---
title: "Immune Checkpoint Inhibitor–Related Myositis, Myocarditis, and Myasthenia Gravis Overlap Syndrome:"
id: "frontiers-in-immunology-11-immune-checkpoint-inhibitor-related-myositis-myocarditis-and-myasthenia-gravis"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-immune-checkpoint-inhibitor-related-myositis-myocarditis-and-myasthenia-gravis"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1854723"
published_at: "2026-07-29T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Immune Checkpoint Inhibitor–Related Myositis, Myocarditis, and Myasthenia Gravis Overlap Syndrome:
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-immune-checkpoint-inhibitor-related-myositis-myocarditis-and-myasthenia-gravis
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1854723)
- **Published At:** 2026-07-29T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source page and metadata reference a systematic review and pooled analysis on overlap syndrome involving **immune checkpoint inhibitors** and the neuromuscular/cardiac conditions **myositis**, **myocarditis**, and **myasthenia gravis**. - The accessible source content contains site navigation and journal information but does not include the article text, methods, case data, pooled results, or conclusions. - Key study elements such as inclusion criteria, number of cases, patient demographics, implicated checkpoint inhibitors, timing of onset, diagnostic criteria, biomarker findings, management strategies, and outcomes are not reported in the available source content. - Because the core article text is missing, no verified quantitative results, pooled estimates, or authors’ recommendations can be extracted or summarized. - Clinically, the title indicates a focus on a recognized and serious immune-related adverse event pattern—concurrent or sequential **myositis**, **myocarditis**, and **myasthenia gravis**—which is important for clinicians prescribing checkpoint inhibitors, but the source provides no case-level details or guidance. - The absence of the article body prevents confirmation of study quality, heterogeneity assessment, bias evaluation, or specific management implications derived by the authors. - Users should consult the full published article (Frontiers in Immunology) or contact the publisher to obtain the complete dataset and authors’ analyses before applying any conclusions to clinical practice.
## Clinical Analysis & Structured Key Points
Frontiers | Immune checkpoint inhibitor–related myositis, myocarditis, and myasthenia gravis overlap syndrome: a systematic review and pooled analysis of individual cases ORIGINAL RESEARCH article Front. Immunol. , 29 July 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1854723 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Combination Cancer Therapies and Systems Immunology Submission open 35k views 25 articles Editor & Reviewers Edited by S R SRINIVASA REDDY TELUKUTLA Reviewed by Ş D Şule Deveci I N Imran Naeem Aziz Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Primary and sensitivity multivariable logistic regression models for factors associated with in-hospital mortality. View in article Table 2 Summary of major clinical characteristics and outcomes of patients with ICI-related 3M overlap syndrome. View in article ORIGINAL RESEARCH article Front. Immunol. , 29 July 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1854723 Immune checkpoint inhibitor–related myositis, myocarditis, and myasthenia gravis overlap syndrome: a systematic review and pooled analysis of individual cases M W Miao Wei 1 T H Tiantian Hu 1 L Y Lili Yang 1 Y D Yan Duan 1 * Y L Yifan Li 2 * 1. 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, Taiyuan, China 2. 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, Taiyuan, China Article metrics View details Abstract Background: Immune checkpoint inhibitor (ICI)–related 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. Methods: 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. Results: 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 ± 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, 16.0–31.0).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], 1.05–1.17; P < 0.001) and complete conduction block (aOR, 2.84; 95% CI, 1.10–7.34; P = 0.031) remained independently associated with in-hospital mortality, whereas fatigue was no longer statistically significant after adjustment (aOR, 1.85; 95% CI, 0.75–4.56; P = 0.181). Exploratory clustering identified a possible bulbar/axial symptom cluster characterized by dysphagia, dysarthria, and neck muscle weakness. Conclusions: 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. Introduction The widespread use of immune checkpoint inhibitors (ICIs) has substantially improved survival across multiple malignancies, but has also led to a broad spectrum of immune-related adverse events (irAEs), some of which are life-threatening ( 1 , 2 ). Among these toxicities, ICI-related myocarditis is uncommon but is characterized by abrupt onset, rapid