV4 in adolescents.