Algorithm for drug safety signal detection.

With the extensive clinical application of immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs) associated with these agents have increasingly garnered significant attention. Unlike other irAEs, endocrine irAEs are mostly irreversible, with variable and nonspecific symptoms, which poses challenges for clinicians in diagnosis. As a result, this study leveraged the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) pharmacovigilance databases to conduct an in-depth investigation into adverse events induced by PD-1/PD-L1 inhibitors, with a focus on irAEs induced by PD-1/PD-L1 inhibitors. This study pioneers the systematic cross-database validation of endocrine irAEs induced by PD-1/PD-L1 inhibitors. The integration of data from the JADER offers unique safety insights for Asian populations, bolsters global pharmacovigilance efforts, and uncovers regional variations in irAEs reporting. Notably, this study revealed a higher prevalence of endocrine irAEs among men aged over 50 years receiving PD-1/PD-L1 inhibitors. Both PD-1 and PD-L1 inhibitors are strongly associated with thyroid dysfunction, adrenal insufficiency, and pituitary inflammation. Additionally, it identifies several previously undocumented endocrine irAEs. This result unearthed safety signals hitherto unreported in drug inserts, underscoring the imperative for updating the safety labeling of PD-1/PD-L1 inhibitors with respect to endocrine irAEs. The emergence of off-label uses further underscores the need for additional clinical trials to assess their efficacy and safety.随着免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）在临床中的广泛应用，此类药物相关的免疫相关不良事件（immune-related adverse events, irAEs）正日益受到广泛关注。与其他免疫相关不良事件不同，内分泌免疫相关不良事件大多不可逆，且症状表现多样且无特异性，这给临床医师的诊断工作带来了挑战。为此，本研究借助美国食品药品监督管理局不良事件报告系统（U.S. Food and Drug Administration Adverse Event Reporting System, FAERS）与日本不良药物事件报告（Japanese Adverse Drug Event Report, JADER）两大药物警戒数据库，针对PD-1/PD-L1抑制剂诱发的不良事件展开深入研究，重点聚焦PD-1/PD-L1抑制剂诱导的免疫相关不良事件。本研究首次对PD-1/PD-L1抑制剂诱导的内分泌免疫相关不良事件开展系统性跨数据库验证。纳入日本不良药物事件报告数据库的数据，可为亚洲人群提供独特的安全性视角，助力全球药物警戒工作，并揭示免疫相关不良事件报告的区域差异。值得注意的是，本研究发现，在接受PD-1/PD-L1抑制剂治疗的人群中，50岁以上男性的内分泌免疫相关不良事件患病率更高。PD-1与PD-L1抑制剂均与甲状腺功能异常、肾上腺功能不全及垂体炎存在显著关联。此外，本研究还发现了若干此前未被记录的内分泌免疫相关不良事件。本研究挖掘出了此前药品说明书中未曾记载的安全性信号，凸显了针对内分泌免疫相关不良事件更新PD-1/PD-L1抑制剂安全标注的必要性。超适应症用药的出现，进一步凸显了开展更多临床试验以评估此类药物疗效与安全性的必要性。