Darllen yn Gymraeg / Read in English

---

Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi infliximab i drin llid difrifol neu sy'n bygwth bywyd yng nghyhyr y galon (myocarditis) a achosir gan feddyginiaethau a elwir yn atalyddion pwynt gwirio imiwnedd. Mae atalyddion pwynt gwirio imiwnedd yn feddyginiaethau sy'n trin canser trwy ysgogi'r system imiwnedd. Dim ond pan nad yw triniaeth â dosau uchel o steroidau wedi gweithio y gellir defnyddio infliximab i drin y math hwn o myocarditis.

Bydd infliximab ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.

Nid yw infliximab wedi'i drwyddedu i drin myocarditis, felly gelwir ei ddefnyddio i drin myocarditis yn ddefnydd "oddi ar y label". Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.

Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.

I gael rhagor o wybodaeth am imiwnotherapi ag atalyddion pwynt gwirio imiwnedd, ewch i: Cancer Research UK - checkpoint inhibitors (Saesneg yn unig)

 

---

What did the One Wales Medicines Assessment Group decide?

Infliximab can be given to treat severe or life-threatening inflammation of the heart muscle (myocarditis) caused by medicines called immune checkpoint inhibitors. Immune checkpoint inhibitors are medicines that treat cancer by stimulating the immune system. Infliximab can only be used to treat this type of myocarditis when treatment with high doses of steroids has not worked.

Infliximab will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.

Infliximab is not licensed to treat myocarditis, so using it to treat myocarditis is called “off-label” use. When a medicine is used “off-label”, your doctor must clearly explain to you the risks and benefits of taking the medicine. Your doctor should give you clear information, talk with you about your options and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines.

The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.

For more information about immunotherapy with immune checkpoint inhibitors visit: Cancer Research UK - checkpoint inhibitors

Medicine: infliximab

Indication: treatment of grade 3–4 steroid-refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy

Meeting date: 11 August 2025

Criterion: Clinical effectiveness and safety

OWMAG note that there is limited clinical evidence available for infliximab for the treatment of grade 3–4 steroid-refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy and that no randomised controlled trials or comparative studies were identified. Evidence comes from systematic reviews, retrospective case series and case reports plus some real-world outcomes for [confidential information removed] patients with this condition treated with infliximab in NHS Wales. OWMAG acknowledge the paucity of data to inform comparisons between different second-line immunosuppressive therapy options for this indication. Taking the evidence as a whole, OWMAG note that just over half of patients (where an outcome was reported) showed a clinical response to infliximab, just over a quarter required additional immunosuppressants after infliximab and just under a quarter had no improvement in their myocarditis symptoms after treatment with infliximab. OWMAG note the limitations of the evidence and acknowledge that case reports are generally the lowest grade of evidence as they may be subject to selection bias, are difficult to compare, involve small patient numbers, differ in the amount of clinical information given and the outcomes reported, and so may not be generalisable to patients with this condition in Wales. They note that many of the case reports were for patients with multiple ICI‑induced toxicities, which may have affected clinical outcomes, that many patients were treated with multiple immunosuppressive agents in addition to steroids making the relative benefit of infliximab difficult to ascertain, and that in some cases infliximab was given in circumstances not reflective of clinical practice in Wales. OWMAG acknowledge that published clinical guidelines, which mainly considered the same published clinical evidence, differ in their recommended second-line options, none of which are licensed for this indication in the UK. OWMAG note that all guideline recommendations on treatment options are based on low-quality evidence, mainly derived from clinical expert opinion and that clinical opinion can also be informed by preference and experience of using specific treatments. OWMAG note the evidence provided by clinical experts, both in the evidence summary report (ESR) and at the meeting, who report that patients who do not respond to intravenous corticosteroid treatment within 1–3 days require prompt and effective treatment with an additional immunosuppressant to prevent further deterioration. Current treatment options used in NHS Wales include mycophenolate mofetil (MMF) and tacrolimus. However, MMF takes a couple of weeks to have a clinical effect and tacrolimus requires extensive monitoring during dose titration, which is resource intensive and turnaround times may be up to a few days. Clinicians in Wales report they have experience and familiarity with using infliximab for myocarditis and some other ICI-induced toxicities and have had experienced positive clinical outcomes for the treatment of myocarditis with infliximab. Infliximab is fast‑acting and does not require additional monitoring. OWMAG note that currently clinicians have to request infliximab on an individual patient basis through local processes which takes time and clinical resource; this can cause delay in initiating treatment and can be detrimental to patient outcomes as patients with this condition can deteriorate rapidly and prompt appropriate treatment is essential. Routine all-Wales access to infliximab will help standardise the treatment pathway in Wales, ensure equity and avoid delay in treatment which may lead to better patient outcomes. OWMAG note that all-Wales guidelines are currently in development by the National Immunotherapy Toxicity Sub-Group on the management of ICI-induced toxicities including myocarditis. OWMAG note that infliximab is contra-indicated in patients with moderate or severe heart failure (NYHA class III/IV) and that one small case series reported that patients who received infliximab for ICI-induced myocarditis were more likely to die from cardiovascular causes than other causes. However, OWMAG also note that another case series reported that none of the 23 patients who received infliximab for ICI-induced myocarditis developed worsening heart failure after infliximab administration in comparison to patients who did not receive infliximab. OWMAG acknowledge that the National Immunotherapy Toxicity Sub-Group advises that tocilizumab will be used in preference to infliximab for patients with an LVEF of below 40% (which may be indicative of heart failure). The clinical expert in attendance also stated that further doses of infliximab would not be given to patients who had not responded to the first dose of infliximab, in line with criteria set out in the starting and stopping criteria accompanying any recommendation for use. Taking into account the limited evidence available, the views of clinical experts and the safety considerations highlighted, OWMAG consider infliximab demonstrates some clinical effectiveness as a treatment option for this indication and that the benefits of its use outweigh the risks.

