{
  "abstract": "ImportanceImmune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood.\n\nObjectiveTo define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway.\n\nDesign and SettingCross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026.\n\nParticipantsAmong 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male.\n\nExposuresICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure.\n\nMain Outcomes and MeasuresReporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset.\n\nResultsOf 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways.\n\nConclusions and RelevanceICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the structure of toxicity associated with immune checkpoint blockade?\n\nFindingsIn this cross-sectional study of 13,701,106 deduplicated adverse-event reports, ICI exposure defined a broad toxicity landscape containing 4 cross-organ communities. Sixty-five drug x ICI interactions were identified across 5 immune-mediated phenotypes and a control (vomiting), and documented time to onset differed by phenotype and checkpoint pathway.\n\nMeaningCheckpoint blockade may create an altered immune state in which the phenotype and timing of drug-associated toxicity depend on both the accompanying drug and the checkpoint pathway inhibited.",
  "abstract_shown": true,
  "affiliations": [
    "Vanderbilt University Medical Center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "E. M. Mukherjee"
    },
    {
      "name": "A. Asiaee"
    },
    {
      "name": "D. Park"
    },
    {
      "name": "M. S. Krantz"
    },
    {
      "name": "C. A. Stone"
    },
    {
      "name": "M. Martin-Pozo"
    },
    {
      "name": "E. J. Phillips"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9ekhwv4k7145s.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.31.26361880",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v1.full",
  "id": "9ekhwv4k7145s",
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  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "dermatology"
    ],
    [
      "openalex",
      "3005|Pharmacovigilance and Adverse Drug Reactions"
    ]
  ],
  "openalex": "W7206183461",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-31",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9ekhwv4k7145s.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:35Z",
      "native_id": "10.64898/2026.08.31.26361880",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v3"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:3005|Pharmacovigilance and Adverse Drug Reactions",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time",
  "title_text": "Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:52Z",
  "url": "https://research.draconitic.com/paper/9ekhwv4k7145s",
  "venue": "medRxiv",
  "versions": []
}