progression, and high fatality ( 3 , 4 ). ICI-related myositis is regarded as one of the earliest and most potentially fatal rheumatic and musculoskeletal irAEs ( 5 ), whereas ICI-related myasthenia gravis (MG) is more likely than classic MG to present with respiratory failure and death ( 6 ). Importantly, these entities are not always isolated. Concurrent involvement of the myocardium, skeletal muscle, and neuromuscular junction may occur, forming a highly fulminant overlap syndrome of myositis, myocarditis, and MG, hereafter referred to as the 3M overlap syndrome ( 7 ). Recognition of ICI-related 3M overlap syndrome has increased in recent years, but the available evidence remains derived largely from case reports, small case series, and descriptive reviews. Previous systematic reviews have suggested that the syndrome occurs predominantly in older men, tends to develop early after ICI initiation, is most frequently reported in patients with melanoma, and carries a high mortality rate ( 8 , 9 ). Nevertheless, several gaps remain. First, earlier studies have focused mainly on descriptive summaries of clinical manifestations and treatment courses, whereas ancillary diagnostic findings, baseline comorbidities, concomitant non-ICI anticancer therapy, treatment patterns, and short-term in-hospital outcomes have not been systematically evaluated. Second, few reviews have examined factors associated with in-hospital mortality at the individual case level, limiting clinically useful clues for early risk stratification. Third, follow-up duration and outcome reporting vary considerably across published cases, making longer-term endpoints—particularly 28-day mortality—difficult to compare consistently. By contrast, in-hospital mortality is more consistently available and may better reflect the true severity of the acute phase of this syndrome. Against this background, we conducted a systematic review of case reports and case series and a pooled analysis of individual case data on ICI-related 3M overlap syndrome, incorporating three additional patients from our center. We aimed to summarize the epidemiologic profile, clinical manifestations, ancillary diagnostic findings (myocarditis evidence, myositis evidence, and MG/neuromuscular-junction evidence), baseline comorbidities, concomitant non-ICI anticancer therapy, treatment strategies, and in-hospital outcomes of this syndrome, and to explore clinical factors associated with in-hospital mortality. By leveraging a larger body of case-level evidence, we sought to provide more targeted evidence for early recognition, risk assessment, and clinical management. Methods Study design and registration This study was a systematic review of published case reports and case series with a pooled analysis of individual case data from patients with ICI-related myositis, myocarditis, and MG overlap syndrome, supplemented by three patients from our center. This study was registered with PROSPERO (CRD420261331490). Search strategy We systematically searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data for studies published from January 1, 2010, to April 1, 2026. Reference lists of the included studies and Google Scholar were also screened to identify additional reports. The search strategy combined controlled vocabulary and free-text terms related to ICIs, myocarditis, myositis, MG, overlap syndrome, case reports, and case series. Detailed search strategies for the core databases are provided in Supplementary Appendix 1, and the search terms were adapted as appropriate for the remaining databases. Eligibility criteria Studies were eligible if they: (1) reported patients exposed to at least one ICI; (2) described concurrent or sequential occurrence of ICI-related myocarditis, myositis, and MG consistent with the 3M overlap syndrome; (3) were published case reports or case series, including the three patients treated at our center; (4) provided extractable individual-level data on demographics, clinical manifestations, investigations, treatment, and/or hospitalization outcomes sufficient for the pooled analysis; and (5) were published in English or Chinese. We excluded: (1) cohort studies, pharmacovigilance studies, reviews, meta-analyses, commentaries, letters, and conference abstracts without extractable individual case data; (2) duplicate publications or overlapping datasets; and (3) cases with insufficient diagnostic evidence or missing key outcome data that precluded inclusion in the primary analysis. During revision, all included reports were re-examined and two cases were identified as duplicate publications of the same patients and were removed, yielding the final cohort of 133 unique published cases plus 3 institutional cases (n = 136). Study selection and data extraction Two investigators independently screened the records according to the predefined search strategy. After title and abstract screening, potentially eligible reports underwent full-text assessment. Disagreements were resolved by discussion or adjudication