检索问题
免疫检查点抑制剂相关心肌炎的发生率、风险因素和管理策略
免疫检查点抑制剂（ICIs）相关心肌炎是一种罕见但可能致命的并发症，其发生率、风险因素和管理策略已成为当前癌症治疗领域的重要关注点。
1. 发生率
免疫检查点抑制剂相关心肌炎的发生率相对较低，但其致命性较高。
-
总体发生率:
- 一项对国际药物警戒数据库（Vigilyze）和7个学术中心的回顾性分析显示，从2009年1月至2018年1月，共报告了613例ICI相关致死性毒性事件 。
- 对112项涉及19217名患者的临床试验进行的荟萃分析显示，毒性相关致死率在不同ICI类型中有所差异：抗PD-1为0.36%，抗PD-L1为0.38%，抗CTLA-4为1.08%，PD-1/PD-L1联合CTLA-4为1.23% 。
- 在7个学术中心对3545名接受ICI治疗的患者进行回顾性分析，发现致死率为0.6%，其中心脏和神经事件尤为突出（43%） 。
- 另一项对589项临床试验（83315名参与者）的荟萃分析发现，抗PD-1和/或PD-L1诱导的心血管不良事件（CVAEs）发生率为0.80%，伊匹木单抗（anti-ipilimumab）治疗后的CVAEs发生率为1.07% 。
- 心肌炎的发生率在双重ICI治疗后显著更高，但CVAE总体发生率并未随着双重ICI、ICI与化疗或酪氨酸激酶抑制剂联合使用而升高 。
- 在一项中国汉族人群的真实世界研究中，203名患者中有4.4%（9/203）出现CVAEs，包括心力衰竭、心律失常、心肌炎和心包疾病，其中6/9为3级或4级严重事件 。该研究报告的ICI相关CVAEs发生率高于一些既往研究 。
- 一项单中心回顾性队列研究分析了7157名接受ICI治疗的患者，其中71名被诊断为ICI相关心肌炎，发生率约为1% 。
- 对免疫相关严重不良事件（irSAEs）的系统评价和网络荟萃分析显示，伊匹木单抗（ipilimumab）的irSAEs发生率最高（848/10000患者），而阿替利珠单抗（atezolizumab）最低（119/10000患者） 。
-
特定类型ICI的发生率和特点:
- 抗CTLA-4治疗导致的死亡主要源于结肠炎（70%），而抗PD-1/PD-L1相关的死亡常由肺炎（35%）、肝炎（22%）和神经毒性效应（15%）引起 。
- PD-1/CTLA-4联合治疗导致的死亡常与结肠炎（37%）和心肌炎（25%）有关 。
- 心肌炎的致死率最高（在131例报告病例中，52例死亡，占比39.7%），而内分泌事件和结肠炎的致死率仅为2%至5% 。
- 致死性毒性事件通常在治疗开始后早期发生，联合治疗、抗PD-1和伊匹木单抗单药治疗的中位时间分别为14.5天、40天和40天 。从症状出现到死亡的中位时间为32天 。
2. 风险因素
ICI相关心肌炎的风险因素包括患者特征、ICI治疗方案以及并发的自身免疫过程。
-
ICI治疗方案:
- 联合使用细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抑制剂和程序性细胞死亡蛋白1（PD-1）或程序性死亡配体1（PD-L1）抑制剂会增加发生ICI相关心肌炎的风险 。这是ICI心肌炎的一个明确的风险因素 。
- 一项研究发现，双重ICI治疗导致心肌炎的发生率显著更高 。
- 与单药治疗相比，联合ICI治疗的患者发生肌炎的风险更高 。
- 最常与黑色素瘤、肺癌和肾癌相关的MMM（心肌炎、肌炎、重症肌无力）重叠综合征，其在院死亡率接近40% 。
-
患者特征和合并症:
- 年龄较大、男性和合并高血压或心力衰竭的患者更容易发生心血管不良事件（CVAEs） 。
- 在食管癌患者中，年龄较大、男性以及肌酸激酶同工酶（CK-MB）和肌酸激酶（CK）水平升高是无症状心肌炎的重要风险因素 。
- 心肌炎严重程度与肌钙蛋白升高幅度、胸腺瘤、心电图QRS波电压降低和左心室射血分数（LVEF）<50%以及心肌症状相关 。
- 活动性胸腺瘤（HR 3.6）、存在心肌症状（HR 2.6）、心电图QRS波电压低（HR 1.9，≤0.5mV vs >1mV）、LVEF < 50%（HR 1.7）和肌钙蛋白逐渐升高（20倍、200倍、2000倍高于参考上限的HR分别为1.8、2.9、4.6）与复合终点（严重心律失常、心力衰竭、呼吸肌衰竭和/或心肌毒性相关死亡）相关 。
-
生物标志物:
- 肌钙蛋白升高是ICI相关心肌炎的重要诊断和预后标志物 。
- N末端B型利钠肽前体（NT-proBNP）水平在严重ICI相关心肌炎的致死病例中显著升高（中位值13804 pg/mL），并且独立预测死亡风险（OR 4.3） 。NT-proBNP被认为是严重ICI相关心肌炎风险分层的重要预后标志物 。
