ICI-associated myocarditis
Also called: checkpoint inhibitor myocarditis · immune-mediated myocarditis · ICI myocarditis · immune checkpoint inhibitor-associated myocarditis
Uncommon and early — 1.14% of an eight-site registry, median 34 days in — but the most lethal irAE by reported share, and the one card in this atlas where the trigger is suspicion of the diagnosis rather than a CTCAE grade. An asymptomatic troponin rise inside 12 weeks of an ICI is a presentation, not an incidental result.
Reported frequency
1.14% — Prevalence of myocarditis
of ICI-treated patients across the registry's 8 sites · Multicentre ICI myocarditis registry, November 2013 to July 2017
cohort · 29567210
Severity and class
50% — Deaths among reported ICI myocarditis cases
of 61 of 122 myocarditis reports · VigiBase spontaneous reports, 1967 to January 2018 — a share of REPORTS, not a case-fatality rate: severe and fatal events are preferentially reported, so this is an upper-bound signal rather than a risk a patient can be quoted
pharmacovigilance · 30442497
34% vs. 2% — Combination ICI exposure among myocarditis cases vs ICI-treated controls
of 35 myocarditis cases vs a random sample of 105 ICI-treated patients without myocarditis · Eight-site multicentre myocarditis registry, November 2013 to July 2017
cohort · 29567210
Onset
Median time of onset 34 days after starting ICI (interquartile range 21 to 75 days) in the eight-site registry. SITC frames the window differently and more usefully for triage: a diagnosis should be considered in any patient who has received an ICI in the past 12 weeks and develops new cardiac symptoms, arrhythmias, heart block, or an asymptomatic troponin elevation. Values are stored in days because that is how both sources state them.
Presentation
- · New cardiac symptoms in a patient who has had an ICI within 12 weeks — SITC's trigger, and the reason this card is entered on suspicion rather than on a grade
- · Asymptomatic troponin elevation — named by SITC as a presenting cardiac lab finding, not as an incidental result to be repeated later
- · New arrhythmia or new heart block
- · A normal ejection fraction does not exclude it: 38% of the registry's major adverse cardiac events occurred with normal ejection fraction
- · Concurrent myositis or myasthenic features — SITC evaluates suspected myositis, myocarditis and myasthenia gravis with a shared set of diagnostics because the presentations overlap
Differential
- · Acute coronary syndrome and other non-immune causes of troponin rise — the reason the work-up is an EKG plus troponin plus imaging rather than troponin alone
- · Myositis with cardiac muscle involvement, and myasthenia gravis: SITC treats the three as an overlapping triad sharing one diagnostic work-up, so finding one is a reason to look for the other two rather than to stop
- · Pericardial disease, which SITC discusses separately and which this atlas does not yet carry as a card — see this entry's omitted[] rather than reading its absence as absence of risk
- · Progression of the underlying malignancy, and cardiotoxicity of a concomitant anti-cancer agent
Work-up
Serum troponin · All patients
SITC's first-line test in suspected myocarditis, and part of what defines the presentation. It also gates the pulse-steroid duration — the pulse runs until troponin normalizes.
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EKG · All patients
Ordered with troponin on suspicion. New arrhythmia or new heart block is itself an entry criterion.
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Hospital admission with cardiology consultation · All patients
SITC attaches both to SUSPICION, not to a confirmed diagnosis and not to a grade. Management is to take place in a coronary care unit with temporary pacemaker support available for rapid access if indicated.
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Cardiac MRI, if available · All patients
SITC's imaging step after EKG and troponin, with or without right heart catheterization and myocardial biopsy.
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Endomyocardial biopsy, with or without right heart catheterization · If atypical
Named by SITC as the gold standard for myocarditis. Positioned after the non-invasive work-up rather than as a first step.
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Shared myositis / myocarditis / myasthenia gravis diagnostic set · All patients
SITC evaluates the three together because symptoms overlap. Confirming one does not close the other two.
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Scheduled surveillance troponin in an asymptomatic patient · If atypical
Listed to record what SITC actually says about it: baseline and scheduled troponins CAN be obtained, but in asymptomatic patients there has been no evidence that this improves outcome or even gives early warning. It is carried as a negative finding so the card cannot be read as endorsing routine surveillance.
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Grade ladder
Grade 1
Hold — consider permanent discontinuationAdmitGrade 1 — ASCO's cross-organ default continues an ICPi with close monitoring at grade 1, and names cardiac toxicity as one of its exceptions. SITC supplies what fills that exception, and it is not graded: any patient with an ICI in the past 12 weeks who develops new cardiac symptoms, new arrhythmias, new heart blocks or an asymptomatic troponin elevation is a suspected case, and suspicion is what triggers admission and treatment. A grade 1 presentation of this entity is therefore managed as a suspected case.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — SITC runs the pulse until troponin normalizes and asks for it as soon as the diagnosis is considered likely — before confirmation, not after. The chapter's cited basis for the urgency is a 126-patient multicentre analysis in which corticosteroids within 24 hours of admission were followed by major adverse cardiac events in 7.0%, against 34.3% at 24 to 72 hours and 85.1% beyond 72 hours.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.
