Association of 9-Valent HPV Vaccination with Risk of Juvenile Idiopathic Arthritis: A Sex-Stratified Real-World Study

To evaluate the association between 9-valent human papillomavirus (HPV9) vaccination and the risk of new-onset juvenile idiopathic arthritis (JIA), with particular attention to sex-specific differences, including the relative lack of evidence in males and the potential impact of the COVID-19 pandemic.

Using the TriNetX U.S. Collaborative Network (2016-2023), children aged 9-13 years who received HPV9 vaccination were compared with unvaccinated controls in prepandemic and pandemic periods. Incident JIA was assessed using matched cohort analyses and time-to-event methods.

Similar sex-specific patterns were observed across both periods. HPV9 vaccination was associated with a lower risk of JIA among girls (HR = 0.45 95% CI = 0.22-0.95 in prepandemic and HR = 0.36 95% CI = 0.17-0.74 during pandemic period), while no increased risk was observed among boys (HR = 1.57 95% CI = 0.67-4.05 in prepandemic and HR = 1.14 95% CI = 0.56-2.34 during pandemic period). Among unvaccinated individuals, girls consistently exhibited a higher incidence of JIA than boys. The COVID-19 pandemic did not alter these associations.

HPV9 vaccination was not associated with an increased risk of JIA in either sex. A consistent sex-specific pattern was observed across both study periods, with a lower risk of JIA among vaccinated girls but not boys. This finding suggests a potential sex difference in the association between HPV9 vaccination and JIA and warrants further investigation. However, residual confounding, including healthy-vaccinee bias and differences in healthcare utilization, cannot be fully excluded.