Immune Checkpoint Inhibitors as Independent and Synergistic Drivers of SJS/TEN: A FAERS-Based Analysis
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Importance
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are rare, potentially fatal adverse drug reactions. As the use of immune checkpoint inhibitors (ICIs) expands, their role as direct inducers or synergistic contributors to SJS/TEN remains incompletely characterized.
Objective
To determine whether ICIs are independent risk factors for SJS/TEN, evaluate their interactions with known culprit drugs, and assess their impact on latency and mortality.
Design
Cross-sectional analysis of adverse event reports submitted to the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) between January 2013 and December 2023, sanitized and de-duplicated. Logistic regression and Cox models were used to assess predictors of SJS/TEN development, mortality, and latency.
Setting
Global pharmacovigilance reports submitted to FAERS.
Participants
A total of 17,495 unique and de-identified patients reported SJS/TEN, of 13,986,839 total reports.
Exposures
Suspected causative drugs, including ICIs.
Main Outcomes and Measures
Primary outcomes were the adjusted odds of developing SJS/TEN, time-to-event (TTE) of reaction/drug latency, and all-cause mortality. Depending on the analysis, covariates included age, sex, number of concomitant drugs, cancer diagnosis, and specific drug exposures.
Results
Of 17,495 SJS/TEN cases (median age 53 years, 37.6% male), 970 (5.5%) had ICI exposure and 653 (3.7%) listed an ICI as the primary suspect. ICI exposure was associated with developing SJS/TEN (adjusted OR, 6.69; 95% CI, 6.19-7.23) while controlling for age, exposure to strong and weak culprits, number of concomitant drugs, and cancer diagnosis. ICI increases SJS-TEN risk among patients exposed to allopurinol (OR, 4.35; 95% CI, 3.12-6.06) and TMP-SMX (OR, 5.68; 95% CI, 4.05-7.95) with the same covariates. Among patients with small-molecule-induced SJS/TEN, mortality was strongly associated with ICI exposure (particularly exposure to multiple ICI, OR, 7.31; 95% CI, 3.09-17.27). Among all SJS/TEN cases, ICI exposure was associated with delayed onset, compared to cancer patients not exposed to ICI and non-cancer patients (median 20 vs 14 vs 13 days; P < .0001).
Conclusions and Relevance
ICIs are associated with increased SJS/TEN risk, both independently and in combination with known culprit drugs, and may delay disease onset. These findings support increased vigilance in prescribing known culprits alongside ICI.
Key Points
Question
Do immune checkpoint inhibitors (ICIs) facilitate Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN), and do they synergize with known culprit drugs or impact disease latency?
Findings
In this cross-sectional study of 17,495 SJS/TEN cases from 13,986,839 deduplicated FAERS reports (2013–2023), ICI exposure, independent of exposure to known culprits, increased the risk of developing SJS/TEN and amplified risk when co-administered with known culprits such as allopurinol and trimethoprim-sulfamethoxazole. ICI-exposed patients also showed significantly delayed onset compared to non-exposed cases.
Meaning
These findings suggest that ICIs directly contribute to SJS/TEN, likely both as a direct cause and through mechanistic synergy with antigenic small molecule drugs. These findings underscore the need for heightened vigilance when combining ICIs with high-risk medications and for recognizing atypical, delayed presentations.