Second line
- Infliximab — Not a second-line option here — this row exists to carry the caution against it.SITC advises caution against the use of infliximab for steroid-refractory myocarditis. It is listed so that a reader who reaches for the TNF-α inhibitor that works in ICI colitis meets the warning on the card rather than missing it.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Manage in a coronary care unit, with temporary pacemaker support available for rapid access if indicated
- · Do not wait for confirmation to start steroids — SITC's instruction is as soon as the diagnosis is considered likely
- · Evaluate for concurrent myositis and myasthenia gravis with the shared diagnostic set
Escalate when: No response to corticosteroids within 24 hours; any arrhythmia, conduction block or haemodynamic change. A normal ejection fraction is not reassurance — 38% of the registry's major adverse cardiac events occurred with one.
Grade 2
Hold — consider permanent discontinuationAdmitGrade 2 — ASCO's general ladder may suspend an ICPi for most grade 2 toxicities. No cardiac-specific grade 2 threshold is stated in any chapter held here, and SITC's plan does not change at this rung: same admission, same work-up, same steroid, same 24-hour second-line trigger.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes, started as soon as the diagnosis is considered likely.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.
Second line
- Infliximab — Not a second-line option here — this row exists to carry the caution against it.SITC advises caution against the use of infliximab for steroid-refractory myocarditis.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Coronary care unit management with rapid access to temporary pacing
- · Serial troponin — it is the marker the pulse duration is indexed to
- · Keep the ICI held; SITC asks that permanent discontinuation be seriously considered
Escalate when: No response within 24 hours of starting corticosteroids, or any new conduction abnormality.
Grade 3
Hold — consider permanent discontinuationICUGrade 3 — ASCO's general ladder suspends the ICPi and starts high-dose corticosteroids at grade 3. SITC's cardiac plan already does both on suspicion, so nothing changes at this rung except that the case is now unambiguous.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes. The 24-hour window is the one that matters — the analysis SITC cites separates 7.0% major adverse cardiac events from 34.3% on that threshold.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.
Second line
- Infliximab — Not a second-line option here — this row exists to carry the caution against it.SITC advises caution against the use of infliximab for steroid-refractory myocarditis.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Coronary care unit, with temporary pacemaker support available for rapid access
- · Cardiology leads; the diagnosis is established alongside treatment, not before it
- · Look for the myositis and myasthenia gravis that travel with it
Escalate when: Cardiogenic shock, cardiac arrest, ventricular arrhythmia or haemodynamically significant complete heart block — the components of the registry's major-adverse-cardiac-event endpoint.
Grade 4
Discontinue permanentlyICUGrade 4 — ASCO's cross-organ rule is permanent discontinuation of ICPis at grade 4, with an endocrine exception that does not apply here. SITC's cardiac chapter states its discontinuation position once, ungraded, as seriously considering permanent discontinuation; the encoded action follows ASCO's explicit grade 4 rule.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes, as soon as the diagnosis is considered likely.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.
Second line
- Infliximab — Not a second-line option here — this row exists to carry the caution against it.SITC advises caution against the use of infliximab for steroid-refractory myocarditis.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Critical care with temporary pacing available; mechanical circulatory support is beyond what any chapter held here states
- · Permanent discontinuation of the ICI
- · Second-line immunosuppression on the 24-hour non-response rule, not after a longer trial
Escalate when: Already the top rung. Management of established fulminant ICI myocarditis is beyond what the chapters held here state, and this atlas stops rather than extrapolating.
Rechallenge
contraindicated
SITC asks that permanent discontinuation of ICI therapy be seriously considered in any suspected case, and ASCO's general rule at grade 4 is permanent discontinuation. Neither chapter held here describes conditions under which an ICI would be resumed after myocarditis, and no source cited here reports what happens when it is. Against a reported fatality of 50% in the pharmacovigilance record, the absence of a rechallenge protocol is not equivalent to an open question — the stance is the conservative reading, and the empty recurrence field says the question has not been answered here rather than answered favourably.
- · None are stated by any source cited here. This is a stopping point, not a gated pathway — a prerequisite list would imply a route through it that no chapter held here describes
Deliberately not carried
- divergences — Empty, and for a structural reason rather than because the sources agree on everything. A divergence needs at least two voices on the same field and grade; only ONE society chapter for this organ is held in this repository. ESMO and ESC have no cardiac chapter here, and ASCO's cardiac chapter was never read — its appearance on this card is its cross-organ ladder, quoted from the abstract, which is why 'cardiac' is deliberately absent from ASCO's IRAE_GUIDELINE_ORGANS row. Where ASCO and SITC touch the same decision they agree: ASCO names cardiac toxicity as an exception to its own continue-at-grade-1 default. Read the empty list as one voice, not as consensus.
