Sex differences in thyroid dysfunction onset timing induced by immune checkpoint inhibitors: JADER disproportionality analysis

BACKGROUND: Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment but can induce thyroid dysfunction. While the incidence of ICI-induced thyroid dysfunction (ICI-TD) has been studied, the timing of onset, particularly in relation to sex differences, remains underexplored. RESEARCH DESIGN AND METHODS: We assessed time to onset of thyroid dysfunction caused by nivolumab, pembrolizumab, and ipilimumab using the Japanese Adverse Drug Event Report (JADER) database. Cases were identified using standardized MedDRA queries. Reporting odds ratios and 95% confidence intervals were calculated. Time-to-onset analysis used the Weibull shape parameter and Mann-Whitney U-test, stratified by sex. RESULTS: Among 914,713 reports, 2468 nivolumab, 3030 pembrolizumab, and 1457 ipilimumab cases of suspected ICI-TD were found. All ICIs detected positive signals. Median onset times for hyperthyroidism were 42, 33 and 44.5 days, for nivolumab, pembrolizumab, and ipilimumab, respectively; hypothyroidism onset times were 85, 60 and 65 days, respectively. Onset time was consistently shorter in females than males. The Weibull analysis indicated a wear-out failure type, except for pembrolizumab-induced hypothyroidism, which showed a random failure type. CONCLUSIONS: ICI-TD occurs earlier in female patients. This finding highlights the need for sex-specific monitoring to optimize early detection and management of thyroid-related adverse events in patients receiving ICIs.