USE OF INFLIXIMAB IN THE TREATMENT OF IMMUNE CHECKPOINT INHIBITORS-RELATED MYOCARDITIS: A SYSTEMATIC REVIEW OF CASE REPORTS

Immune-mediated myocarditis is uncommon, progresses rapidly and has high mortality rate. Infliximab has been used in practice, particularly in steroid refractory cases, but evidence supporting the use is still lacking. This review aims to provide an overview of infliximab use in managing immune-related myocarditis. A systematic search was conducted using the PubMed and Cochrane Library databases as well as manual searching of bibliographies, from inception to 1 October 2021. Eligible studies were selected by the inclusion criteria


INTRODUCTION
The use of immune checkpoint inhibitors (ICIs) is one of the most significant breakthroughs in cancer treatment over the last decade, and it has dramatically changed the therapeutic landscape for various types of advanced cancers.ICI therapy has been shown to improve cancer patients' clinical outcomes and is generally considered more tolerable than chemotherapy.However, ICIs have been associated with immune-related adverse events (irAEs), which can affect a wide spectrum of organ systems but are most frequently seen in the skin, gastrointestinal tract, lungs and endocrine system (Postow, Sidlow and Hellmann 2018;Raschi et al. 2020).Most of these irAEs are generally mild and manageable.However, some are rare but severe, including cardiac, neurological and musculoskeletal adverse effects (Postow, Sidlow and Hellmann 2018).
Myocarditis is one of the rare but potentially fatal irAEs associated with ICI treatment (Wang et al. 2018).The incidence rates ranged from < 0.1% in pharmaceutical safety databases (Johnson et al. 2016) to 1.14% in a multicentre study (Mahmood et al. 2018), but the mortality rate was reported to be as high as 50%.From 2008 to 2018, the World Health Organization (WHO)'s global database of individual case safety reports (VigiBase) revealed an increase in immune-associated myocarditis cases, with 107 reported cases between 2017 and 2018, compared to 15 reported cases between 2013 and 2016 (Salem et al. 2018).This was likely related to the increased use of immune checkpoint inhibitors and increased recognition of irAEs.
Due to the high mortality, rapid deterioration and increased reporting of immunerelated myocarditis, it is crucial to understand its treatment modalities in order to prevent morbidity and mortality.However, prospective studies specifically investigating the treatment of immune-mediated myocarditis are limited due to the rarity of this adverse effect.Most data are available in the form of case reports or case series, which are devoid of scientific and systematic investigation.Currently, several guidelines (Haanen et al. 2017;Brahmer et al. 2018;Brahmer et al. 2021;Thompson et al. 2022) are available for managing this irAE.However, specific and detailed information of the treatment regimen is still lacking, particularly in steroid-refractory cases and the use of second immunosuppressive therapy such as infliximab.Even though infliximab has been used in steroid-refractory patients (Cautela et al. 2020;Dearden et al. 2021;Lipe et al. 2021;Zhang et al. 2021), the evidence supporting its use is still limited.
The purpose of this study is to review reported cases in which infliximab was used for the management of immune-related myocarditis, with the aim of providing useful information on the clinical characteristics of patients who require and benefit from the therapy, as well as the treatment regime, clinical outcomes and safety concerns associated with its use.

METHODS
This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach (Page et al. 2021).The study selection process is summarised and illustrated in Figure 1.

Search Strategy
A systematic electronic literature search was conducted using the PubMed and Cochrane Library databases to identify published studies reporting the use of infliximab in the treatment of immune checkpoint inhibitor-related myocarditis from inception to 1 October 2021.Three search concepts were used to identify studies: infliximab, immune-related myocarditis and immune checkpoint inhibitors.The language of published literature was not restricted to English when searching in the electronic databases.The search terms used are listed in Appendix 1.Additional potentially eligible publications were identified by screening the bibliographies of selected articles and relevant reviews.If the full text was unavailable, extra effort was made to contact the authors.