- CK-MB和CK水平升高是食管癌患者无症状ICI相关心肌炎的风险因素 。结合年龄、性别、CK和CK-MB的预测模型显示出更高的诊断能力（AUC 0.808） 。
-
发病机制:
- ICI心肌炎的机制可能涉及心肌组织和肿瘤之间存在共同抗原，导致单克隆抗体同时攻击心肌组织和肿瘤细胞，即“分子模拟” 。
- ICI通过阻断T细胞免疫反应的负向调节因子（如CTLA-4、PD-1和PD-L1）来增强免疫反应，这种增强的免疫反应可能导致包括心血管毒性在内的免疫相关毒性 。
- ICI心肌炎与CCR2单核细胞源性巨噬细胞和CD8 T细胞在心脏中的显著增殖有关 。炎性CCR2巨噬细胞亚群高表达CXCL9、CXCL10、IFITM3和Fcgr4，并在ICI心肌炎患者中观察到类似的巨噬细胞群扩张 。
- 体外预测的细胞间通讯表明T细胞和CXCL9+巨噬细胞通过IFN-γ和CXCR3信号通路进行相互作用，CD8 T细胞或巨噬细胞耗竭以及IFN-γ信号阻断可抑制心脏中CXCL9+巨噬细胞的扩张并减轻心肌炎 。
3. 管理策略
ICI相关心肌炎的管理需要多学科协作、早期识别、积极干预和个体化治疗。
-
诊断方法:
- 由于ICI相关心肌炎的临床表现和心肌病理发现高度可变，诊断需要结合临床怀疑、心脏生物标志物（特别是肌钙蛋白）和心脏影像学检查，并辅以活检 。
- 心内膜活检（EMB）是诊断的金标准，但心脏磁共振成像（CMRI）在大多数临床场景中已成为主要诊断手段 。然而，在某些特定情况下，组织学信息对优化治疗至关重要，因此EMB仍然是必需的 。
- 应促进基于风险的方法来识别最严重的AM病例，以便提供适当的护理，包括早期识别、转诊至三级中心、积极的循环支持、组织学确认和免疫抑制治疗 。
- 对于疑似ICI相关心肌炎的患者，全面的病史、体格检查、心脏生物标志物、心脏影像学和心内膜活检构成了一种实用的诊断方法 。
- 新型生物标志物和影像学模式的加入是活跃的研究领域，应在更大的队列中进行评估 。
-
治疗原则:
- 早期识别、ICI治疗中断和及时启动皮质类固醇治疗以及升级治疗是实现最佳结果的关键要素 。
- 目前缺乏针对ICI诱导心肌炎推荐监测和治疗策略的随机临床试验证据 。
- 根据既往病例报告和病例系列，ICI诱导心肌炎最初主要用类固醇治疗 。
- 高剂量皮质类固醇是ICI相关心肌炎治疗的基石 。然而，约一半的心肌炎患者在皮质类固醇治疗后未见临床改善 。
- 对于皮质类固醇治疗无效的严重病例，可能需要加强免疫抑制治疗，例如结合其他免疫抑制剂或针对ICI心肌炎病理生理学的靶向治疗 。
- 第二线治疗的选择包括麦考酚酸酯（mycophenolate mofetil）、抗胸腺细胞球蛋白（anti-thymocyte globulin）、英夫利西单抗（infliximab）、阿巴西普（abatacept）、他克莫司（tacrolimus）和托珠单抗（tocilizumab） 。
- 一项研究发现，系统性筛查呼吸肌受累，结合积极通气、及时使用阿巴西普和添加鲁索替尼（ruxolitinib），可以降低心肌炎的死亡率 。
- 对于MMM重叠综合征，高剂量皮质类固醇是主要治疗，并根据临床恶化和自身免疫谱，可以添加其他免疫调节治疗，如静脉免疫球蛋白（IVIG）、血浆置换（PLEX）和利妥昔单抗（rituximab） 。
- 靶向IL-6R（如托珠单抗或沙利珠单抗）可能是一种有效的治疗多种irAEs（包括肌炎/心肌炎/重症肌无力）的方法，且不影响抗肿瘤免疫 。
-
预后和随访:
- 尽管ICI心肌炎的发生率低，但死亡率可高达50% 。
- 一项多中心注册研究发现，748名ICI心肌炎患者中，30天复合主要终点（严重心律失常、心力衰竭、呼吸肌衰竭和/或心肌毒性相关死亡）发生率为33%，心肌毒性相关死亡为13%，总死亡率为17% 。
- 对于轻度心肌炎患者，一项风险评分显示，30天主要终点发生率从4%（风险评分=0）增加到81%（风险评分≥4） 。
- 在严重的ICI相关心肌炎（3-4级）亚组中，总死亡率为54.5%（18/33） 。
- 在临时停用ICI治疗后再次使用ICI是可能的，特别是考虑到其治疗效果，但关于irAE后再次使用的安全性数据有限 。一项研究发现，9名再次接受免疫治疗的患者中，7名（77.8%）能够耐受后续周期而没有复发免疫毒性，而2名曾患2级心肌炎的患者则出现症状复发 。
- 由于缺乏随机对照试验（RCTs）来研究irAE（特别是心肌炎）后再次使用ICI的问题，需要多学科专家工作组根据个体情况做出决策，并需要更多数据发表 。
- 需要进行前瞻性临床试验或至少前瞻性地登记治疗和结果，以提供更强的证据支持监测和管理策略 。