Criterion: Cost-effectiveness

OWMAG opinion OWMAG note that no comparative cost-effectiveness evidence was identified for this use of infliximab, and in the absence of any comparative studies of infliximab for this indication, no cost effectiveness analyses was undertaken by AWTTC. OWMAG consider that the likely costs associated with using infliximab for this indication would be reasonable in considering the potential benefit gained from this intervention.

Criterion: Budget impact

OWMAG opinion OWMAG consider the clinical estimate of patient numbers reported to be reasonable. However, the Group note the statement from the clinical expert that identification of myocarditis in affected patients is increasing and that use of ICI-treatments are likely to increase in future years, treatment-related toxicities including myocarditis are also likely to increase. Therefore, patient numbers may be expected to rise with an accompanying increase in budget impact. OWMAG note additional screening, monitoring and adverse event costs are excluded from the budget impact calculations both for infliximab and for comparator treatments. In particular, monitoring costs for tacrolimus titration may be considerable and the longer onset time for MMF to show clinical effect may mean patients remain in hospital for longer at significant cost. Clinicians indicate the faster clinical response time of infliximab mean patients can return home sooner and receive subsequent doses at home or as an outpatient. Based on outcome data provided by clinicians in Wales for patients treated with infliximab for grade 3–4 steroid-refractory myocarditis, OWMAG note that the degree of displacement of the comparator treatments, MMF and tacrolimus, is difficult to estimate at present. However, acquisition costs of both are low and so the impact of their displacement on the overall budget impact would be expected to be modest. Also, from the outcome data provided, OWMAG note that it’s likely not all patients will receive three doses of infliximab; therefore the budget impact may be overestimated. OWMAG also acknowledge that the lack of comparative data between treatments means that any additional benefit from infliximab cannot be quantified and taken into account in budget impact calculations. OWMAG consider that the base case provided in the report is a reasonable estimate of the associated cost to NHS Wales.

Criterion: Resource use

OWMAG opinion OWMAG note that infliximab is given by intravenous infusion in a healthcare setting whereas some comparator treatments are taken orally. However, due to the severity of the condition and the need for cardiac monitoring, patients with grade 3–4 ICI-induced myocarditis are likely to initially be hospital in-patients and so the addition of the first dose of infliximab to the treatment pathway is likely to have a low additional impact. It is expected that subsequent doses can be administered at home or as an outpatient. As previously mentioned, the use of infliximab may shorten hospital stay in comparison to patients receiving MMF. Infliximab does not need additional monitoring, in contrast to tacrolimus which requires blood trough concentration monitoring during dose titration.

Criterion: Other factors

OWMAG opinion OWMAG acknowledges that myocarditis is a rare but a serious complication of ICI therapy. Myocarditis is potentially fatal and early assessment and intervention are key as patients with this condition can deteriorate rapidly. Whilst patients will generally accept significant toxicities in order to live longer, effective and early interventions are needed to improve patient quality of life and outcomes. OWMAG recognises that a standardised NHS Wales treatment pathway for myocarditis unresponsive to steroids will ensure that appropriate and swift second-line immunosuppression treatment can be given which will help avoid unnecessary long-term complications or death. Making infliximab routinely available for this group of patients will avoid potential delays in getting access, freeing up clinician time and enabling prompt and equitable access for patients across Wales. There are no licensed alternative treatment options routinely available.

Final recommendation

OWMAG recommend the use of infliximab for the treatment of grade 3–4 steroid-refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy. This recommendation is subject to the development of appropriate start/stop criteria.

Summary of rationale

There is some limited evidence to support the use of infliximab as a clinically effective option for the treatment of ICI induced grade 3-4 myocarditis, where symptoms have not responded to first-line immunosuppression with corticosteroids. There are no licensed alternative treatment options and some international guidelines recommend the  use of infliximab for this indication. Clinicians in Wales also report positive outcomes for its use in the treatment of ICI‑induced myocarditis that has not responded to first-line treatment with steroids. Allowing routine access to infliximab will help standardise the treatment pathway in Wales and may enable earlier initiation of treatment resulting in improved patient outcomes. Due to the known cardiovascular side effects associated with infliximab, clinicians in Wales propose using it only in patients who have a left ventricular ejection fraction (LVEF) of 40% or above. The review after 12 months will provide the number of patients who have received this treatment in Wales and more evidence on whether this is an effective treatment for this patient population.

---

Key findings

Licence status: Infliximab is not licensed for treating grade 3–4 steroid-refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy; its use for this indication is off-label.

Clinical evidence: Evidence comes from systematic reviews, retrospective case series and case reports. No randomised control trials of infliximab in the treatment of ICI-induced myocarditis were identified.

Safety: Infliximab is contra-indicated in patients with moderate or severe heart failure (NYHA class III/IV).

Patient factors: Patients would receive the first dose of infliximab in hospital to enable cardiac monitoring. 

Cost effectiveness: No cost-effectiveness evidence was identified for this use of infliximab, and in the absence of any clinical studies of infliximab for this indication, no cost‑effectiveness analyses have been undertaken.

Budget impact: The additional use of infliximab is estimated to increase the annual spend associated with this patient group in Wales by between [commercial in confidence figure removed] depending on the degree of displacement of comparator treatments.

Impact on health and social care services: Minimal – due to the severity of the condition, patients with grade 3 and 4 ICI‑induced myocarditis are commonly admitted to hospital with extensive monitoring. Adding infliximab to the treatment pathway is likely to have a low additional impact.

