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Letter/Communication
Immune Checkpoint Inhibitors as Independent and Synergistic Drivers of SJS/TEN
JAMA oncology
2025
PMID: 41165703
Abstract
Immune checkpoint inhibitors (ICIs) are paradigm-shifting cancer treatments that are increasingly associated with Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN) and other life-threatening cutaneous reactions. Differentiating ICI-induced true SJS/TEN from SJS/TEN-like reactions is difficult, the latter of which may be distinct lichenoid or bullous reactions.1-3 In some cases, ICI-related SJS/TEN-like reactions occur in association with human leukocyte antigen (HLA)–restricted drug culprits like allopurinol, suggesting a 2-hit mechanism.4 With increasing ICI use, a clearer understanding of their role in SJS/TEN is critical.
Methods
We analyzed 13 986 839 deduplicated Food and Drug Administration Adverse Event Reporting System (FAERS) reports (2013-2023), containing 17 495 patients with SJS/TEN. We assessed the impact of ICI using logistic regressions adjusted for age, sex, cancer, polypharmacy, and strong (lamotrigine, trimethoprim-sulfamethoxazole, phenytoin, allopurinol, carbamazepine) or weak (azithromycin, clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, and acyclovir) culprit exposure.
To assess latency patterns, we performed Cox proportional hazards analyses among patients with SJS/TEN with documented latency. In 1 model, we compared latency between ICI-attributed and non–ICI-attributed cases, classifying primary suspect (PS) by ICI mechanism. In another, we used time-dependent Cox regression with interval splitting to dynamically update exposure to programmed cell death 1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), or lymphocyte-activation gene 3 (LAG-3) inhibitors. Both models incorporated the same covariates as the logistic regression. Additional eMethods are in Supplement 1.
Results
In a multivariable logistic regression (Table), ICI exposure was associated with increased risk of SJS/TEN (adjusted odds ratio [aOR], 9.14; 95% CI, 8.42-9.93; P < .001). Strong culprit drugs were the strongest independent predictors of SJS/TEN (aOR, 14.31; 95% CI, 13.77-14.87). Importantly, cancer diagnosis was inversely associated with SJS/TEN risk (aOR, 0.60; 95% CI, 0.58-0.63). Interaction terms revealed additive synergy between ICI exposure and culprit drugs. The ICI–strong culprit interaction yielded an attributable proportion (AP) of 0.38, indicating that 38% of the risk in co-exposed patients was attributable to interaction. For ICI-weak culprits, AP was even higher (0.52).
Details
- Title
- Immune Checkpoint Inhibitors as Independent and Synergistic Drivers of SJS/TEN
- Authors/Creators
- Eric Milan Mukherjee - Vanderbilt University Medical CenterDodie Park - Vanderbilt University Medical CenterAmir Asiaee - Vanderbilt University Medical CenterMatthew S. Krantz - Vanderbilt University Medical CenterCosby A. Stone - Vanderbilt University Medical CenterMichelle Martin-Pozo - Vanderbilt University Medical CenterElizabeth Phillips - Center for Drug Safety and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia
- Publication Details
- JAMA oncology
- Publisher
- JAMA Network
- Number of pages
- 4
- Identifiers
- 991005830343907891
- Copyright
- © 2025 Milan Mukherjee E et al.
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Letter/Communication
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- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
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- ESI research areas
- Clinical Medicine