总结而言，ICI相关心肌炎是一种严重的免疫相关不良事件，其发生率虽然不高，但致死率显著。早期诊断依赖于临床表现、生物标志物和影像学检查，并常需活检确认。高剂量皮质类固醇是主要治疗手段，但对难治性病例，需要考虑升级为其他免疫抑制剂或靶向治疗。多学科协作、个体化风险评估和持续随访对于提高患者预后至关重要 。未来，需要更多研究来明确诊断标准、预测生物标志物和标准化的治疗方案 。
References
1Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.PubMed
Daniel Y Wang, Joe-Elie Salem, Justine V Cohen, et al.
IMPORTANCE: Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. OBJECTIVE: To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. EXPOSURES: Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). MAIN OUTCOMES AND MEASURES: Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. RESULTS: Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). CONCLUSIONS AND RELEVANCE: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.
2Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart.PubMed
Amir Z Munir, Alan Gutierrez, Juan Qin, et al.
Immune-checkpoint inhibitors (ICIs) have revolutionized oncology, with nearly 50% of all patients with cancer eligible for treatment with ICIs. However, patients on ICI therapy are at risk for immune-related toxicities that can affect any organ. Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication. ICI-mediated myocarditis (ICI-myocarditis) is a growing clinical entity given the widespread use of ICIs, its increased clinical recognition and growing use of combination ICI treatment, a well-documented risk factor for ICI-myocarditis. In this Review, we approach ICI-myocarditis from a basic and mechanistic perspective, synthesizing the recent data from both preclinical models and patient samples. We posit that mechanistic understanding of the fundamental biology of immune-checkpoint molecules may yield new insights into disease processes, which will enable improvement in diagnostic and therapeutic approaches. The syndrome of ICI-myocarditis is novel, and our understanding of immune checkpoints in the heart is in its nascency. Yet, investigations into the pathophysiology will inform better patient risk stratification, improved diagnostics and precision-based therapies for patients.