Innovation and/or advantages: Infliximab offers an additional treatment option for some patients in this group. Clinicians in Wales suggest that the specificity of the immunosuppressive activity of infliximab might offer an advantage over other immunosuppressive agents with a broader spectrum of activity which may be detrimental to the ongoing control of the cancer originally targeted by ICI treatment.

back to contents list

---

Background

Clinicians in Wales consider there is an unmet need for treatment of steroid‑refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy. They have identified a cohort of patients who might benefit from infliximab treatment. Infliximab was considered suitable for assessment though the One Wales medicines process following agreement by the AWMSG Scrutiny Panel.

The All Wales Therapeutics and Toxicology Centre (AWTTC) sought opinions from clinical experts in Wales. Clinical experts expressed a need for a clear treatment strategy or clinical guideline to manage ICI-induced myocarditis in Wales. A small number of patients with steroid-refractory ICI-induced myocarditis in Wales have received infliximab (off‑label) through local agreements. A One Wales decision would ensure equity of access to infliximab across the country to treat steroid-refractory ICI‑induced myocarditis.

back to contents list

---

Target group

The indication considered is the treatment of steroid-refractory grade 3–4 myocarditis induced by immune checkpoint inhibitors.

back to contents list

---

Marketing authorisation date

Not applicable for this indication, off-label. 

Infliximab is not licensed for the treatment of steroid-refractory grade 3–4 myocarditis induced by immune checkpoint inhibitors. There are no plans to license infliximab for the indication under consideration. 

back to contents list

---

Dosing information

The proposed dose is 5 mg/kg by intravenous infusion over a 2-hour period at Week 0. This dose is the recommended infliximab dose for the majority of licensed indications¹. Patients should be observed for at least 1–2 hours post-infusion for acute infusion-related reactions. A second, and third dose may be given, 2 and 6 weeks later. In some cases a shorter interval may be required between doses and specialist advice should be sought from the immunotherapy team.

back to contents list

---

Clinical background

back to contents list

---

Incidence/prevalence

Severe myocarditis develops in <1% of cases, but with increased use of troponin measurement and cardiac imaging, cardiovascular complications can occur in ≤ 5% of patients treated with ICIs⁷. In up to 50% of patients, myocarditis may not respond to high-dose corticosteroids and will require treatment with a second-line immunosuppressant⁸.

The Wales National Immunotherapy Toxicity Sub-Group estimates that there are approximately 42 patients across Wales with grade 3-4 ICI-induced myocarditis unresponsive to steroids who would be eligible for treatment each year. Infliximab would not be used for patients with a left ventricular ejection fraction (LVEF) of less than 40%, which accounts for around 20% of cases. Therefore, clinicians estimate that approximately 34 patients per year would be eligible to receive infliximab.

back to contents list

---

Current treatment options and relevant guidance

All guidelines recommend that ICI treatment should be stopped for patients who develop grade 2 or higher myocarditis, and that high-dose corticosteroid treatment is started^4,7,9-11. If myocarditis does not respond to high-dose steroids, then additional immunosuppressive agents should be considered^4,9.

The Society for Immunotherapy of Cancer (SITC) consensus definitions for steroid‑unresponsive immune-related adverse events state that for life-threatening (grade 3 or 4) adverse events such as myocarditis, steroid-unresponsive immune‑related adverse events are those in which there is no clinical improvement after 1–3 days of appropriate steroid therapy¹². The definition has important implications for informing the time interval to wait before offering additional lines of immunosuppression¹².

Guideline 28 of the UK Acute Oncology Initial Management Guidelines Version 4 (2023) recommends considering mycophenolate mofetil (MMF) or tacrolimus in patients whose condition is not responding optimally to high-dose steroids⁴. If there is a limited response, consider a biologic, such as infliximab, tocilizumab or abatacept. A further DMARD, such as azathioprine, could also be considered, and local or national subsequent management guidelines should be considered⁴.

In up to 50% of patients, myocarditis may not respond to high-dose corticosteroids and will require treatment with a second-line immunosuppressant⁸. There is a lack of data to recommend a specific medicine to use, and current guidelines differ slightly in their suggested medicines for use as additional immunosuppressive agents (see Table 1).

Table 1. Guideline recommendations for additional immunosuppression for steroid-refractory ICI-induced myocarditis (opens image in new tab) 

Velindre Cancer Centre’s Immunotherapy Toxicity Guideline (v3) states that for myocarditis (grade 3 or 4) that does not respond to steroids, use second-line immunosuppression, such as tacrolimus or MMF or to consider infliximab.

Clinicians in Wales say that when ICI-induced myocarditis does not respond to steroids, they currently use tacrolimus or MMF as second-line immunosuppression. Some patients have received infliximab (see Table 2 for real world data). Clinicians say they would give infliximab to patients who have a preserved LVEF, partly due to their familiarity with using infliximab for treating other immunotherapy toxicities. In addition, clinicians think it appears to be effective without having broad‑spectrum effects, unlike abatacept (stated as an option in some clinical guidelines), for example, which has anti cytotoxic T‑lymphocyte-associated antigen 4 properties that might affect ongoing cancer control. For patients who have a reduced LVEF (less than 40%) they would prefer to use tocilizumab (requested through an IPFR or non-formulary application).

Clinicians in Wales say that the aim is to give three doses of infliximab (5 mg/kg) – given intravenously at Week 0, then a second dose at Day 15 if symptoms remain. A third dose could be given at Day 43. If the myocarditis did not respond to infliximab, or the patient’s condition deteriorated, then there would be an MDT discussion, to agree additional immunosuppression. Clinicians in Wales have already reported their experience in using infliximab for this indication (see Table 2).