Study Selection
The titles and abstracts of the retrieved studies were reviewed and examined for initial inclusion by the first reviewer (CP).Further examination of the full texts was conducted to ensure the studies met the inclusion criteria.The second and third reviewer (BT and SG) performed cross-checking.All the relevant case reports and case series were selected.
Studies were required to meet the following inclusion criteria to be considered eligible.First, research with human subjects; second, data of patients' demographic data, clinical characteristics, treatment and outcome were available; third, patients received immune checkpoint inhibitor(s); forth, immune-related myocarditis was reported as an adverse event and fifth, infliximab was used to treat immune-related myocarditis.
Malay J Pharm Sci, Vol. 22, No. 1 (2024):  Contrarily, studies that fulfilled the specified exclusion criteria, including animal experimental research, cohort studies, case-control studies, cross-sectional studies, randomised controlled trials, post-marketing surveillance studies, republished articles, reviews, editorials, commentaries, presentations of ongoing trials, as well as publications lacking sufficient data of interest, such as demographic characteristics, clinical descriptions, treatment and outcome, were excluded.
In the event of duplication, ambiguity or publications reporting on the same case, the most recent and comprehensive publication was included in the analysis.All disagreements were resolved by discussion and consensus.

Quality Assessment
The methodological quality of publications fulfilling inclusion criteria was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports (Moola et al. 2020) (Appendix 2).Ten case reports and four individual cases from three case series were included in the assessment.Each case was evaluated using the eight items in the instrument, with responses of yes, no, unclear or not applicable.The assessment was performed by the first reviewer (CP) and cross-checked by the second and third reviewers (BT and SG).Cases that met most of the criteria in the checklist were included (Appendix 3).All disagreements were resolved through consensus.

Data Extraction
One of the reviewers (CP) extracted data from the study on patient demographics, clinical descriptions of ICI-associated myocarditis, investigative findings, treatment and outcomes.The second and third reviewers (BT and SG) verified the accuracy of the extracted data.All necessary data for the included studies were extracted from the main texts and supplementary documents and tabulated in a predefined data extraction form.All disagreements were resolved through discussion.

Demographic and Clinical Characteristics
Males and females were equally represented in the 14 studied cases.The mean age of the patients was 67 years old, ranging from 47 years old to 88 years old.Nearly half of them (six patients, 42.9%) had melanoma, two had lung cancer and others had ovarian cancer, renal cancer, urothelial cancer, multiple myeloma, glioblastoma and thymoma, with one respectively.Of these 14 patients, 9 patients had underlying medical conditions.Four patients were reported to have a history of cardiovascular diseases, two denied any history of cardiovascular diseases, one without prior autoimmune disorders, and the remaining two patients denied both histories of cardiovascular diseases and autoimmune disorders.
Most of the patients (11 out of 14) were treated with single immune checkpoint inhibitor, whereas three patients received a combination of nivolumab and ipilimumab.Of these 11 patients, 6 patients (54.5%) received single-agent of nivolumab and 5 patients (45.5%) received pembrolizumab.In most of the patients, the onset of the symptoms occurred early, namely after 1-3 cycles following initiation of ICI therapy.Only two patients reported by Gallegos et al. (2019) and Frigeri et al. (2018) presented the symptoms after 120 days and seven cycles of therapy, respectively.
As shown in Table 2, clinical presentations of the patients were heterogeneous, and the severity ranged from mild such as fatigue, to severe or life-threatening signs and symptoms.Most of the patients showed symptoms consistent with myocarditis, such as dyspnoea, chest pain and palpitation, whereas some patients presented with neuromuscular symptoms predominantly, for instances, myalgia, ptosis and diplopia.Two patients reported non-specific symptoms such as fatigue and generalised weakness.All patients had troponin elevation upon presentation except for the patient reported by Gallegos et al. (2019).Nine of fourteen case reports described the occurrence of the concomitant neuromuscular irAEs, i.e. myositis and/or myasthenia gravis.One patient was reported to develop neuritis four months after recovery from myocarditis (Agrawal et al. 2019).
Of 14 patients, 11 patients were categorised as grade 4 myocarditis according to the grading of the American Society of Clinical Oncology (ASCO) practice guidelines (Brahmer et al. 2018).Only three patients were considered as mild to moderate in severity, with two patients had grade 3 myocarditis and one patient exhibited grade 2 clinical features.Several potentially fatal complications such as arrhythmia, conduction abnormalities, heart failure, respiratory failure and multiple organ failure were reported.Most of the patients developed at least two of these complications, seven of them developed arrhythmia, nine had conduction disorders, nine showed symptoms of heart failure or reduced ejection fraction, four had cardiogenic shock, four developed respiratory failure and three succumbed to multiorgan failure.The complication of respiratory failure observed in the patients was associated with the concomitant immune-related myositis and myasthenia gravis.