3Clinical Strategy for the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Associated Myocarditis: A Narrative Review.PubMed
Lorenz H Lehmann, Jennifer Cautela, Nicolas Palaskas, et al.
IMPORTANCE: In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor-associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed. OBSERVATIONS: Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte-associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis. CONCLUSION AND RELEVANCE: This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.
4Immune checkpoint inhibitor-associated myocarditis: a novel risk score.PubMed
John R Power, Charles Dolladille, Benay Ozbay, et al.
BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyotoxicity' are lacking. The main aim of this study was to determine predictors and construct a risk score associated with negative outcomes in patients admitted for ICI myocarditis. METHODS: A multicentre registry collected data retrospectively from 17 countries between 2014 and 2023. A multivariable Cox regression model was used to determine risk factors for the primary composite outcome: time to severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardiomuscular symptoms, diagnostics, and treatments. Time-dependent covariates were used, and missing data were imputed. A point-based prognostic risk score was derived and externally validated. RESULTS: In 748 patients (67% male, age 23-94 years), 30-day incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17%, respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7), presence of cardiomuscular symptoms (HR 2.6 [1.5-4.2]), low QRS voltage on presenting electrocardiogram (HR for ≤0.5 mV vs >1 mV 1.9 [1.1-3.1]), left ventricular ejection fraction (LVEF) < 50% (HR 1.7 [1.1-2.6]), and incremental troponin elevation (HR 1.8 [1.4-2.4], 2.9 [1.8-4.7], and 4.6 [2.3-9.3], for 20, 200, and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-day primary outcome incidence increased gradually from 4% (risk score = 0) to 81% (risk score ≥ 4). This risk score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low-risk patients who were managed with no immunosuppression resulting in no cardiomyotoxic events. CONCLUSIONS: ICI-associated myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low QRS voltage, depressed LVEF, and cardiomuscular symptoms. A risk score incorporating these features performed well. CLINICAL TRIAL REGISTRATION: NCT04294771 and NCT05454527.
5Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review.PubMed
Rohail Gul, Muhammad Shehryar, Anber Mahboob, et al.
Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use. Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.
6Immune Checkpoint Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis.PubMed
Dorte Lisbet Nielsen, Carsten Bogh Juhl, Ole Haagen Nielsen, et al.
IMPORTANCE: Immune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur. OBJECTIVE: To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs. DATA SOURCES: PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023. STUDY SELECTION: Two separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2. DATA EXTRACTION AND SYNTHESIS: The PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: In study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began. RESULTS: In study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti-programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate. CONCLUSIONS AND RELEVANCE: Immune checkpoint inhibitor-induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.
7Update on acute myocarditis.PubMed
Enrico Ammirati, Giacomo Veronese, Maurizio Bottiroli, et al.