Most guidelines recommend that ICI therapy should not be restarted in patients with severe or life-threatening (grade 3 or 4) ICI-induced myocarditis.

back to contents list

---

Summary of evidence on clinical effectiveness

The All Wales Therapeutics and Toxicology Centre (AWTTC) conducted a literature search during 29–30 May 2025, and 3 June 2025 to look for evidence about the use of infliximab to treat steroid-refractory ICI-induced myocarditis.

Database searches were performed using MEDLINE, EMBASE and the Cochrane Library. Our search terms were: infliximab, renflexis, remicade, zessly, remsima, inflectra, flixabi; myocarditis, carditis, cardiotoxicity, cardiac toxicity (cardiotoxicit* or cardio toxicit* or cardiactoxicit* or cardiac toxici*), (cardi* adj1 toxicit*); immune checkpoint inhibitor, immune checkpoint inhibit*, (immune adj2 checkpoint adj2 (inhibit* or blockade*)), ((ICI or ICIs) adj2 myocarditis).

The primary outcomes of interest were symptom improvement or resolution in randomised controlled trials (RCT), systematic reviews, network meta-analyses, guidelines, case series, case reports, conference abstracts, retrospective studies, health-related quality of life, economic evaluations, adverse events. No date restrictions were applied; results were restricted to English language. Targeted searches of Google and Google Scholar were also performed. Conference abstracts were included; letters and editorials were excluded. Clinical authors at AWTTC sifted and screened the results of the clinical searches, and health economics authors sifted and screened the results of the searches for economic evaluations and quality of life. See the PRISMA diagram in Appendix 1.

A total of 271 clinical papers were retrieved during the literature search, from which 12 duplicates were removed. 259 clinical papers were screened by inspecting titles and abstracts, and the full texts of 45 papers were reviewed for suitability in this report.

Our literature search identified no clinical trials of infliximab in steroid-refractory ICI-induced myocarditis; only systematic or literature reviews, case reports and case series were identified. Some case reports were published with a systematic review. Other case reports were identified by cross-referencing.

In this evidence summary report we included: 8 guidelines, 6 reviews, 28 case reports of myocarditis (30 patients) and 4 case series (38 patients; outcome data for 15). We excluded reviews in which all of the cases they reported were covered in other reviews. The case reports and cohort studies are listed in Appendix 2. Table 4 also includes case reports and case series mentioned in the systematic reviews covered, some of which were not identified in our literature search, and some were screened out by title and/or abstract. The systematic and narrative reviews are briefly discussed below.

Efficacy

Systematic and narrative reviews

Of the seven systematic literature reviews (CADTH, Daetwyler et al., Phing et al., Wang et al., Tan et al. [all published in 2024], Cozma et al. [2022], Matzen et al. [2021], three searched the PubMed database only, two searched PubMed and Embase, one searched Embase and Cochrane, and one (CADTH) searched Medline, Embase and Cochrane databases^3,5,14-18.

Information provided about the search and methodology varied; some limited their searches or results by date, the search terms used differed slightly. Only two reviews (Tan et al. 2024 and Wang et al. 2024) searched specifically for the treatment of steroid-refractory ICI myocarditis; Phing et al. (2024) searched for infliximab to treat ICI myocarditis, Cozma et al. (2022) searched for treatment of ICI-related cardiotoxicities including myocarditis and Matzen et al. (2021) searched for treatment of ICI-induced myocarditis. Two reviews were broader searches for treatment of all types of immune therapy-related adverse events (Daetwyler et al. 2024), and for infliximab to treat immune ICI-related toxicities (CADTH 2024)^3,5. One review, Tan et al., also included two case reports¹⁶.

All the systematic literature reviews identified only case reports and case series. The conclusions of each review were broadly similar; the evidence identified is very low quality (case reports and case series), and there is not enough published evidence to recommend the use of infliximab to treat ICI-induced steroid-refractory myocarditis.

The authors of one review stated that for steroid-refractory immune-related myocarditis, infliximab has been reported to be completely effective in a limited number of cases. They propose a potential algorithm for treatment of steroid‑refractory ICI-related myocarditis¹⁵ and indicate the use of infliximab only when TNF-alfa is elevated and there are no other therapeutic options¹⁵.

Clear evidence with regard to treatment cannot be provided as all available publications are case reports of one patient or only small case series. Details of the cases included in each review, including dosing (where available) and outcomes are given in Appendix 2 and summarised in the section below.

Case reports and case series

Thirty case reports are listed in Table 4 in Appendix 2. Four of these case reports were not covered in any of the reviews: Vu et al. 2025, Gomez et al. 2025, Qin et al. 2024 and Dearden et al. 2021^19-22.

Of the 30 cases, nine had other ICI-induced toxicities in addition to myocarditis including myositis (2 cases)^23,24, myasthenia gravis (2)^25,26, myasthenia gravis and myositis (3)^16,20,27, hepatitis, nephritis, pancreatitis and peripheral nervous system toxicity (1)²¹ and, myasthenia gravis, myositis, pneumonitis, thyroiditis and hepatitis (1)²⁸.

In 23 cases the dose of infliximab given was specified. The most common dose was 5 mg/kg, given to 15 patients^{19,24,26,28-38}. Three patients had 500 mg^20,27,39, one had 350 mg⁴⁰ and two had 200 mg¹⁶ (patient weights not given), and one patient had 10 mg/kg⁴¹. The number of doses of infliximab given was reported in 29 cases. Of these, 20 patients received one dose^{19-21,23,24,26-29,31-33,37-40,42-45}, six patients had two doses^{22,25,30,34,35,41} and three patients had three doses^16,36.

Myocarditis symptoms improved in all three patients who had three doses of infliximab^16,36. Of those patients who had two doses, myocarditis improved in three cases^25,30,34, did not improve in two cases^22,41 and further immunosuppressive treatment was required in the other case³⁵. Of the 20 patients who had one dose, myocarditis resolved in eight cases^{19-21,29,32,40,43}, in eight cases patients went on to other treatments^{23,27,28,33,38,42,44,45} and in four patients one dose of infliximab did not improve symptoms^26,31,37,39.

