| アブストラクト | Immune checkpoint inhibitors (ICIs) are transformative cancer therapies but have been implicated in rare, life-threatening cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN). Whether ICIs serve as independent causative agents or amplify risk from other drugs remains incompletely understood. METHODS: We analyzed 13.9 million deduplicated reports from the FDA Adverse Event Reporting System (FAERS) between 2013 and 2023, including 17,495 cases of SJS/TEN. We conducted multivariable logistic regression to assess the independent effects of ICIs, high-risk ("strong") and moderate-risk ("weak") culprit drugs, as well as their interactions. Age was modeled using natural splines. Additive interaction was assessed using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S). We also performed Cox regression analyses using time-to-event (TTE) data to evaluate latency patterns associated with different ICI classes. RESULTS: ICI exposure was independently associated with increased risk of SJS/TEN (adjusted OR 9.14, 95% CI 8.42-9.93). Strong culprit drugs (e.g., allopurinol, TMP-SMX) and weak culprits (e.g., fluoroquinolones, macrolides) also conferred elevated risk. Notably, we observed significant additive interaction between ICIs and both strong (RERI 13.69, AP 0.38) and weak culprits (RERI 12.92, AP 0.52), indicating synergistic risk amplification. In time-to-event analyses of 4,086 cases with latency data, PD-1 inhibitors were consistently associated with delayed onset of SJS/TEN compared to non-ICI triggers (HR 0.71-0.82), with median latency nearly doubled. CONCLUSIONS: Our findings support a two-hit immunopathogenic model in which ICIs lower the activation threshold for drug-specific T-cell responses, enabling otherwise tolerated medications to trigger severe cutaneous reactions. These results have critical implications for the co-prescription of high-risk drugs in patients receiving ICIs and underscore the need for enhanced pharmacovigilance and risk mitigation in cancer immunotherapy. |
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| 投稿者 | Mukherjee, Eric M; Park, Dodie; Asiaee, Amir; Krantz, Matthew S; Stone, Cosby A; Martin-Pozo, Michelle; Phillips, Elizabeth Jane |
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