Treatment
Steroid was used as first-line therapy in all 14 patients, with variable initial dosing, and the dose was tapered according to clinical response.In most of the patients (11 out of 14), infliximab was given as add-on therapy due to steroid refractory myocarditis and other concomitant non-cardiac immune-related adverse events.One patient was given infliximab for the indication of recurrent myocarditis, whereas another patient received infliximab with concomitant initiation of steroid.No clear indication of infliximab was documented in one reported case following steroid administration.Timing of starting infliximab ranged from 0 day (concurrently with steroid) to 9 days after steroid initiation, with no specific interval documented in five patients.Most of the patients received a dose of 5mg/kg, one patient was prescribed with 10mg/kg for 2 days and the dosage received by two patients was not documented.Most of the patients (10 out of 14) were given a single dose of infliximab, three patients were reported to receive 2 doses and one patient was prescribed with 3 doses.In those patients with multiple doses of infliximab, the second dose was given as early as the next consecutive day, 5 days and 11 days following the first dose, respectively.No specific interval was indicated in one reported case.
In addition to infliximab, the use of at least one of the other immunosuppressive agents was reported in seven patients.These included anti-thymocyte globulin (ATG), mycophenolate mofetil, intravenous immunoglobulin (IVIG) and plasma exchange.The use of anti-thymocyte globulin was reported in two patients following failure of infliximab to improve the clinical condition.Tay et al. (2017) described the successful use of antithymocyte globulin, in contrast, Portolés Hernández et al. (2021) reported a patient who failed to respond after 2 doses of anti-thymocyte globulin.Use of mycophenolate mofetil was documented in two patients.First, in the case reported by Zlotoff et al. (2019), failure of the first dose of infliximab prompted the use of a second dose of infliximab and add-on of mycophenolate mofetil and IVIG.Second, Tay et al. (2017) reported the initiation of mycophenolate mofetil after the patient showed significant improvement with anti-thymocyte globulin, and it was continued for 4 weeks and weaned over 12 weeks.Five authors reported the use of immunoglobulin as an add-on therapy.Plasma exchange was performed in two out of five patients.Shah et al. (2019) reported that plasma exchange and immunoglobulin were added on infliximab therapy following the mild steroid response.In the case presented by Frigeri et al. (2018), plasma exchange and immunoglobulin were initiated before the administration of infliximab.In two cases reported by Saibil et al. (2019) and Fuentes-Antrás et al. (2020), immunoglobulins were given with infliximab when the patients did not respond to steroid therapy.In the case described by Zlotoff et al. (2019), immunoglobulin was administered after initiation of infliximab and mycophenolate mofetil.

Clinical Outcome
Four patients were reported to have improvement clinically or biochemically following infliximab therapy, with reduction or normalisation of troponin, improvement of ECG and resolution of arrhythmia or conduction disorders.All four patients recovered from myocarditis.In contrast, 10 patients showed a lack of improvement or deterioration of clinical condition with the addition of infliximab.
Out of the 14 patients, seven (50%) died from immune-mediated myocarditis and related complications.These patients showed rapid deterioration, developed grade 4 myocarditis and died as early as 7 days and up to 18 days after admission.Complications that contribute to mortality include multiorgan failure, cardiogenic shock, cardiac arrest and respiratory failure.Of note, all these patients did not show significant improvement after receiving infliximab.Interestingly, nearly all of these patients had at least one neuromuscular irAEs concurrently, four developed myositis, one had myasthenia gravis, and one had multiple irAEs consisting of myositis, myasthenia gravis, pneumonitis, hepatitis and thyroiditis.
On the other hand, seven patients survived myocarditis and its complications.Four patients were reported to show clinical and biochemical improvement following treatment of infliximab but three patients did not.However, of the seven survived patients, two patients died later due to cancer progression and development of bacteremia and pulmonary embolism, respectively.

