{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:13:57Z","timestamp":1793121237107,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"unspecified","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,9,30]]},"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Twenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067\u2009and 0.002, respectively). CD4+\/CD8+ T\u2009cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T\u2009cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Liver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005635","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:34:37Z","timestamp":1667205277000},"page":"e005635","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-3160","authenticated-orcid":false,"given":"Alexander","family":"Coukos","sequence":"first","affiliation":[{"name":"Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Vionnet","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland"},{"name":"Transplantation Center, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2095-2677","authenticated-orcid":false,"given":"Michel","family":"Obeid","sequence":"additional","affiliation":[{"name":"Immunology Division, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasna","family":"Bouchaab","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solange","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofiya","family":"Latifyan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Wicky","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Michielin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haithem","family":"Chtioui","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Moradpour","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Fasquelle","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Sempoux","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Fraga","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"2025100309265249000_10.10.e005635.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"2025100309265249000_10.10.e005635.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"2025100309265249000_10.10.e005635.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature10673"},{"key":"2025100309265249000_10.10.e005635.4","doi-asserted-by":"publisher","DOI":"10.1097\/COC.0000000000000239"},{"key":"2025100309265249000_10.10.e005635.5","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz011"},{"key":"2025100309265249000_10.10.e005635.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.001"},{"key":"2025100309265249000_10.10.e005635.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0218-0"},{"key":"2025100309265249000_10.10.e005635.8","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1053\/j.gastro.2021.06.025","article-title":"Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis","volume":"161","author":"Sasson","year":"2021","journal-title":"Gastroenterology"},{"key":"2025100309265249000_10.10.e005635.9","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0779-6"},{"key":"2025100309265249000_10.10.e005635.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"2025100309265249000_10.10.e005635.11","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41571-022-00600-w","article-title":"Immune-checkpoint inhibitors: long-term implications of toxicity","volume":"19","author":"Johnson","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"2025100309265249000_10.10.e005635.12","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/liv.13746","article-title":"Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents","volume":"38","author":"Suzman","year":"2018","journal-title":"Liver Int"},{"key":"2025100309265249000_10.10.e005635.13","doi-asserted-by":"crossref","first-page":"5376","DOI":"10.3748\/wjg.v27.i32.5376","article-title":"Immune checkpoint inhibitor-related hepatotoxicity: a review","volume":"27","author":"Remash","year":"2021","journal-title":"World J Gastroenterol"},{"key":"2025100309265249000_10.10.e005635.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2016.02.001"},{"key":"2025100309265249000_10.10.e005635.15","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.72.1167"},{"key":"2025100309265249000_10.10.e005635.16","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx225"},{"key":"2025100309265249000_10.10.e005635.17","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1016\/S1470-2045(18)30828-3","article-title":"New therapeutic perspectives to manage refractory immune checkpoint-related toxicities","volume":"20","author":"Martins","year":"2019","journal-title":"Lancet Oncol"},{"key":"2025100309265249000_10.10.e005635.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.01.033"},{"key":"2025100309265249000_10.10.e005635.19","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/his.14000","article-title":"Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes","volume":"76","author":"Zen","year":"2020","journal-title":"Histopathology"},{"key":"2025100309265249000_10.10.e005635.20","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1053\/j.semdp.2019.07.009","article-title":"Checkpoint inhibitor-induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy","volume":"36","author":"Zen","year":"2019","journal-title":"Semin Diagn Pathol"},{"key":"2025100309265249000_10.10.e005635.21","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/s41379-018-0013-y","article-title":"Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury","volume":"31","author":"Zen","year":"2018","journal-title":"Mod Pathol"},{"key":"2025100309265249000_10.10.e005635.22","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2017-000268"},{"key":"2025100309265249000_10.10.e005635.23","first-page":"439","article-title":"Nivolumab-induced cholangitis in patients with non-small cell lung cancer: case series and a review of literature","volume":"11","author":"Izumi","year":"2019","journal-title":"Mol Clin Oncol"},{"key":"2025100309265249000_10.10.e005635.