{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:07Z","timestamp":1792790347220,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,2]]},"group-title":"Dermatology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["U01AI154659"],"award-info":[{"award-number":["U01AI154659"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50GM115305"],"award-info":[{"award-number":["P50GM115305"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HG010863"],"award-info":[{"award-number":["R01HG010863"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AI139021"],"award-info":[{"award-number":["R21AI139021"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI152183"],"award-info":[{"award-number":["R01AI152183"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2 D43 TW010559"],"award-info":[{"award-number":["2 D43 TW010559"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K08AR088287"],"award-info":[{"award-number":["K08AR088287"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Health and Medical Research Council of Australia","id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"PCORI","award":["ME-2023C1-32148"],"award-info":[{"award-number":["ME-2023C1-32148"]}],"id":[{"id":"https:\/\/ror.org\/014q65q44","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Immune checkpoint inhibitors (ICIs) are usually treated as direct culprits in immune-related adverse events, but checkpoint blockade may also reset tolerance to other medications. We tested whether ICI exposure reshapes the organization, drug specificity and timing of reported treatment toxicity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed 13,701,106 deduplicated FDA Adverse Event Reporting System reports from 2016 through 2025. Cancer-restricted reporting associations and cross-organ community detection characterized the ICI-associated toxicity landscape. Adjusted logistic models tested primary-suspect drug x ICI interactions for Stevens-Johnson syndrome\/toxic epidermal necrolysis (SJS\/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, interstitial nephritis, drug-induced liver injury, anaphylaxis and vomiting. Accelerated failure-time models evaluated documented onset according to ICI exposure and checkpoint pathway.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 2,365,278 cancer-associated reports, 256,940 contained an ICI. Of 3001 eligible Preferred Terms, 2091 differed between ICI-containing and non-ICI reports at false discovery rate (FDR) &lt;0.05, and four cross-organ toxicity communities emerged. Drug-phenotype associations were reweighted: 71 of 147 eligible pairs had FDR-significant interactions, including 56 amplifications and 15 attenuations. Signals included marked moxifloxacin-SJS\/TEN amplification (interaction OR 100.51, 95% CI 38.58 to 261.84), a submultiplicative enfortumab vedotin-SJS\/TEN interaction (0.17, 0.13 to 0.23) and omeprazole-interstitial nephritis amplification (10.33, 7.60 to 14.04). Among 64,593 reports with documented onset of 1-365 days, ICI exposure was associated with longer adjusted onset for five of seven phenotypes (time ratios 1.37-1.58); 10 of 19 estimable checkpoint-phenotype coefficients remained FDR significant.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Checkpoint blockade was associated not simply with additional toxicity, but with a change in treatment context: drug-phenotype associations shifted in both directions, adverse events formed cross-organ structure and documented onset varied by checkpoint pathway. These findings support ICIs as modifiers of drug toxicity and identify specific signals for longitudinal and mechanistic validation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>KEY MESSAGES<\/jats:title>\n                  <jats:sec>\n                    <jats:title>WHAT IS ALREADY KNOWN ON THIS TOPIC<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Experimental PD-1\/PD-L1 blockade can lower the threshold for drug-specific T-cell priming, and hypersensitivity to previously tolerated medications has emerged after ICI exposure. Whether this immune rewiring systematically changes how other drugs produce toxicity across phenotypes is unknown.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT THIS STUDY ADDS<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Across 13,701,106 deduplicated FAERS reports, 71 of 147 eligible primary-suspect drug-phenotype pairs had FDR-significant drug x ICI interactions, with amplification and attenuation differing sharply by phenotype. Cross-organ organization and checkpoint-dependent timing provided complementary signatures of an altered treatment state.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>The findings support a two-hit treatment-state model: checkpoint blockade may alter immune permissiveness, while a second medication helps determine whether and how toxicity is expressed. Individual signals require longitudinal and mechanistic validation and should not be used to estimate incidence or justify drug avoidance from spontaneous-reporting data alone.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.31.26361880","type":"posted-content","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:00:18Z","timestamp":1788397218000},"source":"Crossref","is-referenced-by-count":0,"title":["Immune checkpoint blockade reshapes drug-associated toxicity: a pharmacovigilance atlas of drug-ICI interactions"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8715-1378","authenticated-orcid":false,"given":"Eric Milan","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Center for Drug Safety and Immunology, 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