DISCUSSION
The review of 14 cases revealed that most patients developed immune-related myocarditis with a high grade of severity, concomitant irAEs, particularly neuromuscular irAEs and multiple potentially fatal complications.Most of them were treated with a single dose of infliximab, whereas a few only received multiple doses.Only about a quarter of individuals showed clinical or biochemical improvement.Half of the patients did not survive due to myocarditis and its complications.

Steroid Refractory Myocarditis
High-dose corticosteroid is the standard initial treatment once ICI-associated myocarditis is suspected or confirmed (Haanen et al. 2017;Brahmer et al. 2018;Brahmer et al. 2021;Thompson et al. 2022).Several studies (Wang et al. 2017;Mahmood et al. 2018;Zhang et al. 2020) showed that patients who received earlier and higher initial doses of corticosteroid had more favourable outcomes such as less occurrence of major adverse cardiovascular events (MACE) and lower troponin levels.When clinical deterioration occurs despite high dose corticosteroid therapy, treatment should be escalated by adding other immunosuppressants such as infliximab, mycophenolate mofetil, IVIG, and tacrolimus, ATG or plasmapheresis, which may help in the functional improvement and increased survival (Haanen et al. 2017;Brahmer et al. 2018;Brahmer et al. 2021;Thompson et al. 2022).However, there is no clear definition for steroid failure.In general, response to steroids is monitored based on the clinical symptoms and biomarkers such as the resolution of symptoms, normalisation of troponin levels, resolution of ECG abnormality and improvement of ejection fraction.Several studies have shown that corticosteroids alone might not be sufficient to resolve immune-mediated myocarditis, as many patients still developed complications such as malignant arrhythmias and heart failure (Heinzerling et al. 2016;Mahmood et al. 2018).Only about 50% of patients with fulminant myocarditis responded to corticosteroid monotherapy (Agrawal et al. 2019) and up to two-thirds of patients showed reversal of cardiotoxicity due to systolic dysfunction with corticosteroid therapy (Escudier et al. 2017).Literature on the timing of initiation and selection of secondline immunosuppressive therapies is still lacking.In general, most guidelines recommended additional therapies should be considered if patients did not respond to corticosteroid therapy within 24 h (Brahmer et al. 2021;Thompson et al. 2022).Some suggested adding second-line immunosuppressive agents such as mycophenolate mofetil, infliximab or ATG with higher doses of corticosteroid for those with more severe disease (grade 3 to 4) and failed to respond to initial corticosteroid dosing within 3 days to 5 days (Brahmer et al. 2018).

Clinical Characteristics Associated with the Use of Additional Immunosuppressive Therapy
In this review, we found that most of the patients (9 out of 14) treated with infliximab had concomitant neuromuscular irAEs.Approximately 90% of these nine patients had grade 4 myocarditis.Two-thirds of them required at least two additional immunosuppressive treatments following initiation of corticosteroid.This highlighted the severity of the overlap syndrome and it caused the treatment to be more complicated.This finding was consistent with the results from several studies.Power et al. (2020) reported that having one or more concomitant non-cardiac irAE(s) was one of the predictors of steroidrefractory myocarditis, particularly concomitant myasthenia gravis-like syndrome and myositis.In another study, Cautela et al. (2020) reported similar findings, patients requiring intensified immunosuppressive therapy (IIST) were more likely to have other irAEs simultaneously, particularly myositis and myasthenia gravis.Arora et al. (2020) also reported a case series of ICI-associated myocarditis overlapping with neuromuscular toxicities, which presented in severe form and required treatment of multiple immunosuppressant and/or antibody depleting therapies, including infliximab.Other studies also showed that treating patients with multiple irAEs was challenging as these patients tended to have a more severe clinical presentation and are frequently related to poorer outcomes (Safa et al. 2019;Suzuki et al. 2017;Aldrich et al. 2021).
Apart from having concurrent irAEs, we found that most patients who developed complications such as heart failure, conduction abnormalities, arrhythmia, cardiogenic shock and cardiac arrest progressed very rapidly.This was consistent with the findings from a study conducted by Zhang et al. (2021), whereby patients in the infliximab group had more severe myocarditis by ASCO classification and a higher rate of complications such as MACE, ventricular tachycardia and cardiogenic shock compared to those who received corticosteroid alone.
Another potential predictor that is associated with escalation of treatment is troponin level.Power et al. (2020) reported higher initial troponin level was significantly related to steroid failure.Cautela et al. (2020) also revealed that persistently elevated troponin was an indication of intensive immunosuppressive therapy beyond corticosteroid.Similarly, Zhang et al. (2021) found patients in the infliximab group were more likely to have higher troponin levels, which was associated with an increased risk of MACE, compared to those who received corticosteroid alone.Other predictors of using additional immunosuppressive agents include female (Power et al. 2020), higher body mass index (Power et al. 2020), higher initial creatine kinase (Power et al. 2020), prior treatment of combined ICIs (Zhang et al. 2021) and earlier occurrence of myocarditis after ICI administration (Zhang et al. 2021).Due to insufficient data retrieved from the case reports, we cannot conclude whether these factors are associated with the use of add-on immunosuppressants.