Acute myocarditis (AM), a recent-onset inflammation of the heart, has heterogeneous clinical presentations, varying from minor symptoms to high-risk cardiac conditions with severe heart failure, refractory arrhythmias, and cardiogenic shock. AM is moving from being a definitive diagnosis based on histological evidence of inflammatory infiltrates on cardiac tissue to a working diagnosis supported by high sensitivity troponin increase in association with specific cardiac magnetic resonance imaging (CMRI) findings. Though experts still diverge between those advocating for histological definition versus those supporting a mainly clinical definition of myocarditis, in the real-world practice the diagnosis of AM has undoubtedly shifted from being mainly biopsy-based to solely CMRI-based in most of clinical scenarios. It is thus important to clearly define selected settings where EMB is a must, as information derived from histology is essential for an optimal management. As in other medical conditions, a risk-based approach should be promoted in order to identify the most severe AM cases requiring appropriate bundles of care, including early recognition, transfer to tertiary centers, aggressive circulatory supports with inotropes and mechanical devices, histologic confirmation and eventual immunosuppressive therapy. Despite improvements in recognition and treatment of AM, including a broader use of promising mechanical circulatory supports, severe forms of AM are still burdened by dismal outcomes. This review is focused on recent clinical studies and registries that shed new insights on AM. Attention will be paid to contemporary outcomes and predictors of prognosis, the emerging entity of immune checkpoint inhibitors-associated myocarditis, updated CMRI diagnostic criteria, new data on the use of temporary mechanical circulatory supports in fulminant myocarditis. The role of viruses as etiologic agents will be reviewed and a brief update on pediatric AM is also provided. Finally, we summarize a risk-based approach to AM, based on available evidence and clinical experience.
8Acute myocarditis: an overview of pathogenesis, diagnosis and management.PubMed
Marina Zafeiri, Kristopher Knott, Temi Lampejo
Acute myocarditis encompasses a diverse presentation of inflammatory cardiomyopathies with infectious and non-infectious triggers. The clinical presentation is heterogeneous, from subtle symptoms like mild chest pain to life-threatening fulminant heart failure requiring urgent advanced hemodynamic support. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, diagnostic approach, management strategies, and directions for future research in acute myocarditis. The pathogenesis of myocarditis involves interplay between the inciting factors and the subsequent host immune response. Infectious causes, especially cardiotropic viruses, are the most frequently identified precipitants. However, autoimmune processes independent of microbial triggers, as well as toxic myocardial injury from drugs, chemicals or metabolic derangements also contribute to the development of myocarditis through diverse mechanisms. Furthermore, medications like immune checkpoint inhibitor therapies are increasingly recognized as causes of myocarditis. Elucidating the nuances of viral, autoimmune, hypersensitivity, and toxic subtypes of myocarditis is key to guiding appropriate therapy. The heterogeneous clinical presentation coupled with non-specific symptoms creates diagnostic challenges. A multifaceted approach is required, incorporating clinical evaluation, electrocardiography, biomarkers, imaging studies, and endomyocardial biopsy. Cardiovascular magnetic resonance imaging has become pivotal for non-invasive assessment of myocardial inflammation and fibrosis. However, biopsy remains the gold standard for histological classification and definitively establishing the underlying etiology. Management relies on supportive care, while disease-specific therapies are limited. Although some patients recover well with conservative measures, severe or fulminant myocarditis necessitates aggressive interventions such as mechanical circulatory support devices and transplantation. While immunosuppression is beneficial in certain histological subtypes, clear evidence supporting antiviral or immunomodulatory therapies for the majority of acute viral myocarditis cases remains insufficient. Substantial knowledge gaps persist regarding validated diagnostic biomarkers, optimal imaging surveillance strategies, evidence-based medical therapies, and risk stratification schema. A deeper understanding of the immunopathological mechanisms, rigorous clinical trials of targeted therapies, and longitudinal outcome studies are imperative to advance management and improve the prognosis across the myocarditis spectrum.
9Cardiovascular toxicities associated with immune checkpoint inhibitors.PubMed
Jiun-Ruey Hu, Roberta Florido, Evan J Lipson, et al.
Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year.
