Introduction

Immune checkpoint inhibitors (ICIs) are a class of monoclonal antibodies that interact with the programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) molecular pathways to enhance T cell-mediated antitumor effects [1]. With the application of ICIs over the last decade, immune-related adverse events (irAEs) have increased, such as myocarditis [2,3,4,5,6].

According to the recommendations of the European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC) and National Comprehensive Cancer Network (NCCN), ICIs need to be discontinued in moderate and severe cases [2, 7,8,9]. For moderate cases, 1 to 2 mg/kg prednisone is recommended as first-line therapy [2, 7,8,9]. In patients without an immediate response to intravenous steroids, a pulse-dose of corticosteroid (methylprednisolone 500–1000 mg/day) should be considered [9, 10]. Due to the treatment of steroid, nearly 50% of patients with myocarditis can be improved without use of additional immunosuppressive drugs [11,12,13]. While remaining patients may be diagnosed with steroid-refractory myocarditis after receiving at least 3 days of adequate steroid treatment on the basis of one of the following situations [2, 7, 10, 11, 14]: (1) troponin T does not significantly decrease (decrease < 50% of the peak); (2) atrioventricular block, ventricular arrhythmia, or left ventricular dysfunction still persists; (3) after normal reduction of steroid, cardiac biomarkers or symptoms worsen. Other immunosuppressive drugs, such as mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIG) or specific cytokine inhibitors (infliximab or tocilizumab), are considered for patients who are severe (grade 3 or grade 4) or refractory to steroid [2, 7,8,9, 15,16,17,18,19,20]. In recent cases, specific cytokine inhibitors showed potential effects on irAEs [21]. However, guidance for irAEs management is based on case reports that lacked of cytokine monitoring [7, 21]. Therefore, the personalized anti-cytokine strategies remain unclear.

Here, we report two cases and present a literature review of steroid-refractory myocarditis induced by ICI. The two cases with elevated TNF-α level benefited from infliximab. In this review, we discussed a potential personalized anti-cytokine strategy that considered the levels of the inflammatory cytokines IL-6 and TNF-α. This study complied with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of West China Hospital (No. 2024-197). Written informed consent was obtained from the patients for publication of this case report and any accompanying images. We present this article in accordance with the CARE reporting checklist.

Case Presentation

Case 1

A 62-year-old male (height: 165 cm; weight: 65 kg), with a history of hypertension, diabetes and an allergy to sulfanilamide, was diagnosed with lung squamous cell carcinoma (cT4N2M0, stage IIIB) in June 2020. The patient had been treated with amlodipine besylate (10 mg/day), glimepiride (2 mg/day) and metformin hydrochloride (2000 mg/day) for 5 years and was subsequently treated with pembrolizumab plus carboplatin and paclitaxel without radiotherapy. Two weeks after 2 cycles of ICIs combination treatment, the patient presented to the emergency department with dizziness, bilateral ptosis and eye movement disorders. Physical examination did not reveal lower-extremity swelling or jugular vein distention bilaterally. An initial examination revealed that levels of serum troponin T, creatine kinase-myocardial band and myoglobin were elevated at 442.1 ng/L (reference value: 0–14.0 ng/L), 75.21 ng/mL (reference value < 4.94 ng/mL) and 892.3 ng/mL (reference value: 28.0–72.0 ng/mL), respectively. The level of N-terminal pro-B-type natriuretic peptide (BNP) was normal (40.00 ng/L, reference value: 0–227.00 ng/L). Echocardiography revealed normal left systolic function (ejection fraction, 68%) without wall motion abnormalities. Electrocardiogram and coronary contrasted computed tomography (CT) did not show abnormalities. The patient denied any family history of autoimmune rheumatic diseases. The diagnosis of ICI-induced myocarditis (grade 3) was considered according to recent usage of ICIs. Repetitive nerve stimulation decreased the amplitude by 77%. The acetylcholine receptor (AchR) antibody was positive (1.526 nmol/L), and myositis-myasthenia gravis overlap syndrome was diagnosed.