by a third investigator. Data were extracted using a standardized form that captured:(1) demographic and oncologic data (age, sex, malignancy type, ICI agent and regimen, ICI cycles, and time from first ICI exposure to symptom onset); (2) baseline comorbidities, with pre-specified extraction of hypertension, diabetes mellitus, chronic kidney disease, coronary artery disease/ischemic heart disease, and obesity, together with other reported conditions; (3) concomitant non-ICI anticancer therapy administered with the ICI regimen at the index event, categorized as chemotherapy, chemoradiotherapy, or targeted/anti-VEGF/tyrosine kinase inhibitor therapy (dual ICI regimens were not counted as concomitant non-ICI therapy); (4) presenting symptoms and signs; (5) ancillary diagnostic findings, recorded separately as myocarditis evidence (cardiac biomarkers, ECG, echocardiography, cardiac MRI, endomyocardial biopsy, and autopsy), myositis evidence (CK or aldolase, EMG/NCS, muscle MRI, and muscle biopsy), and myasthenia gravis/neuromuscular-junction (MG/NMJ) evidence (acetylcholine receptor and other relevant antibodies, repetitive nerve stimulation, and edrophonium/ice-pack testing); (6) treatments, including systemic corticosteroids (with explicit recording of pulse-dose use), IVIG, PLEX, other immunosuppressive or targeted immunomodulatory agents, MG-directed symptomatic therapy, and supportive care; (7) length of hospital stay and time from symptom onset to initiation of irAE-directed treatment, when explicitly reported; and (8) clinical outcomes, with a focus on all-cause in-hospital mortality and patient-level disposition. A finding was coded as present only when explicitly reported, as absent when explicitly denied or normal, and as “not reported” when the source did not address it; investigations or comorbidities not reported in the source publication were not assumed to be negative or absent, and denominators therefore vary across variables according to information available. Clinical data for the three institutional patients were collected retrospectively from the electronic medical record after approval by the ethics committee. Diagnostic criteria and reclassification Two investigators independently reclassified the diagnoses of myocarditis, myositis, and MG using predefined criteria derived from the published literature ( 5 , 10 , 11 ). In brief, ICI-related myocarditis was diagnosed on the basis of compatible clinical features plus evidence of myocardial injury and supportive ECG, echocardiographic, cardiac magnetic resonance, endomyocardial biopsy, or autopsy findings after exclusion of alternative causes ( 10 ). ICI-related myositis was defined by compatible symptoms together with elevated CK or aldolase and supportive electromyography, skeletal muscle magnetic resonance imaging, or muscle biopsy findings ( 5 ). ICI-related MG was defined by compatible symptoms and/or signs together with positive MG-associated autoantibodies, positive pharmacologic or ice-pack testing, or abnormal electrophysiology ( 11 ). Any discrepancies in reclassification were resolved by consensus. Treatment and supportive care definitions Treatment and supportive care definitions. Immunomodulatory treatment was categorized as systemic corticosteroids (including pulse-dose methylprednisolone, defined as ≥500 mg/day for at least three consecutive days) and second-line immunomodulatory therapy, comprising IVIG, PLEX, and additional immunosuppressive or targeted immunomodulatory agents. Because the timing of second-line therapy was inconsistently or incompletely reported, upfront versus stepwise escalation could not be reliably distinguished, and second-line use was therefore summarized descriptively. Mechanical circulatory support was defined a priori as venoarterial extracorporeal membrane oxygenation (VA-ECMO), Impella, intra-aortic balloon pump (IABP), or ventricular assist device; pacemaker or ICD implantation and continuous renal replacement therapy or dialysis were not considered mechanical circulatory support and were tabulated separately. Vasoactive or inotropic therapy and antiarrhythmic drugs were inconsistently reported and could not be pooled quantitatively. Risk of bias assessment Methodological quality was assessed using the Joanna Briggs Institute critical appraisal tools for case reports and case series. The assessment focused on the reporting of patient demographics, diagnostic ascertainment, interventions, and outcomes. Study quality was appraised descriptively and was not used as an exclusion criterion. Statistical analysis All analyses were conducted using R version 4.2.2 ( http://www.R-project.org , R Foundation) and Free Statistics software (version 2.0). Continuous variables are presented as mean ± standard deviation or median (interquartile range [IQR]), as appropriate according to their distribution. Categorical variables are reported as n/N (%), using the number of patients with available data for each variable as the denominator. A statistical P-value