10NT-proBNP serves as a prognostic marker for adverse outcomes in severe immune checkpoint inhibitor-associated myocarditis.PubMed
Cheng He, Linjuan Xu, Zhihong Zhang, et al.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but carry risks of rare, life-threatening immune-related adverse events, particularly myocarditis. Prognostic biomarkers and optimal management strategies for severe ICI-associated myocarditis remain poorly defined. METHODS: This single-center retrospective cohort study analyzed 71 patients diagnosed with ICI-associated myocarditis among 7,157 ICI-treated individuals at a tertiary center (August 2018-August 2024). Myocarditis severity was graded per American Society of Clinical Oncology (ASCO) guidelines. Cardiac biomarkers, including NT-proBNP and troponin T, were assessed. Binary logistic regression identified predictors of mortality. Treatment protocols and immunotherapy rechallenge outcomes were evaluated. RESULTS: Severe myocarditis (Grades 3-4) occurred in 33 patients (46.5%), with an overall mortality rate of 54.5% in this subgroup (18/33). NT-proBNP levels were significantly elevated in fatal cases survivors (median: 13,804 4,050 pg/mL; < 0.001) and independently predicted mortality risk (odds ratio (OR) 4.3, 95% confidence interval (CI) [1.2-21.9]; = 0.023). A multimodal regimen combining plasmapheresis with high-dose corticosteroids, intravenous immunoglobulin, and mycophenolate mofetil was associated with improved survival. Among nine patients rechallenged with immunotherapy, seven (77.8%) tolerated subsequent cycles without recurrent immune toxicity, while two with prior Grade 2 myocarditis experienced symptom recurrence. DISCUSSION: Elevated NT-proBNP emerges as a critical prognostic marker for risk stratification in severe ICI-associated myocarditis. Immunotherapy rechallenge appears feasible in select patients but warrants caution in those with prior moderate-grade myocarditis. These findings advocate for biomarker-guided escalation of therapies and shared decision-making frameworks to balance oncologic efficacy with cardiovascular safety.
11Immune Checkpoint Inhibitor-induced Myositis.PubMed
Athira Jayan, Andrew L Mammen, Maria E Suarez-Almazor
Myositis induced by immune checkpoint inhibitors (ICIs) is an infrequent, potentially fatal, immune-related adverse event. It has higher incidence in patients who receive combination ICI therapy compared to monotherapy. Patients can present with clinical manifestation symptoms of myositis alone or in combination with myocarditis and/or myasthenia gravis, which significantly worsens the course and prognosis. Diagnosis can generally be made on the basis of clinical presentation, elevation of muscle enzymes, and electromyographic changes, but some patients may require a muscle biopsy. The first line of therapy is high-dose corticosteroids, followed by immunosuppression, plasmapheresis, or intravenous immunoglobulin in patients with severe disease.
12Management of immune-related myocarditis, myositis and myasthenia gravis (MMM) overlap syndrome: a single institution case series and literature review.PubMed
Alberto Sánchez-Camacho, Alberto Torres-Zurita, Laura Gallego-López, et al.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies, particularly melanoma. However, immune-related adverse events (irAEs) pose significant challenges, particularly in cases of severe toxicity syndromes. One such life-threatening irAE is the myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome, which occurs in less than 1% of patients but has in-hospital mortality rates ranging from 40 to 60%. Due to its rarity and complexity, early recognition and a multidisciplinary approach are critical to improving outcomes. METHODS: We present a single-institution case series of four patients diagnosed with MMM overlap syndrome following ICI therapy. Clinical presentation, laboratory findings, imaging, and electrophysiological tests were analyzed to confirm the diagnosis. Therapeutic interventions-including corticosteroids, intravenous immunoglobulins (IVIG), plasma exchange (PLEX), tocilizumab, and rituximab- were evaluated in terms of efficacy and clinical outcomes. RESULTS: The onset of MMM syndrome varied from 2 to 4 weeks after initiating ICI therapy. Patients presented with rapidly progressive symptoms, including ptosis, bulbar dysfunction, respiratory distress, myopathy, and cardiac conduction abnormalities. Immunosuppressive therapy with high-dose corticosteroids was initiated in all cases. Additional immunomodulatory treatments (IVIG, tocilizumab, PLEX, and rituximab) were administered based on clinical deterioration and autoimmune profile. Two patients achieved complete recovery, one remains on maintenance immunosuppression, and one died due to respiratory failure despite aggressive treatment. CONCLUSION: MMM overlap syndrome is a severe and often fatal irAE associated with ICI therapy. Early identification, aggressive immunosuppressive treatment, and individualized therapeutic strategies are essential to optimize patient outcomes. Further research is needed to refine diagnostic criteria, identify predictive biomarkers, and establish standardized treatment protocols.
