Risk elements and diagnostic indicators for asymptomatic immune checkpoint inhibitor-associated myocarditis in esophageal cancer

Abstract

This article pertains to the study by Liu et al. Myocarditis caused by immune checkpoint inhibitors in patients with esophageal cancer is a concerning issue. This was found to be linked by increased levels of creatine kinase (CK) and CK isoenzymes, as well as older age and male gender. All these risk factors behind this phenomenon, which could be incorporated into a unified prediction model, have been briefly discussed. Several recommendations have been made to validate this prediction model for use in different clinical scenarios.

Key Words: Myocarditis; Immune checkpoint inhibitors; Esophageal cancer; Immunotherapy; Risk factor

Core Tip: Immune checkpoint inhibitors, which play a significant role in esophageal cancer therapy, can cause myocarditis in these patients. Several risk factors, such as advanced age, male sex, elevated creatine kinase (CK) and CK isoenzymes, contribute to this phenomenon. All these indicators can be combined into a single model to aid in early detection and personalized risk management. Prospective cohort studies with large sample sizes should be conducted, utilizing modern imaging modalities like magnetic resonance imaging.

TO THE EDITOR

We read with delight the retrospective study by Liu et al[1]. The authors of this letter largely agree with their uniform prediction model, but they suggest several additional factors that can be considered to improve its effectiveness in different clinical scenarios.

Esophageal cancer is a significant global health concern with a mortality rate that varies between 15% and 20%, ranking it fourth among all cancer-related deaths[2]. Immune checkpoint inhibitors (ICIs) have shown clinical efficacy in treating esophageal cancers across multiple cancer types. It is widely regarded as the fifth pillar of cancer treatment, alongside surgery, chemotherapy, radiation, and molecular targeted therapies[3,4]. However, it does not come without complications. Over 70% of cancer patients treated with ICIs suffered from immune-related adverse events (irAEs) in the heart, lung, liver, gut, and skin. Myocarditis in ICI-treated cancer patients is an uncommon irAE but devastating, with a 40% reported fatality rate[5].

According to Liu et al’s study[1], male sex, and age were important risk factors for myocarditis development. Myocardial reserve and renewal capacity diminish with advanced aging, possibly contributing to immune-mediated myocardial injury. Males are twice as afflicted by this condition as females due to sex-based differences in immune response strength and genetic predisposition. This sex-based difference in myocardial inflammation may be associated with sex hormones. In males, testosterone increases the proinflammatory M1 macrophage response, though females have a significant M2 macrophage response, which reduces the inflammatory effect[6,7]. Liu et al[1] has done a highly commendable job by showing that all these risk factors [age, sex, creatine kinase (CK) and CK isoenzymes (CK-MB)] alone are low [are under the receiver operating characteristic curve (AUC) = 0.579-0.608], whereas their combination in the prediction model improves diagnostic efficacy (AUC = 0.808). A recent study by Nielsen et al[8] has found 0.24% incidence of ICI-induced myocarditis, whereas Liu et al[1] showed quite high myocarditis incidence (33.66%), which is a striking feature.

Nevertheless, some concerns remain. First, this study did not use cardiac magnetic resonance imaging (MRI) as an imaging method, which may have overlooked many subclinical myocarditis cases. Cardiac MRI is better suited for diagnosing acute myocarditis, mainly because of its ability to perform dual analysis both functional and tissue and because it is noninvasive. Regarding the possible structural alterations, like dilation of the heart chambers, and thus the study of the ejection fraction, MRI finds its proper place. Echocardiography is also sensitive to these changes, but with lesser precision than MRI, particularly while analyzing the kinetics of the inferolateral region, which is the predominant damaged area of myocarditis[9]. Because of its remarkable spatial resolution, cardiac MRI can identify whether the afflicted myocardium is primarily epicardial or endocardial in location, and whether its myocardial delayed enhancement pattern fits in with a specific coronary vascular area. It can detect small, patchy areas of myocardial damage, while echocardiography is a less precise method that depicts the damage that happens after the insult[10]. Endomyocardial biopsy, considered the diagnostic gold standard in myocarditis, is accompanied by sampling errors due to localized involvement of the myocardium, reducing its diagnostic sensitivity. In that case, cardiac MRI with contrast combined with cine-MRI can be used as an alternative to endomyocardial biopsy[11]. However, when a patient has suspected myocarditis, an MRI should be done as soon as feasible because the diagnostic sensitivity is at its peak 2 to 4 weeks after the onset of symptoms. Myocardial edema, which is a hallmark early sign of acute myocarditis, normally resolves over days to weeks and can be missed if cardiac MRI is conducted late after symptom onset[12,13].

Secondly, the role of genetic factors behind autoimmune processes is highlighted by familial aggregation, the existence of antibodies to cardiac antigens, the relationship of human leukocyte antigen (HLA) with dilated cardiomyopathy (DCM) and antibodies, and aberrant expression of HLA class II on cardiac endothelium. Individuals with HLA-DR4/DR1 and HLA-DQ1, DQ5 have been found to have a higher risk of myocarditis, DCM, or both[14,15]. Because myocarditis is heterogeneous in origin, it is probable that HLA-DQ8 may predispose females to myocarditis and DCM, whereas males may acquire DCM owing to viral etiology, which is more often associated with other HLA molecules. DQ8 can positively select autoreactive T cells that can be expressed in the heart or in the periphery. When these activated autoreactive T cells get to the heart, an inflammatory scenario ensues due to chemokines and cytokines, thus intensifying the inflammatory loop[15,16]. Liu et al’s study did not shed light on the genetic predisposition[1].

Third, the study did not give longitudinal follow-up data. ICI-induced myocarditis clinical courses are extremely variable, and it may take days for laboratory patterns to develop. Although myocarditis mostly arises immediately after commencing ICI therapy, delayed ICI myocarditis can also happen. Moreover, late-onset ICI-induced myocarditis is associated with long-term survival. Long-term monitoring is therefore required[17,18].

Fourth, there was no mention of the exact ICI dosage or duration. As a result, it could not yield a dose-exposure dependence picture of ICI-induced myocarditis. Nevertheless, this study has done an impressive job developing a unified prediction model that includes risk factors for early detection and specific risk management of ICI-induced myocarditis. All older male esophageal cancer patients with elevated CK-MB and CK levels might benefit from cardiovascular monitoring and personalized immunotherapy, which could ultimately improve clinical decision-making. Multicenter and large-sample prospective cohort studies are necessary to validate their effectiveness and expand their usefulness across different clinical settings. Future research should utilize advanced imaging techniques to diagnose myocarditis and explore whether cytokines can serve as disease risk predictors or biological markers in the development of ICI-induced myocarditis.