Consequently, pembrolizumab was discontinued, and the patient was treated with respiratory support, cardiac monitoring and methylprednisolone (80 mg/day) immediately. While aggravated clinical symptoms and increased troponin T level even reached a maximum value of 934.0 ng/L on day 9, the patient was treated with pulse-dose methylprednisolone (500 mg/day) for 7 days (Fig. 1A). Heart failure due to steroid-related fluid retention, pulmonary embolism or infection was excluded after symptoms of dizziness and bilateral ptosis without chest pain, elevated body temperature or lower-extremity swelling were observed. BNP, echocardiography, chest CT and respiratory pathogen panels revealed no significant abnormalities. Owing to the rapid increase in troponin T after the discontinuation of pulse-dose steroids, he was diagnosed with steroid-refractory myocarditis induced by ICI and treated with IVIG (20 g/day) and MMF (1,000 mg/day) for 6 days. On day 23, symptoms persisted and a high troponin T level (561.9 ng/L) was maintained. Laboratory examination revealed an elevated TNF-α level (40.9 pg/ml, reference value < 8.1 pg/ml) and decreased IL-6 level (< 1.5 pg/ml, baseline level: 4.74 pg/ml, reference value: 0-7 pg/ml), and infliximab (at a dose of 200 mg per 2 weeks) was administered (Fig. 1B). Symptoms of ptosis and eye movement disorders gradually disappeared, and the troponin T level gradually decreased to 487.9 ng/L on day 35. Oral prednisone (50 mg/day, with gradually decreasing doses) was maintained. The second and third infusions of infliximab were administered on days 37 and 64, respectively.

Fig. 1
figure 1

Timeline of major events in Case 1 (Patient No. 11). A The main treatment for Case 1 (Patient No. 11) who presented with symptoms of myocarditis. B Levels of inflammatory cytokine Inflammatory cytokine levels (TNF-α and IL-6) of Case 1 (Patient No. 11) during the treatment. The red line represents the dose of steroids used during the patient's treatment. The blue line represents the troponin T level during the patient's treatment. The green block represents the MMF treatment. The yellow block represents the IVIG treatment. The pink arrow represents the IFX treatment. ①, ② and ③ represent the first, second and third infusions of IFX, respectively. The dark green line represents IL-6 levels during the treatment. The purple line represents the TNF-α levels during the treatment. Steroid: including methylprednisolone sodium succinate, methylprednisolone, oral prednisone. TNF-α tumor necrosis factor-α, IL-6 interleukin-6, IVIG intravenous immunoglobulin, MMF mycophenolate mofetil, IFX infliximab

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At the five-month follow-up, the patient was alive, with a troponin T level of 34 ng/L, and did not experience any recurrence of adverse cardiac events or myositis. CT scan revealed significant regression of the primary tumor > 30% reduction, and the therapeutic evaluation indicated partial response (PR) (Fig. 2A, B). Unfortunately, progressive disease of the primary tumor was detected via CT scan in February 2022 (Fig. 2C). He subsequently received carboplatin and paclitaxel. Chest CT revealed progression of the pulmonary lesions, which were 7.2 × 3.3 cm in size (Fig. 2D). Thereafter, the patient received 3 cycles of gemcitabine and cisplatin and 25 cycles of thoracic radiation without an increase in troponin T.

Fig. 2
figure 2

Dynamic imaging of thoracic computed tomography (CT) scan of a patient with lung squamous cell carcinoma (Case 1, Patient No. 11). A The primary tumor was 10.3 × 5.2 cm in size before the patient received immunotherapy in July 2020. B The primary tumor with unmeasurable tumor size after the patient received three doses of infliximab in November 2020. C The primary tumor was 3.0 × 1.9 cm in size before the patient received chemotherapy in February 2022. D The primary tumor was 7.8 × 3.2 cm in size after three cycles of gemcitabine and cisplatin-treated with the patient in November 2023. The white arrow in the figure highlights the area of the primary tumor

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Case 2

A 57-year-old female (height: 155 cm; weight: 62.5 kg), without a history of coronary disease, chronic heart disease, autoimmune rheumatic diseases or allergies, who presented with right-sided chest pain, was diagnosed with lung adenocarcinoma (cT4N2M1a, stage IVA, EGFRL858R) in September 2022. After resistance to icotinib, the patient was treated with SHR-1701(anti-PD-L1/TGF-βR fusion protein) plus carboplatin and paclitaxel. Prior to receiving the fourth cycle, she presented with a one-week symptom of dyspnea. A physical examination did not reveal lower-extremity swelling, jugular vein distention or rales in her lower lung lobes bilaterally. An initial examination revealed the levels of troponin T and creatine kinase-myocardial band were elevated at 299.5 ng/L (reference value: 0–14.0 ng/L) and 77.92 ng/mL (reference value < 2.88 ng/mL), respectively, whereas BNP was normal (236.00 ng/L, reference value: 0–334.00 ng/L). Echocardiography revealed an enlarged left atrium, a thickened interventricular septum, a widened ascending aorta, pulmonary artery, and the ejection fraction mildly decreased from 73 to 63%. Coronary contrasted CT did not show any abnormalities in the coronary arteries. The diagnosis of ICI-induced myocarditis (grade 3) was considered.