13Risk factors and diagnostic biomarkers for asymptomatic immune checkpoint inhibitor-related myocarditis in patients with esophageal cancer after immunotherapy.PubMed
Jing-Yu Liu, Dong-Lai Gao, Xin Cao
BACKGROUND: Esophageal cancer is a serious global health concern with poor prognosis in advanced stages. Immune checkpoint inhibitors (ICIs) have shown promise in enhancing survival, but they are associated with immune-related adverse events, including potentially life-threatening myocarditis. Moreover, ICI-induced myocarditis can be asymptomatic, necessitating early diagnosis. Specific risk factors and biomarkers for esophageal cancer remain poorly characterized. AIM: To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers. METHODS: A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024. RESULTS: Older age, male gender, and elevated creatine kinase isoenzymes (CK-MB) and CK levels were found to be significant risk factors for asymptomatic myocarditis. The myocarditis occurrence group had higher CK-MB (3.05 ng/mL 5.02 ng/mL; < 0.001) and CK levels (187.29 U/L 212.25 U/L; = 0.005), and the predictive value of age, gender, CK, and CK-MB was low [are under the receiver operating characteristic curve (AUC) = 0.579-0.608]. However, their combination in a predictive model showed improved diagnostic capability, with an AUC of 0.808. CONCLUSION: Age, gender, and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer. The integration of these factors into a predictive model enhances early diagnosis, facilitating personalized risk management.
14Characteristics, Incidence, and Management of Immune Checkpoint Inhibitors Related Cardiovascular Adverse Events in Real-World Practice-A Retrospective Study in Chinese Han Population.PubMed
Rong-Hua Wang, Yin Chen, Ya-Ling Lou, et al.
PURPOSE: This study aimed to elaborate on the incidence, clinical features, and management of immune checkpoint inhibitors (ICIs) related cardiovascular adverse events (CVAEs) in real-world practice. PATIENTS AND METHODS: We performed a retrospective chart review study on patients receiving at least one dose of ICI therapy at a Chinese tertiary hospital from March 2020 to March 2021. CVAEs were identified through clinical assessment and the Naranjo algorithm. The management and outcomes of CVAEs were monitored over a median follow-up duration of 8 months. RESULTS: Among the included 203 patients, 4.4% (9/203) developed CVAEs, including heart failure (n = 3), arrhythmia (n = 2), myocarditis (n = 2), and pericardial disease (n = 2), with a proportion (6/9) tending to be severe (grade 3 or grade 4). CVAEs were more common in older patients (mean age: 73.6 ± 9.2 years) and those with hypertension (p = 0.02) or heart failure (p = 0.01). Adherence to the American Society of Clinical Oncology (ASCO) guidelines for managing CVAEs was low (44%), with most cases showing partial resolution by the last follow-up. CONCLUSION: We reported that the incidence of ICI-related CVAEs in the Chinese institution was higher than that in some prior studies. Adherence to guidelines for managing ICI-related CVAEs is found to be suboptimal in real-world practice and highlighted as a needed improvement.
15Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.PubMed
Clara Oliveira, Beatrice Mainoli, Gonçalo S Duarte, et al.
PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.
16Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.PubMed
Pan Ma, Jing Liu, Juan Qin, et al.
BACKGROUND: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. METHODS: We used an established murine ICI myocarditis model ( mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. RESULTS: We observed marked increases in CCR2 (C-C chemokine receptor type 2) monocyte-derived macrophages and CD8 T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2 subpopulation highly expressing (chemokine [C-X-C motif] ligand 9), (chemokine [C-X-C motif] ligand 10), (interferon-induced guanylate-binding protein 2b), and (Fc receptor, IgG, low affinity IV) that originated from CCR2 monocytes. It is important that a similar macrophage population expressing , , and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8 T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. CONCLUSIONS: These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.