Treatment Regime of Infliximab
In most guidelines or consensus, infliximab has been recommended as one of the immunosuppressive agents to be considered if corticosteroid fails to resolve myocarditis (Haanen et al. 2017;Brahmer et al. 2018;Thompson et al. 2022).However, no specific dose, indication of re-dosing and dosing intervals have been recommended.The use of infliximab has been mostly extrapolated from the management of other immune-related adverse events, particularly colitis (Pages et al. 2013;Merrill et al. 2014;Hillock et al. 2017;Nassri et al. 2019).In this review, most patients received a single dose of 5 mg/ kg, whereas few were treated with multiple doses with varying dosing intervals.Limited data showed that a single dose of infliximab 5 mg/kg had been effective and safe in the treatment of ICI-associated myocarditis (Zhang et al. 2021).Timing of starting infliximab following initiation of steroid varied widely, and it was inconclusive whether earlier use of infliximab was associated with better clinical outcomes, particularly in patients showing rapid deterioration of the clinical condition.Similarly, it was also unclear whether multiple doses of infliximab or add-on of other immunosuppressive agents had beneficial effects, especially when initial use of infliximab failed to show improvement.

Clinical Outcome
Consistent with the clinical outcomes from several studies (Cautela et al. 2020;Zhang et al. 2021), our review of 14 reported cases also showed mixed results on using infliximab in treating immune-related myocarditis.Nearly one-third of the patients showed improvement, whereas about two-thirds of them did not improve or deteriorate with addition of infliximab.Half of the patients did not survive from myocarditis and its complications.
The lack of standardised guide to monitor the response of infliximab treatment is another concern.Similar to steroids, monitoring of the response to treatment is generally based on the resolution of clinical symptoms and improvement of biomarkers such as troponin levels.Troponin is deemed as a reliable and early predictor of progression to severe myocarditis and mortality (Sarocchi et al. 2018).In this review, nearly all patients had troponin elevation upon presentation to hospitals; however, the progress of troponin levels following infliximab was not clearly documented.
Compared to the use of infliximab in the treatment of ICI-related myocarditis, research on its use in managing ICI-related colitis is more extensive.However, efficacy data reported in these studies may not be applicable in managing myocarditis.In a study conducted on patients with immune-mediated colitis, the median time to symptoms resolution and total steroid duration were shorter in the infliximab group compared to the corticosteroid monotherapy group (Johnson et al. 2018).In contrary to this, in a study of patients with ICI-myocarditis, Zhang et al. (2021) found that both duration of troponin normalisation and steroid taper were longer in the patients treated with infliximab compared to those treated solely with corticosteroid.This could be explained by higher grade of severity, higher cardiac complication rates and higher troponin levels at admission in the infliximab group.
In a retrospective study conducted by Kadokawa et al. (2021), patients with steroidrefractory immune related colitis responded to infliximab at a median of 18 (range 9-32) days after administration.Even though this finding was derived from patients with immunemediated colitis, few case reports in our review also showed a similar outcome.In a case reported by Padegimas et al. (2019), it took 2 weeks to resolve the ECG abnormalities and 9 months to normalise the troponin levels.In addition to this, several case reports (Haanen et al. 2017;Martinez-Calle et al. 2018;Giancaterino et al. 2020;Portolés Hernández et al. 2021) in this review showed the patients did not survive after receiving infliximab; this could be attributed to rapid deterioration before infliximab showing any positive effects.