Consequently, SHR-1701 was discontinued, and the patient was treated with methylprednisolone (80 mg/day for 9 days, with gradually decreasing doses) (Fig. 3A). After the symptom of dyspnea resolved and troponin T level gradually decreased to 123.2 ng/L, she was discharged on day 10. However, she returned on day 16 for severe dyspnea and chest tightness with increased troponin T (210.0 ng/L, reference value: 0–14.0 ng/L), no signs of lower-extremity swelling or jugular vein distention. She was diagnosed with steroid-refractory myocarditis induced by ICI according to a nonsignificant reduction in troponin T after adequate steroid for 16 days. Primary cardiac diseases and serious infections were excluded according to the examination including the electrocardiogram, serological respiratory pathogen panel and chest CT. She was treated with pulse-dose methylprednisolone (500 mg/day) for 3 days, MMF (1,000 mg/day) for 11 days and IVIG (20 g/day) for 3 days. The patient's dyspnea has not been relieved and the level of troponin T was 169.1 ng/L. Laboratory testing revealed an increasing trend of TNF-α (1.2 pg/ml, baseline level: 0.72 pg/ml, reference values < 8.5 pg/ml) and a decreasing trend of IL-6 (< 1.5 pg/ml, baseline level: 6.81 pg/ml, reference value: 0–7.0 pg/ml) (Fig. 3B). Infliximab (at a dose of 200 mg per 2 weeks) was administered on day 31. Oral prednisone (50 mg/day, with gradually decreasing doses) was maintained. The second and third infusions of infliximab were administered on days 45 and 73, respectively.

Fig. 3
figure 3

Timeline of major events in Case 2 (Patient No. 12). A The main treatment for Case 2 (Patient No. 12) who presented with symptoms of myocarditis. B Levels of inflammatory cytokine (TNF-α and IL-6) of Case 2 (Patient No. 12) during the treatment. The red line represents the dose of steroids used during the patient's treatment. The blue line represents the troponin T level during the patient's treatment. The green block represents the MMF treatment. The yellow block represents the IVIG treatment. The pink arrow represents the IFX treatment. ①, ② and ③ represent the first, second and third infusions of IFX, respectively. The dark green line represents IL-6 levels during the treatment. The purple line represents the TNF-α levels during the treatment. Steroid: including methylprednisolone sodium succinate, methylprednisolone, oral prednisone. TNF-α tumor necrosis factor-α, IL-6 interleukin-6, IVIG intravenous immunoglobulin, MMF mycophenolate mofetil, IFX infliximab

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At the five-month follow-up, the patient denied any episodes of chest tightness or dyspnea. The efficacy evaluation was PR based on the image of CT scan (Fig. 4A, B). She subsequently started pemetrexed, carboplatin and bevacizumab for antitumor therapy.

Fig. 4
figure 4

Dynamic imaging of thoracic CT scan of a patient with lung adenocarcinoma in Case 2 (Patient No. 12). A The primary tumor was 7.9 × 4.0 cm in size before the patient received immunotherapy in March 2023. B The primary tumor was 5.4 × 4.5 cm size after three doses of infliximab in August 2023. The white arrow in the figure highlights the area of the primary tumor

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Discussion

We reported two cases of steroid-refractory myocarditis induced by ICI that were not affected by immunosuppressant drugs such as IVIG and MMF. Considering the elevated TNF-α and lower IL-6 levels, patients were treated with the personalized anti-cytokine inhibitors of infliximab. After three cycles of infliximab treatment, our patients’ symptoms resolved, and the troponin T and TNF-α levels gradually returned to normal. Infliximab as a potential strategy could be considered for patients with low IL-6 level and elevated TNF-α level.