17Management of Triple M Syndrome: A Narrative Review of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis, Myositis and Myocarditis.PubMed
Martin Furlepa, Isabella Watts, Aisling S Carr
The advent of immunotherapy has revolutionised cancer treatment by harnessing the immune system to target tumour cells. However, there is increasing awareness of immunotherapy-related adverse events, which can be severe and even fatal. While system-specific immune-related adverse events (ir-AEs) are well documented, growing evidence suggests the existence of overlap syndromes-distinct clusters of immune-mediated complications. One such syndrome is the overlap of myasthenia gravis, myositis and myocarditis, collectively known as Triple M (3M) syndrome. This syndrome is complex, varying in presentation and severity, with in-hospital mortality rates approaching 40%. Whilst there is consensus on the management of system-specific complications, there is no consensus guidance for the management of these overlap syndromes. In this paper, we conduct a review of the literature, analysing reported cases of 3M syndrome, focusing on treatment approaches and patient outcomes at an individual level. This review highlights the complexity of diagnosing and managing 3M syndrome due to inconsistent reporting, lack of standardised criteria for diagnosis, and treatment variability. While evidence remains limited, we offer broad clinical recommendations and underscore the urgent need for consensus definitions, prospective data collection, and structured treatment guidance.
18Treatment of Immune Checkpoint Inhibitor-associated Myocarditis.PubMed
Julius C Heemelaar, Maria Louisa, Tomas G Neilan
Immune checkpoint inhibitors (ICIs) are a form immunotherapy where the negative regulators of host immunity are targeted, thereby leveraging the own immune system. ICIs have significantly improved cancer survival in several advanced malignancies, and there are currently more than 90 different cancer indications for ICIs. Most patients develop immune-related adverse events during ICI therapy. Most are mild, but a small subset of patients will develop severe and potentially fatal immune-related adverse events. A serious cardiovascular complication of ICI therapy is myocarditis. Although the incidence of myocarditis is low, mortality rates of up to 50% have been reported. The mainstay of ICI-associated myocarditis treatment is high-dose corticosteroids. Unfortunately, half of patients with myocarditis do not show clinical improvement after corticosteroid treatment. Also, high doses of corticosteroids may adversely impact cancer outcomes. There is an evidence gap in the optimal second-line treatment strategy. Currently, there is a paradigm shift in second-line treatment taking place from empirical corticosteroid-only strategies to either intensified initial immunosuppression where corticosteroids are combined with another immunosuppressant or targeted therapies directed at the pathophysiology of ICI myocarditis. However, the available evidence to support these novel strategies is limited to observational studies and case reports. The aim of this review is to summarize the literature, guidelines, and future directions on the pharmacological treatment of ICI myocarditis.
19Myocarditis, Myositis, and Myasthenia Gravis Overlap Syndrome Associated with Immune Checkpoint Inhibitors: A Systematic Review.PubMed
Demis N Lipe, Aiham Qdaisat, Pavitra P Krishnamani, et al.
Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment, but their use is linked to immune-related adverse events (irAEs), including the rare ICI-associated myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome. This systematic review aims to highlight MMM's clinical implications in emergency departments. PubMed and Embase were searched using a specific search strategy. Reports were eligible for inclusion if all three conditions were present and associated with the use of an ICI. Data were extracted by independent reviewers using the Rayyan web application for systematic reviews. Descriptive statistics and qualitative synthesis were used to summarize demographic, clinical, and treatment data for the reported cases. Among 50 cases, predominantly associated with melanoma, lung cancer, and renal cancer, the in-hospital mortality rate was 38.0%. The most commonly presenting symptoms were ptosis (58%), dyspnea (48%), diplopia (42%), or myalgia (36%). The median time from ICI initiation to MMM presentation was 21 days (interquartile range: 15-28 days). Corticosteroids were the primary treatment for the irAEs. MMM, a rare but potentially fatal complication of ICI therapy, requires prompt recognition in emergency settings. Corticosteroids should be initiated if suspected, without waiting for confirmation. Multidisciplinary collaboration is vital for diagnosis and treatment planning. Research on MMM's link to specific cancers and ICIs is imperative for better risk assessment and interventions.
20Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.PubMed
Faisal Fa'ak, Maryam Buni, Adewunmi Falohun, et al.
BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).