Safety of Infliximab
In this review, despite adverse effects were not identified in most of the case reports, there were some safety concerns associated with the use of infliximab.These included the use of infliximab in patients with heart failure as well as increased risk of cardiovascular death, opportunistic infection, pulmonary embolism and hepatoxicity.
Malay J Pharm Sci, Vol. 22, No. 1 (2024):  Few unfavourable reports showed that use of infliximab was associated with heart failure.According to Kwon et al. (2003), infliximab might induce new-onset heart failure or exacerbate existing disease based on the FDA's MedWatch programme adverse events reports of using TNF-alpha antagonists in the treatment of various diseases such as rheumatoid arthritis and Crohn's diseases.Curtis et al. (2007) observed similar findings in their study, which showed an increased relative risk of heart failure among the patients receiving TNF-alpha antagonists for treatment of rheumatoid arthritis and Crohn's diseases, but the results were not statistically significant.On the other hand, Zhang et al. (2021) reported that infliximab improved decompensated heart failure and cardiogenic shock due to ICI-related myocarditis.Similarly, our review also showed the mixed outcome in nine patients who showed signs and symptoms of heart failure upon presentation to the hospital or throughout the clinical course of myocarditis.Of these nine patients, four patients died, whereas five patients survived from myocarditis.Patients showed improvement in ejection fraction after administration of infliximab in the cases reported by Padegimas et al. (2019) (case 2) and Frigeri et al. (2018).On the other hand, Tay et al. (2017), Martinez-Calle et al. (2018), Gallegos et al. (2019) and Portolés Hernández et al. (2021) observed that infliximab treatment resulted in a worsening of heart failure.Gallegos et al. (2019) also reported that a patient who was treated with a higher dose (10 mg/kg) of infliximab for 2 consecutive days concurrently with the initiation of corticosteroid did not show improvement but developed cardiogenic shock and died.According to Chung et al. (2003), high doses (10 mg/kg) of infliximab adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure, increasing the combined risk of death from any cause or hospitalisation for heart failure.It is worth noting that early initiation of infliximab with 5 mg/kg-10 mg/kg dosing may be offered in other grade 4 immune-related adverse events such as colitis, it is however contraindicated in myocarditis patients with moderate-severe heart failure according to ASCO guidelines (Brahmer et al. 2018).
Given the increased risk of heart failure, numerous guidelines and consensus (Brahmer et al. 2018;Palaskas et al. 2020;Brahmer et al. 2021;Thompson et al. 2022) suggested using infliximab with extreme caution in patients with heart failure or reduced ejection fraction and highlighted high doses should be avoided in patients with moderatesevere heart failure.Additionally, it is also crucial for clinicians to be aware of the treatment modalities and their safety considerations in managing this group of patients (Atallah-Yunes et al. 2019).Evidence on the use of other immunosuppressive agents in the treatment of ICI-related myocarditis with the presence of heart failure is also limited.In the unstable patients who do not respond to corticosteroids, ATG, IVIG or plasma exchange can be considered (Wang et al. 2017;Ganatra and Neilan 2018;Kociol et al. 2020).In stable patients who failed to respond to corticosteroids, tacrolimus or mycophenolate mofetil can be considered based on their efficacy in treating cardiac allograft rejection (Kobashigawa et al. 2006;Ganatra and Neilan 2018;Hu et al. 2019).
In a retrospective study conducted by Cautela et al. (2020), the use of infliximab for the treatment of ICI-induced myocarditis was associated with a significantly increased risk of cardiovascular death (OR = 12.0, p = 0.005).Additionally, the authors revealed that patients who received second-line immunosuppressive agents had a greater allcause mortality rate than those treated with steroids alone (50% versus 21%, p = 0.02).This has raised the safety concern of infliximab use as second-line therapy in steroidrefractory myocarditis.However, the result should be interpreted with caution due to the small sample size and absence of a control group in the study design.
Infliximab carries a black box warning of increased risk of opportunistic infection (Janssen Biotech, Inc. 2021) as it has been associated with reports of mycobacterial infections, invasive fungal infections, viral infections as well as bacteraemia (Wolfe et al. Malay J Pharm Sci, Vol. 22, No. 1 (2024):  2004; Koo, Marty and Baden 2010;Ali et al. 2013;Andersen and Jess 2014).Several cases of pulmonary embolism associated with infliximab use were documented (Eklund, Peltomaa and Leirisalo-Repo 2003;Lee and Moosavy 2014;Bala et al. 2020).In this review, Padegimas et al. (2019) reported that a patient died due to bacteraemia and pulmonary embolism.However, there was no clear or direct causal relationship between the incident and the use of infliximab in this patient.Concomitant corticosteroid treatment in this patient also increased the risk of infection and the underlying malignancy was considered a risk factor for developing venous thromboembolism (Biedka, Ziółkowska and Windorbska 2012;Qdaisat et al. 2020).
A rare but significant side effect of infliximab treatment is hepatoxicity (Mancini et al. 2010;Sokolove et al. 2010;Ghabril et al. 2013).The FDA issued a drug warning on the risk of hepatotoxicity in course of infliximab therapy (Janssen Biotech, Inc. 2021).In this review, Fuentes-Antrás et al. (2020) reported a patient who developed grade 4 hepatitis concomitantly with myocarditis.Given the risk of liver injury, infliximab should be best avoided and other immunosuppressants such as mycophenolate mofetil may serve as a better alternative (Thompson et al. 2022;Brahmer et al. 2018;Haanen et al. 2017).

