{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:44:16Z","timestamp":1793295856999,"version":"4.5.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitor (ICI)\u2013related overlap syndrome involving myositis, myocarditis, and myasthenia gravis (3M overlap syndrome) is rare but potentially fatal. Current evidence is derived mainly from case reports and small case series, and individual case-level data on ancillary diagnostic findings, baseline comorbidities, treatment patterns, and short-term outcomes remain limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a systematic review of published case reports and case series and a pooled analysis of individual case data on ICI-related 3M overlap syndrome, supplemented by three patients from our center. The primary endpoint was all-cause in-hospital mortality. Univariable and multivariable logistic regression were used to explore factors associated with in-hospital mortality, and exploratory symptom correlation and hierarchical clustering analyses were performed to describe symptom co-occurrence patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ninety-five published reports comprising 133 patients were included, together with 3 additional institutional cases, for a total of 136 patients. The mean age was 69.8 \u00b1 11.2 years, and 96\/136 (70.6%) were male. Melanoma was the most common underlying malignancy (40\/136, 29.4%). The median time from first ICI exposure to symptom onset was 22.0 days (IQR, 16.0\u201331.0).In-hospital outcome was ascertainable for all 136 patients; 53 (39.0%) died during hospitalization and 83 (61.0%) survived to discharge or transfer. Most patients received systemic corticosteroids (133\/136, 97.8%) and second-line immunomodulatory therapy (119\/136, 87.5%). In the pre-specified multivariable analysis (age, fatigue, and complete conduction block), older age (adjusted odds ratio [aOR], 1.11 per year; 95% confidence interval [CI], 1.05\u20131.17; P &amp;lt; 0.001) and complete conduction block (aOR, 2.84; 95% CI, 1.10\u20137.34; P\u00a0=\u00a00.031) remained independently associated with in-hospital mortality, whereas fatigue was no longer statistically significant after adjustment (aOR, 1.85; 95% CI, 0.75\u20134.56; P\u00a0=\u00a00.181). Exploratory clustering identified a possible bulbar\/axial symptom cluster characterized by dysphagia, dysarthria, and neck muscle weakness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ICI-related 3M overlap syndrome is an early-onset, fulminant immune-related adverse event with substantial in-hospital mortality. Older age and complete conduction block were factors associated with poorer in-hospital outcomes in this exploratory analysis; these findings should be regarded as hypothesis-generating and require validation in prospective registries or multicenter cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1854723","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:02:19Z","timestamp":1785304939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Immune checkpoint inhibitor\u2013related myositis, myocarditis, and myasthenia gravis overlap syndrome: a systematic review and pooled analysis of individual cases"],"prefix":"10.3389","volume":"17","author":[{"given":"Miao","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit , Shanxi Province Cancer Hospital \/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences \/ Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit , Shanxi Province Cancer Hospital \/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences \/ Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit , Shanxi Province Cancer Hospital \/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences \/ Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit , Shanxi Province Cancer Hospital \/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences \/ Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery , Shanxi Province Cancer Hospital \/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences \/ Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.07.004","article-title":"Clinical challenges of immune checkpoint inhibitors","volume":"38","author":"de Miguel","year":"2020","journal-title":"Cancer Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0393","article-title":"Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis","volume":"5","author":"Wang","year":"2019","journal-title":"JAMA Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2024.02.003","article-title":"Immune checkpoint inhibitor-induced myositis","volume":"50","author":"Jayan","year":"2024","journal-title":"Rheum Dis Clin North Am"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(18)31240-3","article-title":"Myocarditis in patients treated with immune checkpoint inhibitors","volume":"71","author":"Mahmood","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.803410","article-title":"Incidence and distinct features of immune checkpoint inhibitor-related myositis from idiopathic inflammatory myositis: a single-center experience with systematic literature review and meta-analysis","volume":"12","author":"Hamada","year":"2021","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.858628","article-title":"Association between clinical factors and outcomes of immune checkpoint inhibitor-related myasthenia gravis: a single-center experience and systematic review","volume":"13","author":"Shi","year":"2022","journal-title":"Front Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics14161794","article-title":"Myocarditis, myositis, and myasthenia gravis overlap syndrome associated with immune checkpoint inhibitors: a systematic review","volume":"14","author":"Lipe","year":"2024","journal-title":"Diagnostics (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1186\/s40425-019-0774-y","article-title":"Immune checkpoint inhibitor-related myasthenia gravis: single-center experience and systematic review of the literature","volume":"7","author":"Safa","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13931","article-title":"Immune checkpoint inhibitor-induced myocarditis with myositis\/myasthenia gravis overlap syndrome: a systematic review of cases","volume":"26","author":"Pathak","year":"2021","journal-title":"Oncologist"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.117.030571","article-title":"Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity","volume":"136","author":"Escudier","year":"2017","journal-title":"Circulation"},{"key":"B11","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/s0140-6736(18)30533-6","article-title":"Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis","volume":"391","author":"Moslehi","year":"2018","journal-title":"Lancet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.640985","article-title":"Role of cardiac imaging in the diagnosis of immune checkpoint inhibitor-related myocarditis","volume":"11","author":"Ederhy","year":"2021","journal-title":"Front Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1372861","DOI":"10.1111\/j.1468-1331.2010.03017.x","article-title":"Prognosis of immune checkpoint inhibitor-induced myasthenia gravis: a single-center experience and systematic review","volume":"15","author":"Qin","year":"2024","journal-title":"Front Neurol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5050","article-title":"Immune checkpoint inhibitor-induced myocarditis, myasthenia gravis, and myositis: a single-center case series","volume":"12","author":"Longinow","year":"2023","journal-title":"Cancer Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.124.038719","article-title":"Predictors of long-term survival in patients with immune checkpoint inhibitor-associated myocarditis","volume":"14","author":"Dubey","year":"2025","journal-title":"J Am Heart Assoc"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2024.2343023","article-title":"Immune checkpoint inhibitor-related myositis: an observational, retrospective, pharmacovigilance study","volume":"24","author":"Yang","year":"2025","journal-title":"Expert Opin Drug Saf"},{"key":"B17","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s40959-023-00185-y","article-title":"Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis","volume":"9","author":"O\u2019Shea","year":"2023","journal-title":"Cardio-Oncology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/ehjci\/jeac106","article-title":"2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society","volume":"43","author":"Lyon","year":"2022","journal-title":"Eur Heart J"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.1093\/eurheartj\/ehaf192","article-title":"2025 ESC Guidelines for the management of myocarditis and pericarditis","volume":"46","author":"Schulz-Menger","year":"2025","journal-title":"Eur Heart J"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1609214","article-title":"Fulminant myocarditis with combination immune checkpoint blockade","volume":"375","author":"Johnson","year":"2016","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05432-3","article-title":"T cells specific for \u03b1-myosin drive immunotherapy-related myocarditis","volume":"611","author":"Axelrod","year":"2022","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00715-5","article-title":"Immune checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart","volume":"24","author":"Munir","year":"2024","journal-title":"Nat Rev Cancer"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s40674-023-00212-0","article-title":"Treatment of myositis associated with immune checkpoint inhibitors","volume":"9","author":"Matas-Garc\u00eda","year":"2023","journal-title":"Curr Treat Options Rheumatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.10.001","article-title":"Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"33","author":"Haanen","year":"2022","journal-title":"Ann Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1854723\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:02:20Z","timestamp":1785304940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1854723\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":24,"alternative-id":["10.3389\/fimmu.2026.1854723"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1854723","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"article-number":"1854723"}}