For the 21 cases where only myocarditis was present, infliximab treatment led to improvement of myocarditis symptoms in 10 cases^{16,19,29,30,32,34,36,40,43}. In five cases infliximab treatment failed to improve myocarditis^{22,31,37,39,41}, and in six cases patients were given additional immunosuppressants after infliximab^{33,35,38,42,44,45}. For the cases with multiple toxicities, infliximab treatment led to improvement in four of the nine cases reported^16,20,21,25.

Case series

Zhang et al. (2021) noted myocarditis improved in all four patients given one dose of 5 mg/kg infliximab; however, two later died from septic shock, both were receiving steroids⁴⁶. Lipe et al. (2021) of three patients with confirmed ICI-induced myocarditis given infliximab, all required further immunosuppressive treatments⁴⁷. In a case series of eight patients given infliximab (Cautela et al. 2020), myocarditis symptoms improved in four⁴⁸. The authors noted that patients who received infliximab were more likely to die from cardiovascular causes (OR, 12.0; 95% CI 2.1 to 67.1; p=0.005)⁴⁸ .

Ali et al. (2024) investigated outcomes on ICI-induced myocarditis in relation to TNF-alpha levels, and included 23 patients with grade 3 or 4 myocarditis who were given infliximab (5 mg/kg)⁴⁹. None of the patients who received infliximab developed worsening heart failure after infliximab administration, and MACE-free and overall survival were similar between all patients and those with elevated TNF-alpha levels. The number of patients with grade 3 or 4 cardiotoxicity was too small for a comparison of outcomes for those receiving infliximab versus those who did not receive it. They concluded that the role of TNF-alpha levels in the prognosis and guidance of immunomodulatory treatment is limited⁴⁹ .

Overall, the evidence for the use of infliximab from the case reports and case series is mixed, and of very low quality. It is not clear how many patients had grade 3 or 4 myocarditis.

Safety

Discussion

In this evidence summary, we identified 68 patients from the published literature and [confidential data removed] from NHS Wales who have received infliximab to treat ICI-induced myocarditis. Of these, outcomes are available for 50 patients, of which [data removed due to deductive disclosure] reported a response to treatment with infliximab, 11 reported no improvement (10 deaths from myocarditis and one from multi-organ failure) and 13 were given additional immunosuppressants after infliximab. [Confidential information removed].

There are no clinical studies that evaluated the efficacy of infliximab to treat ICI‑induced myocarditis. Evidence is only available from case reports and case series, and systematic narrative reviews of case reports and case series; overall patient numbers remain low. Case reports are generally the lowest grade of evidence. It is difficult to compare cases; cases may not be generalisable. The amount of information given about each case varies; dose and outcome data vary. In some cases, it is not clear when infliximab was given (if the case was steroid-refractory). Patients often had complex diagnoses with multiple immune-related toxicities and treatment rarely followed clinical guidelines in terms of escalation of additional immunosuppression treatments after inadequate response to first-line steroids.

Although the grade of myocarditis was not stated in many studies, nearly all case reports are for patients where myocarditis symptoms were severe. Nearly one-third of the case reports were for patients with multiple ICI-induced toxicities, which may have affected clinical outcomes. Many patients were treated with a number of immunosuppressive agents in addition to steroids and so the relative benefit of infliximab is difficult to ascertain. The concomitant use of immunosuppressive agents may be expected to have a compounding effect on suppressing the immune system; a number of patients developed infections, some proving fatal, which may have been attributable to this effect. Some cases reported LVEFs of below 40% and a dose of 10 mg/kg was given in one case; this would not normally be recommended in this patient group due to the risk of the known cardiovascular side effects associated with infliximab.

The systematic reviews identified have included different case reports. The search terms used by each review team varied widely and the number of databases searched also varied. Some of the reviews limited their searches by date. Evidence was difficult to identify; some case reports were initially excluded by screening, as the report focused on a different aspect or did not mention infliximab in the abstract.

The systematic reviews conclude that the evidence for the use of infliximab to treat steroid-refractory ICI-induced myocarditis is mixed and inconclusive.

Guidelines differ in their suggestions of additional immunosuppressive medicines to treat steroid-refractory ICI-induced myocarditis; some guidelines state that use of infliximab should be considered; others do not include infliximab as a medicine to consider using. There is a paucity of data to inform comparisons between different second line immunosuppressive therapies for this indication. All guidelines indicate that recommendations on treatment options are based on a low-quality evidence base, mainly derived from clinical expert opinion and that clinical opinion can also be informed by preference and experience of using specific treatments.

All guidelines recommend stopping or discontinuing (rather than pausing) ICI therapy in cases of ICI‑induced myocarditis. One states that the appropriateness of rechallenge is unknown.

Infliximab is contra-indicated in heart failure. Two guidelines caution against its use and the European guideline (ESMO) does not suggest it as an additional immunosuppressant. However, patients in Wales with an LVEF of 40% or below (indicative of heart failure) would be given tocilizumab in preference to infliximab for the treatment of ICI-induced myocarditis unresponsive to steroids.

back to contents list

---

Patient submission

We received a submission from the patient organisation Melanoma Focus, commenting on our assessment of infliximab to treat steroid-resistant ICI myocarditis. The main points of the submission are listed below.