Limitation
Literature on infliximab use in the management of immune-related myocarditis is not extensive and the available studies vary significantly in quality.This review is based on the small number of reported cases.Hence, its generalisability is limited.Due to the retrospective design of case reports, we could not retrieve the missing data to determine the efficacy and safety of infliximab in treating steroid-refractory myocarditis.However, it provides exploratory data and raises some safety concerns on the use of infliximab.In addition, few cases were reported using multiple immunosuppressive agents, which could add to the difficulties in interpreting the response to infliximab.Adverse effects associated with infliximab use were not reported in most of the case reports.Thus, we do not have sufficient data to discuss drug safety issues.

CONCLUSION
Concomitant irAEs, high grade of severity and presence of potentially fatal complications are the indicators of escalating the immunosuppressive therapy.Infliximab may be considered an option, however, there is no standardisation on the treatment regime, and the outcome was inconsistent.Safety data on infliximab use is scarce and should be avoided in patients with heart failure.Due to the rarity of this irAE, our knowledge of the use of infliximab in managing immune-related myocarditis is still restricted to the data from case reports, case series and retrospective studies.From this review, we learned that the rates of mortality and complications remain high despite the use of multiple immunosuppressive drugs.Hence, it is crucial to identify the patients with more severe myocarditis as corticosteroid therapy alone may not be sufficient and these patients may require more intensive immunosuppressive therapy.This can be achieved by standardising therapeutic strategies and adopting a multidisciplinary approach in managing immune-related myocarditis.We hope this review provides the groundwork for further studies to further explore the use of immunosuppressive agents in the treatment of ICI-associated myocarditis.

Figure 1 :
Figure 1: PRISMA flowchart of the study selection process.

Table 1 :
Demographic characteristics and clinical descriptions of the 14 reported cases of ICI-related myocarditis treated with infliximab.

Table 2 :
Clinical descriptions of the 14 reported cases of ICI-related myocarditis treated with infliximab.

Table 3 :
Treatment and outcome of the 14 reported cases of ICI-related myocarditis treated with infliximab.

APPENDIX 3: METHODOLOGICAL QUALITY ASSESSMENT OF THE RETRIEVED STUDIES BASED ON JBI CRITICAL APPRAISAL CHECKLIST FOR CASE REPORTS
Abbreviations: Y = Yes, N = No, UC = Unclear