A previous study reported that the incidence of cardiotoxicity caused by paclitaxel was nearly 0.5% within 1 h to 14 days following therapy [22]. The events that were most commonly reported were decreases in heart rate and blood pressure, whereas myocarditis was rare [22]. In addition, several cases reported that myocarditis occurred during the administration of ICI combination with carboplatin/paclitaxel [23,24,25]. Moreover, randomized controlled trials and retrospective studies have indicated that the use of ICI alone or ICI plus chemotherapy resulted in greater risk of cardiotoxicity than chemotherapy alone [26, 27]. On the basis of previous studies and the clinical course, we consider that our patients had ICI-induced myocarditis and the combination of ICI and chemotherapy may increase the risk of myocarditis. ICI-induced myocarditis is rare and fatal, with a reported incidence of 0.06–1.00% and a maximum fatality rate of 37% [2,3,4,5, 28]. Most cases occur after the first or second ICI infusion, with a median duration of 30 days [29]. However, the exact mechanism remains unclear, and further evidence is needed. The PD-1/PD-L1 and CTLA-4 signaling pathways were shown to play key roles in protecting the myocardium from excessive immune responses [30,31,32]. This effect is likely associated with a systemic inflammatory response with increased levels of cytokines [33, 34]. Recent studies have demonstrated that increased IL-6 and decreased PD-1 levels lead to decreased regulatory T cell (Tregs) with an aggravated inflammatory response [35,36,37,38,39,40]. Several studies have suggested that TNF-α, IL-6, interferon (IFN)-γ and C-reactive protein should be used as monitoring indicators to detect and manage cytokine release syndrome (CRS) induced by immunotherapy [34, 41,42,43,44]. Endomyocardial biopsy and autopsy results from multiple series revealed more PD-1− CD4+ T cells, PD-1− CD8+ T cells, inflammatory macrophages and less Treg infiltration (Table 1) [16, 18, 19, 32, 35, 45,46,47,48,49,50].

Table 1 Levels of cytokine and autopsy or biopsy results in patients treated with infliximab or tocilizumab
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We conducted a comprehensive literature search of PubMed and Embase for cases of steroid-refractory myocarditis induced by ICI. Patients with “steroid-refractory myocarditis induced by ICI” were defined as those who were refractory to steroid with a new diagnosis of ICI-induced myocarditis. We used the following keywords to search for articles in PubMed and Embase: “pembrolizumab”, “nivolumab”, “ipilimumab”, “atezolizumab”, “tislelizumab”, “durvalumab”, “avelumab”, “tremelimumab”, “sintilimab”, “toripalimab”, “cemiplimab”, “PD-1/PD-L1 inhibitors”, “anti-CTLA4 antibody”, “immune checkpoint inhibitor”, “ICI”, “immunotherapy” and “myocarditis”. A total of 76 cases were initially selected; 23 cases were excluded because of the unjustifiable use of steroid and immunosuppressive drugs (n = 6), lack of treatment with other immunosuppressive drugs (n = 9) or lack of detailed case presentation (n = 8). Ultimately, we reviewed 53 cases of steroid-refractory myocarditis induced by ICI including 2 cases in our hospital and 51 cases in literatures [11, 12, 16,17,18,19, 45,46,47,48, 51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] in Table 2.

Table 2 Case reports and retrospective series of patients diagnosed with steroid-refractory myocarditis induced by ICI
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In previous cases and studies, 53 patients who were diagnosed with steroid-refractory myocarditis, 45.5% (10/22) of patients benefited from immunosuppressive drugs (IVIG, MMF, plasmapheresis or tacrolimus), and 71.4% (15/21) of patients benefited from infliximab. Three patients were treated with tocilizumab, and 7 patients received abatacept, alemtuzumab or rituximab. A summary of these cases is provided in Table 2. Recently, an international multicenter retrospective observational study showed that early and high-dose steroid treatment can mitigate myocardial injury and reduce the risk of cardiac adverse events [76]. Studies have suggested that earlier initiation of other additional immunosuppressive drugs combined with initial high-dose steroid may reduce the total duration of steroid exposure and may not decrease the efficacy of ICI [12, 77, 78]. Compared with immunosuppressive drugs, specific cytokine inhibitors, such as infliximab and tocilizumab, have demonstrated better therapeutic efficacy in resolving steroid-refractory myocarditis induced by ICI in previous studies (Table 2). However, patient No.17 deteriorated progressively and succumbed to multiple organ failure with infliximab. The case proposed prompt tocilizumab treatment in addition to steroid for patients on the basis of elevated serum levels of IL-6 and normal TNF-α [16]. Therefore, we aimed to investigate the clinical characteristics and inflammatory cytokine levels of patients to predict the effects of infliximab or tocilizumab (Table 1). A summary of IL-6 and TNF-α in the serum is provided (Fig. 5A, B).