• There is a growing population of melanoma patients who are younger in age; in the 15–44 years age group, melanoma is the second most common form of cancer in males and the third most common cancer in females.
• Checkpoint inhibitors, alone or in combination, are standard of care for all patients with metastatic melanoma.
• Patients will generally accept significant toxicities in order to live longer. For metastatic melanoma, the longer-term survival rate is better for those treated with combination treatment. Therefore, patients, if fit enough, will likely be treated with combination therapy at the expense of approximately 60% of patients reporting grade 3–4 toxicities.
• Immune checkpoint inhibitors (ICIs) have revolutionised melanoma care; 50% of patients treated with metastatic disease are now alive at 10 years. However, life‑threatening (grade 3–4) toxicities are reported in 50–60% of patients on combination ICI therapy, and in about 20% of patients on single agent ICI therapy.
• Cardiac toxicity is an increasingly recognised complication of ICI therapy, occurring in around 10% of treated patients. Myocarditis can occur in 4% of patients and its incidence is rising every year.
• Myocarditis is potentially fatal and early assessment and intervention are key. Standard guidelines for grade 3–4 toxicity recommend initial, high-dose corticosteroid treatment. Patients with myocarditis often need additional immunosuppression with additional medicines, some of which target different chemicals released as part of the inflammatory process associated with checkpoint inhibitors and include infliximab, tocilizumab and abatacept.
• Melanoma Focus supports the co-creation of guidelines for worsening or refractory myocarditis with the cardiologist or medical oncologist.  As patients with this condition can deteriorate rapidly, patients and emergency departments need to be aware to swiftly report symptoms which may suggest possible myocarditis, and that it should be treated appropriately to avoid unnecessary long-term complications or worse, death.

back to contents list

---

Ongoing clinical studies

Two clinical studies are under way of abatacept in the treatment of ICI-induced myocarditis^50,51. No studies are under way for infliximab in this indication.

back to contents list

---

Cost-effectiveness evidence

No cost-effectiveness evidence was identified for this use of infliximab, and in the absence of any clinical studies of infliximab for this indication, no cost‑effectiveness analyses have been undertaken.

back to contents list

---

Budget impact

Infliximab procurement costs are informed by a confidential NHS Wales contract price with a unit cost of a 100 mg vial ranging between [commercial in confidence figure removed] for the various biosimilars on all-Wales contract. NHS Wales prescribing figures from 2024 for infliximab 100 mg are used to calculate a weighted average procurement cost. The weighted average cost per 100 mg vial is [commercial in confidence figure removed] excluding VAT.

The average patient weight is calculated using population averages with an equal percentage of male and females. The recommended dose of 5 mg/kg for an average patient weight of 79 kg results in 4 vials per dose⁵². There is an assumption of no vial sharing; wastage is applied. The total infliximab procurement cost for a single dose is [commercial in confidence figure removed] excluding VAT.

The administration cost for the delivery of infliximab is sourced from the NHS reference costs 2023/24 with cost code SB12Z used for the first administration and SB15Z for additional delivery⁵³. The first administration cost is £418. Delivery of subsequent dose is costed at £426. Based on clinical expert opinion, it is assumed patients receive three doses of infliximab at 5 mg/kg, the cost of which is [commercial in confidence figure removed] per patient excluding VAT.

Clinicians in Wales indicate that currently patients with steroid-refractory ICI-induced myocarditis are predominantly treated with mycophenolate mofetil (MMF) and/or tacrolimus. A typical regimen for MMF is 500 mg twice daily for 3 days increasing to between 1 – 1.5 g twice daily depending on response. Tacrolimus is usually initiated at a dose of 3 mg twice daily and adjusted according to trough levels. Treatment with MMF or tacrolimus is continued until the patient has been weaned off steroids and is stable; this is usually between 8-12 weeks after initiation of treatment.

MMF and tacrolimus procurement costs are informed by confidential NHS Wales contract prices for each. The unit cost of MMF for 50 x 500 mg tablets ranges from [commercial in confidence figure removed] excluding VAT. Using the second lowest price of [commercial in confidence figure removed], the maximum acquisition cost of 1.5 mg MMF twice daily for 12 weeks is calculated as [commercial in confidence figure removed]. The unit cost of tacrolimus (100 x 1 mg tablets) is [commercial in confidence figure removed] excluding VAT. The maximum acquisition cost of 3 mg tacrolimus twice daily for 12 weeks is [commercial in confidence figure removed].

The NHS Wales National Immunotherapy Toxicity Sub-Group estimates that approximately 42 patients with steroid-resistant grade 3-4 ICI-induced myocarditis across Wales would be eligible for treatment each year. However, tocilizumab would be used in preference to infliximab for patients with a LVEF of less than 40%. Clinicians estimate that 1 in 5 patients would be treated with tocilizumab meaning that approximately 34 patients per year would receive infliximab. The estimated range of total annual costs for 3 doses of infliximab, assuming both full and no displacement of comparator treatments is given in Table 3.

Table 3. Estimated annual net cost for infliximab in comparison to MMF and tacrolimus in Wales (opens image in new tab) 

The introduction of infliximab for the treatment of grade 3–4 steroid refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy will increase the spend for this patient group. Based on an estimated uptake of 34 patients receiving three doses of 5 mg/kg infliximab, the annual net budget impact is expected to range between [commercial in confidence figure removed] depending on the degree of displacement of comparator treatments.

Budget impact issues

---

Equality and health impact assessment

AWTTC have completed an Equality and Health Impact Assessment in parallel with each development stage of the project. This follows the five ways of working for public bodies, and work to achieving the wellbeing goals, outlined in the Well‑Being of Future Generations (Wales) Act 2015. It is not expected that infliximab will have significant potential negative impact on people based on the protected characteristics of the Equality Act 2010.

---

Additional factors

Prescribing unlicensed medicines

Infliximab is not licensed to treat this indication and is therefore prescribed ‘off label’. Prescribers should consult their relevant guidelines on prescribing unlicensed medicines before any off-label medicines are prescribed.  

Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. 

Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Evidence Status Report. Assessment of infliximab for the treatment of steroid‑refractory myocarditis induced by immune checkpoint inhibitor (ICI) therapy OW31. 2025.
Copyright AWTTC 2025. All rights reserved.

back to contents list

---

References

1. Janssen-Cilag Ltd. Remicade^®. 100mg powder for concentrate for solution for infusion. Summary of Product Characteristics.  May 2025. Available at: https://www.medicines.org.uk/emc/product/3831/smpc. Accessed Jun 2025.
2. Cancer Research UK. Checkpoint inhibitors. . Available at: https://www.cancerresearchuk.org/about-cancer/treatment/targeted-cancer-drugs-immunotherapy/checkpoint-inhibitors. Accessed Jun 2025.
3. Canadian Agency for Drugs and Technologies in Health (CADTH). CADTH health technology review. Infliximab for immune checkpoint inhibitor therapy-related toxicities. Canadian Journal of Health Technologies. 2024;4(6):1-50.
4. UK Oncology Nursing Society. UKONS - Acute Oncology Initial Management Guidelines. Version 4.0. .  Feb 2023. Available at: https://www.ukacuteoncology.co.uk/information-hub/ao-guidelines. Accessed Jun 2025.
5. Daetwyler E, Wallrabenstein T, Konig D et al. Corticosteroid-resistant immune-related adverse events: a systematic review. Journal for ImmunoTherapy of Cancer. 2024;12:e007409.
6. Mahmood SS, Fradley MG, Cohen JV et al. Myocarditis in patients treated with immune checkpoint inhibitors. Journal of the American College of Cardiology. 2018;71(16):1755-1764.
7. Haanen J, Obeid M, Spain L et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2022;33(12):1217-1238.
8. Tocchetti CG, Farmakis D, Koop Y et al. Cardiovascular toxicities of immune therapies for cancer – a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology. . European Journal of Heart Failure. 2024;26:2055–2076.
9. Schneider BJ, Naidoo J, Santomasso BD et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. Journal of Clinical Oncology. 2021;39(36):4073-4126.
10. Thompson JA, Schneider  BJ, JR B et al. Management of Immunotherapy-Related Toxicities, Version 1.2020. Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network. 2020;18(3):230-241.
11. Brahmer JR, Abu-Sbeih H, Ascierto PA et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. Journal for ImmunoTherapy of Cancer. 2021;9:e002435.
12. Naidoo J, Murphy C, Atkins MB et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology. Journal for ImmunoTherapy of Cancer. 2023;11:e006398.
13. Lyon AR, Lopez-Fernandez T, Couch LS et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). European Heart Journal. 2022;43(41):4229-4361.
14. Phing KC, Gnanasan S, and Tangiisuran B. Use of infliximab in the treatment of immune checkpoint inhibitors-related myocarditis: a systematic reviw of case reports. Malaysian Journal of Pharmaceutical Sciences. 2024;22(1):105-137.
15. Wang Y, Li S, Shi H et al. Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review. Cardiovascular Diagnosis and Therapy. 2024;14(4):679-697.
16. Tan S, Qi C, Zeng H et al. Steroid‑refractory myocarditis induced by immune checkpoint inhibitor responded to infiximab: report of two cases and literature review. Cardiovascular Toxicology. 2024;24:1174–1191.
17. Cozma A, Sporis ND, Lazar AL et al. Cardiac toxicity associated with immune checkpoint inhibitors: a systematic review. International Journal of Molecular Sciences 2022;23:10948.
18. Matzen E, Bartels LE, Logstrup B et al. Immune checkpoint inhibitor-induced myocarditis in cancer patients: a case report and review of reported cases. Cardio-Oncology. 2021;7(27):1-14.
19. Vu M, Yousif A, Rusia A et al. One is all it takes: a case of immune checkpoint inhibitor-induced myocarditis, complete heart block, and cardiogenic shock. Journal of Cardiac Failure. 2025;31(1):277.
20. Gomez L, Lozano T, Jovani V et al. Triple M overlap syndrome following pembrolizumab treatment: importance of multidisciplinary approach. BMJ Case Reports. 2025;18:e260349.
21. Qin Y, Zhang T, Du Z et al. Prognosis of immune checkpoint inhibitor-related myocarditis: retrospective experience of a single institution. International Immunopharmacology. 2024;136:112385.
22. Dearden H, Au L, Wang DY et al. Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy. European Journal of Cancer. 2021;153:168-178.
23. Barry T, Gallen R, Freeman C et al. Successful treatment of steroid refractory checkpoint inhibitor myocarditis with globulin derived therapy: a case report and literature review. The American Journal of the Medical Sciences. 2021;362(4):424-432.
24. Johnson DB, Balko JM, Compton ML et al. Fulminant myocarditis with combination immune checkpoint blockade. New England Journal of Medicine. 2016;375(18):1749-1755.
25. Feng Y, Zheng P, Zhang W et al. Immune checkpoint inhibitor myocarditis in thymic epithelial tumors: a case report and literature review. Translational Cancer Research. 2024;13(2):1208-1218.
26. Portoles Hernandez A, Blanco Clemente M, Escribano Garcia D et al. Checkpoint inhibitor-induced fulminant myocarditis, complete atrioventricular block and myasthenia gravis—a case report. Cardiovascular Diagnosis and Therapy. 2021;11(4):1013-1019.
27. Deharo F, Carvelli J, Cautela J et al. Immune checkpoint inhibitor-induced myositis/myocarditis with myasthenia gravis-like misleading presentation: a case series in intensive care unit. Journal of Clinical Medicine. 2022;11:5611.