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.06.030"},{"key":"2025100309265249000_10.10.e005635.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.03.022"},{"key":"2025100309265249000_10.10.e005635.26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510240201"},{"key":"2025100309265249000_10.10.e005635.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1509660"},{"key":"2025100309265249000_10.10.e005635.28","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12766"},{"key":"2025100309265249000_10.10.e005635.29","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12030738","article-title":"Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence","volume":"12","author":"Vaddepally","year":"2020","journal-title":"Cancers"},{"key":"2025100309265249000_10.10.e005635.30","first-page":"6129","article-title":"Multinational association of supportive care in cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors","volume":"28","author":"Dougan","year":"2020","journal-title":"Support Care Cancer"},{"key":"2025100309265249000_10.10.e005635.31","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2020.100170","article-title":"Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors","volume":"2","author":"De Martin","year":"2020","journal-title":"JHEP Rep"},{"key":"2025100309265249000_10.10.e005635.32","doi-asserted-by":"crossref","unstructured":"Kubo T , Sugawara T , Shinkawa T . Fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma. Immunol Med 2020:1\u20136.","DOI":"10.1080\/25785826.2020.1788229"},{"key":"2025100309265249000_10.10.e005635.33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1080\/17425255.2019.1574744","article-title":"Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies","volume":"15","author":"Jennings","year":"2019","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"2025100309265249000_10.10.e005635.34","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1001\/jamaoncol.2017.2391","article-title":"Measuring toxic effects and time to treatment failure for nivolumab plus ipilimumab in melanoma","volume":"4","author":"Shoushtari","year":"2018","journal-title":"JAMA Oncol"},{"key":"2025100309265249000_10.10.e005635.35","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1159\/000509953","article-title":"Pembrolizumab-induced delayed-onset hepatitis","volume":"14","author":"Kanaoka","year":"2020","journal-title":"Case Rep Gastroenterol"},{"key":"2025100309265249000_10.10.e005635.36","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10637-017-0453-0","article-title":"Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer","volume":"35","author":"Kawakami","year":"2017","journal-title":"Invest New Drugs"},{"key":"2025100309265249000_10.10.e005635.37","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41379-020-00653-1","article-title":"Liver biopsy findings in patients on immune checkpoint inhibitors","volume":"34","author":"Cohen","year":"2021","journal-title":"Mod Pathol"},{"key":"2025100309265249000_10.10.e005635.38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1503093"},{"key":"2025100309265249000_10.10.e005635.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.12.008"},{"key":"2025100309265249000_10.10.e005635.40","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/annonc\/mdw443","article-title":"Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab","volume":"28","author":"Menzies","year":"2017","journal-title":"Ann Oncol"},{"key":"2025100309265249000_10.10.e005635.41","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1001\/jamaoncol.2015.4368","article-title":"Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders","volume":"2","author":"Johnson","year":"2016","journal-title":"JAMA Oncol"},{"key":"2025100309265249000_10.10.e005635.42","doi-asserted-by":"publisher","DOI":"10.1016\/S1386-6346(02)00274-7"},{"key":"2025100309265249000_10.10.e005635.43","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abi7083"},{"key":"2025100309265249000_10.10.e005635.44","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.jtho.2020.09.007","article-title":"Personalized cytokine-directed therapy with tocilizumab for refractory immune checkpoint inhibitor-related cholangiohepatitis","volume":"16","author":"Moi","year":"2021","journal-title":"J Thorac Oncol"},{"key":"2025100309265249000_10.10.e005635.45","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000604"},{"key":"2025100309265249000_10.10.e005635.46","doi-asserted-by":"publisher","DOI":"10.1177\/1078155217745144"},{"key":"2025100309265249000_10.10.e005635.47","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.2217\/imt-2019-0121","article-title":"Nivolumab-induced large-duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab","volume":"11","author":"Reddy","year":"2019","journal-title":"Immunotherapy"},{"key":"2025100309265249000_10.10.e005635.48","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1001\/jamaoncol.2021.4342","article-title":"Utility of liver biopsy in diagnosis and management of high-grade immune checkpoint inhibitor hepatitis in patients with cancer","volume":"7","author":"Li","year":"2021","journal-title":"JAMA Oncol"},{"key":"2025100309265249000_10.10.e005635.49","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31629"},{"key":"2025100309265249000_10.10.e005635.50","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.it.2019.04.002","article-title":"Adverse events following cancer immunotherapy: obstacles and opportunities","volume":"40","author":"Pauken","year":"2019","journal-title":"Trends Immunol"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-005635","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T16:27:00Z","timestamp":1759508820000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-005635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,25]]},"published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1136\/jitc-2022-005635"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-005635","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10]]}}}