below 0.05 was considered statistically significant. The primary endpoint was all-cause in-hospital mortality. Univariable logistic regression assessed the association of clinical, diagnostic, and treatment-related variables with in-hospital mortality ( Supplementary Table 4 ). Given the case-level nature of the source data, the variable completeness of reporting, and multiple comparisons, all univariable and multivariable analyses are interpreted as exploratory and hypothesis-generating; throughout the manuscript these results are described as “factors associated with in-hospital mortality” or “exploratory mortality-associated factors” rather than as predictors. The pre-specified multivariable logistic regression model ( Table 1 ) included age (per year), fatigue, and complete conduction block. Mechanical ventilation was excluded from the main multivariable model because it likely represents a downstream marker of disease severity on the causal pathway between severe 3M overlap syndrome and death; adjusting for it would risk overcontrol bias. Second-line immunomodulatory therapy was excluded because treatment exposure is time-dependent and is subject to survival-time and treatment-selection bias in retrospective case-level data. Complete-case analysis was used; complete conduction block was analyzed only among patients with available ECG information, and unreported ECG findings were not assumed to be normal. Missing data were not imputed. To further explore symptom co-occurrence patterns, we performed pairwise correlation analyses of commonly reported symptoms and visualized the symptom correlation matrix using hierarchical clustering. Given the heterogeneity and missingness inherent to case reports, this analysis was considered exploratory and was not intended for causal inference or formal subtype definition. For exploratory symptom analyses, pairwise associations among binary symptom variables were quantified using phi coefficients (equivalent to Pearson correlations for binary variables coded as 0/1) based on available case-level data, and hierarchical clustering was performed on the correlation matrix using Ward’s method. Table 1 Variable Adjusted OR 95% CI P value Primary multivariable model Age (per 1-year increase) 1.11 1.05–1.17 <0.001 Fatigue 1.85 0.75-4.56 0.181 Complete conduction block 2.84 1.1-7.34 0.031 Sensitivity model Age (per 1-year increase) 1.11 1.05–1.17 <0.001 Dyspnea plus fatigue 2.37 0.69-8.07 0.168 Complete conduction block 2.72 1.07-6.94 0.031 Primary and sensitivity multivariable logistic regression models for factors associated with in-hospital mortality. OR indicates odds ratio; CI, confidence interval. In the sensitivity model, dyspnea plus fatigue was entered in place of fatigue to assess the robustness of the association while avoiding collinearity or conceptual overlap. Ethics This study was primarily a systematic review and did not involve direct patient intervention. Collection of the three institutional cases was approved by the hospital ethics committee, which waived the requirement for informed consent (approval number: KY2025024). The study was conducted in accordance with the Declaration of Helsinki. Results Study selection Through database and supplementary searches, 1436 records were identified (236 from PubMed, 642 from Embase, and 558 from other databases and supplementary sources). After removal of duplicates, 131 records underwent title and abstract screening, and 106 reports were assessed in full text. Ninety-three published reports were ultimately included, yielding 133 unique patients with ICI-related 3M overlap syndrome after two cases were identified as duplicate publications during revision and removed. Together with three patients from our institution, 136 patients were included in the pooled analysis ( Figure 1 ). Figure 1 Study selection flow diagram for the systematic review and pooled individual case-level analysis. Baseline characteristics A total of 136 patients were included. Age ranged from 33 to 89 years, and the mean age was 69.8 ± 11.2 years. Among 136 patients with available sex data, 96/136 (70.6%) were male. Melanoma was the most common underlying cancer (40/136, 29.4%), followed by urologic malignancies (35/136, 25.7%) and lung cancer (24/136, 17.6%). Pembrolizumab was the most frequently reported agent (53/136, 39.0%), followed by dual ICI regimens (22/136, 16.2%) and durvalumab (14/136, 10.3%). Dual ICI regimens were defined as concurrent administration of two immune checkpoint inhibitors and were not counted as concomitant non-ICI anticancer therapy. The median time from first ICI exposure to symptom onset was 22.0 days (IQR, 16.0–31.0), and the mean number of treatment cycles before onset was 1.5 ± 0.8. Clinical manifestations and ancillary findings Common manifestations included ptosis (93/136, 68.4%), diplopia (70/136, 51.5%), limb muscle weakness (67/136, 49.3%), dyspnea (60/136, 44.1%), dysphagia (47/136, 34.6%), fatigue (43/
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