Fig. 5
figure 5

Changes in inflammatory cytokines (TNF-α and IL-6) in patients No. 11, No. 12, No. 17, No. 20, and No. 22. A Levels of TNF-α in patients during the process of myocarditis. B Levels of IL-6 in patients during the process of myocarditis. The horizontal axis represents the time point at which the patient was tested for TNF-α/IL-6. The vertical axis represents the level of TNF-α/IL-6. Initial: the level of TNF-α/IL-6 when the patient was tested for the first time. Top: the top level of TNF-α/IL-6 during the process of myocarditis. After: the level of TNF-α/IL-6 when patient with normal troponin T. TNF-α tumor necrosis factor-α, IL-6 interleukin-6

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The patients were divided into two groups (Group I and Group II) according to their levels of IL-6 and TNF-α (No. 11 and No. 12.; No. 17, No. 20 and No. 22). In Group I, patients No. 20 and No. 22 had elevated levels of IL-6 and TNF-α. Patient No. 17 had elevated levels of IL-6 and stable TNF-α. In Group II, patients No. 11 and No. 12 were characterized by decreasing trend in IL-6 and an increasing trend in TNF-α. Patients No. 20 and No. 22 in Group I improved from tocilizumab, and the patients in Group II benefited from infliximab. It seems that infliximab is effective in patients with elevated TNF-α levels but not in those with elevated IL-6 levels. Tocilizumab is more likely suitable for patients with elevated IL-6 level and elevated/lower TNF-α level.

Infliximab (anti-TNF-α Ab), the first monoclonal antibody that blocks TNF/tumor necrosis factor receptor (TNFR)-1 signaling, reverses CD8+T-cell dysfunction and decreases the levels of proinflammatory cytokines produced by fibroblasts, leading to the amelioration of myocardial injury and improved antitumor immunity [79,80,81,82]. Zinc finger (de)ubiquitinating enzyme A20/TNF-α-induced protein 3 (TNFAIP3) is associated with autoinflammation and autoimmunity by controlling nuclear factor-κB (NF-κB) activity [83]. We reviewed 21 patients who were treated with infliximab, 5 (23.8%) of whom died from cardiovascular events. The dose of 10 mg/kg of infliximab is likely harmful in patients with class III-IV heart failure and should be avoided [13, 84, 85]. Given that the use of infliximab in patients with heart failure is controversial, we discussed the patients grouped by heart failure status. Cardiovascular-related mortality was greater in patients with heart failure, while the difference was not statistically significant (33.3% vs. 25.0%, P > 0.05). Short-term infliximab may not adversely affect the clinical condition of these patients [85, 86]. Prior studies suggested that optimized infliximab treatment (5 mg/kg) reduces inflammatory activity and was safe without worsening prevalent heart failure in patients with colitis, ICI-induced myocarditis, rheumatoid arthritis and refractory cardiac sarcoidosis [12, 87,88,89,90]. In a recent study, 4 patients with severe steroid-resistant colitis who received infliximab and ICI therapy improved, and disease stability [87]. This effect was related to preventing the activation-induced death of tumor-infiltrating lymphocytes induced by anti-PD-1 therapy and decreasing the expression of PD-L1 and TIM-3 [91]. Thus, low-dose infliximab seems safe and effective for ICI-induced myocarditis in prior studies and in our cases. Since the patients were diagnosed with serve myocarditis (grade 3 or grade 4), immunotherapy was discontinued according to the guidelines of the ASCO, NCCN, ESMO and SITC [2, 7,8,9].

Tocilizumab (anti-IL-6 receptor Ab), a humanized anti-human IL-6 receptor monoclonal antibody, has been successfully used to treat CRS associated with ICI-induced myocarditis [17,18,19]. Previous studies have indicated that targeting IL-6R could be an effective and safe approach for treating several types of irAEs without severe adverse events or hindering antitumor immunity [92,93,94]. Mechanistically, combined blockade of the IL-6 and PD-1/PD-L1 signaling pathways can regulate immunosuppressive activities and enhance antitumor effects, especially the Th1 response in tumor-bearing mice [95]. Clinical trials (NCT04940299 and NCT03999749) to evaluate the safety and efficacy of tocilizumab in combination with ICIs are currently underway [96, 97]. It has been confirmed that tocilizumab decreases the levels of the inflammatory cytokines TNF-α and IL-1β and the infiltration of CD3+ T cells and CD68+ macrophages by blocking signaling pathways [98, 99]. Therefore, tocilizumab is effective in patients with high levels of IL-6 and TNF-α. On the basis of these findings, considering the levels of inflammatory cytokines (TNF-α and IL-6) is a potential personalized cytokine inhibitor strategy.

Our study shows that cytokine inhibitors combined with the level of cytokines have the potential to benefit patients. A limitation of our review should be noted. The majority of the clinical information was based on case reports, and more cases and studies need to be conducted to verify and confirm the efficacy of these treatments in the future. In addition, owing to the retrospective study, the data of cytokines was uncompleted, and standardized and dynamic monitoring of cytokine changes is essential in the further study.

Conclusions

Infliximab shows therapeutic effects for selected patients with steroid-refractory myocarditis induced by ICI. The serum levels of cytokine, including IL-6 and TNF-α, have potential value in guiding the selection of cytokine inhibitors.