28. Fuentes-Antras J, Peinado P, Guevara-Hoyer K et al. Fatal autoimmune storm after a single cycle of anti-PD-1 therapy: a case of lethal toxicity but pathological complete response in metastatic lung adenocarcinoma. Hematology/Oncology and Stem Cell Therapy. 2022;15(1):63-67.
29. Eslinger C, Walden D, Barry T et al. Rechallenge with switching immune checkpoint Inhibitors following autoimmune myocarditis in a patient with Lynch syndrome. Journal of the National Comprehensive Cancer Network. 2023;21(9):894-899.
30. Kadokawa Y, Takagi M, Yoshida T et al. Efficacy and safety of Infliximab for steroid‑resistant immune‑related adverse events: a retrospective study. Molecular and Clinical Oncology. 2021;14(65):10.3892/mco.2021.2227.
31. Giancaterino S, Abushamat F, Duran J et al. Complete heart block and subsequent sudden cardiac death from immune checkpoint inhibitor–associated myocarditis. Heart Rhythm Case Reports. 2020;6(1):761-764.
32. Padegimas A, Agarwal P, Fleitman J et al. Case series of ventricular tachycardia and myocarditis from programmed cell-death protein-1 inhibitor treated with infliximab. Journal of the American College of Cardiology: Clinical Electrophysiology. 2019;5(8):987-992.
33. Saibil SD, Bonilla L, Majeed H et al. Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab. Current Oncology. 2019;26(3):e418-e421.
34. Agrawal N, Khunger A, Vacchani P et al. Cardiac toxicity associated with immune checkpoint inhibitors: case series and review of the literature. Case Reports in Oncology. 2019;12:260-276.
35. Zlotoff DA, Cohen JV, Zubiri L et al. Steroid-Refractory Immune Checkpoint Inhibitor-Associated Myocarditis. Journal of Cardiac Failure. 2019;25(8 Supplement):S125.
36. Frigeri M, Meyer P, Banfi C et al. Immune checkpoint inhibitor-associated myocarditis: a new challenge for cardiologists. Canadian Journal of Cardiology. 2018;34(1):92.e91-92.e93.
37. Martinez-Calle N, Rodriguez-Otero P, Villar S et al. Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity. Haematologica. 2018;103(7):e318-e321.
38. Tay RY, Blackley E, McLean C et al. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. British Journal of Cancer. 2017;117:921-924.
39. Wang C, Lin J, Wang Y et al. Case series of steroid-resistant immune checkpoint inhibitor associated myocarditis: a comparative analysis of corticosteroid and tofacitinib treatment. Frontiers in Pharmacology. 2021;12:770631.
40. Wintersperger BJ, Calvillo-Arguelles O, Lheureux S et al. Immune checkpoint inhibitor-related myocarditis: an illustrative case series of applying the updated Cardiovascular Magnetic Resonance Lake Louise Criteria. European Heart Journal - Case Reports. 2022;00:1-9.
41. Gallegos C, Rottmann D, Nguyen VQ et al. Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic resonance with pathology correlate. European Heart Journal. 2019;3:1-4.
42. Koelmeyer H, Buckley K, Feradov D et al. Complete heart block in a patient undergoing combination immune checkpoint inhibitor therapy. Cureus. 2024;16(8):e66776.
43. Puzanov I, Subramanian P, Yatsynovich YV et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. Journal for ImmunoTherapy of Cancer. 2021;9:e002553.
44. Norwood TG, Lenneman CA, Westbrook BC et al. Evolution of immune checkpoint blockade–induced myocarditis over 2 years. Journal of the American College of Cardiology Case Reports. 2020;2(2):203-209.
45. Shah M, Tayar JH, Abdel-Wahab N et al. Myositis as an adverse event of immune checkpoint blockade for cancer therapy. Seminars in Arthritis and Rheumatism. 2019;48(4):736-740.
46. Zhang RS, Padegimas A, Murphy KM et al. Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with infliximab: a case series. Cardio-Oncology. 2021;7(13):10.1186/s40959-40021-00095.
47. Lipe DN, Galvis-Carvajal E, Rajha E et al. Immune checkpoint inhibitor-associated myasthenia gravis, myositis, and myocarditis overlap syndrome. American Journal of Emergency Medicine. 2021;46:51-55.
48. Cautela J, Zeriouh S, Gaubert M et al. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. Journal for ImmunoTherapy of Cancer. 2020;8:e001887.
49. Ali A, Caldwell R, Pina G et al. Elevated IL-6 and tumor necrosis factor-α in immune checkpoint inhibitor myocarditis. Diseases. 2024;12(88):10.3390/diseases12050088.
50. Massachusetts General Hospital. NCT05335928: Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM). Nov 2024. Available at: https://clinicaltrials.gov/study/NCT05335928. Accessed Jul 2025.
51. Assistance Publique - Hôpitaux de Paris. NCT05195645: AbataCept for the Treatment of Immune-cHeckpoint Inhibitors Induced mYocarditiS (ACHLYS). Dec 2024. Available at: https://clinicaltrials.gov/study/NCT05195645. Accessed Jul 2025.
52. NHS England Digital. Health survey for England 2021. Part 4: Trends.  Dec 2022. Available at: https://digital.nhs.uk/data-and-information/publications/statistical/health-survey-for-england/2021/part-4-trends. Accessed Jul 2025.
53. NHS England. 2023/24 National Cost Collection Data Publication.  Nov 2024. Available at: https://www.england.nhs.uk/publication/2023-24-national-cost-collection-data-publication/. Accessed Feb 2025.

back to contents list

• Original assessment: OWMAG recommendation with starting and stopping criteria September 2025 PDF 70KB
• Original assessment: OWMAG decision rationale September 2025 PDF 33KB
• Original assessment: Evidence Status Report September 2025 PDF 370KB
• Original assessment: Equality and Health Impact Assessment September 2025 PDF 137KB