- gradeThreePlus — No source cited here reports a CTCAE grade ≥3 rate for ICI myocarditis. The registry's 46% major-adverse-cardiac-event figure is a composite study endpoint — cardiovascular death, cardiogenic shock, cardiac arrest, haemodynamically significant complete heart block — measured among patients who already have myocarditis. Filing it here would render a study endpoint as a severity rate in a field the UI treats as one; it is carried as prose and as escalation triggers instead.
- onset.medianWeeks — Both sources state onset in days (median 34, IQR 21-75). Converting to weeks produces 4.857, a number no source printed, and this field's contract forbids an estimated median. The days figure is in onset.note verbatim.
- ladder[].taper step cadence — SITC states a 4–6 week 1–2 mg/kg prednisone taper and a start trigger, and no step size or step interval. All three cadence fields are null together rather than back-filled from the renal taper tool's illustrative 25%-every-1-2-weeks, which is an example rather than a cardiac recommendation (D-STEROID).
- diagnostic test performance — SITC states that nearly all registry myocarditis cases had elevated troponin and an abnormal EKG and that ejection fraction was normal in about half, attributing the figures to Mahmood et al. Those numbers are not in Mahmood's abstract, so within this repository they exist only as one document's summary of another's full text. No sensitivity or negative predictive value is stored, and the work-up rows say what to order and why without one.
- second-line comparative outcomes — SITC cites a 60-patient retrospective in which patients needing second-line immunosuppression had higher all-cause mortality than those on steroids alone, and in which infliximab carried an odds ratio of 12.0 for cardiovascular death. That record was not resolved to a PMID in this pass. The infliximab CAUTION is carried because it is in SITC's own recommendation sentence; the numbers behind it are not.
- other cardiac phenotypes — This organ has one card. Pericardial disease has reporting data here (20 of 95 reports fatal) but no management ladder in any chapter held, and would ship as four unsourced rungs. Thromboembolic events are covered by SITC, but its own text declines to separate ICI-induced from cancer-induced events and its recommendation is to anticoagulate and NOT give steroids — a different shape from an irAE ladder. Accelerated atherosclerosis has no grade ladder at all. All three are recorded as outstanding in the citation ledger rather than sketched here.
- guidelinePmids — Left empty although ASCO and SITC are both rows in guidelines.ts: their stored keyRecommendation strings are renal-scoped, and linking them would surface kidney dosing on a cardiac card. The cardiac chapter is carried in citations with its own quote.
Sources
- Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: That cardiac irAEs are uncommon but carry a high mortality rate; the diagnostic sequence and the explicit finding that scheduled troponins in asymptomatic patients have not been shown to help; the MACE-by-steroid-timing figures from Zhang et al; and the whole management ladder — the suspicion trigger, hospital admission with cardiology, the imaging and biopsy pathway, the pulse-dose steroid with its taper, the 24-hour non-response threshold for second line, the caution AGAINST infliximab, and the coronary-care-unit setting with pacing available.Supporting text: the full text
- Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: That ASCO's general continue-at-grade-1 default explicitly EXCLUDES some cardiac toxicities, and that permanent discontinuation is its grade 4 rule. Cited as the cross-organ ladder it is, not as an ASCO cardiac chapter — no such chapter is held in this repository.Supporting text: the PubMed abstract (checkable at the link above)
- Mahmood SS, et al. (2018) Myocarditis in Patients Treated With Immune Checkpoint Inhibitors.Cited for: Prevalence, onset window, the combination-ICI exposure skew, the MACE rate and its composition, the proportion of MACE occurring at a normal ejection fraction, the troponin-T threshold associated with MACE, and the observation that lower steroid doses tracked with higher residual troponin and higher MACE.Supporting text: the PubMed abstract (checkable at the link above)
- Salem JE, et al. (2018) Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.Cited for: The disproportionate reporting of myocarditis with ICIs, and the fatal share among reported cardiovascular irAEs — 50% of myocarditis reports, against 21% for pericardial disease and 6% for vasculitis. A share of REPORTS in a spontaneous-reporting database, which is what the framings built on it say.Supporting text: the PubMed abstract (checkable at the link above)
- Zhang L, et al. (2020) Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis.Cited for: That the timing and dose of corticosteroids in ICI-associated myocarditis has been studied against a major-adverse-cardiovascular-event endpoint. The figures themselves are carried on SITC's span, not this one.Supporting text: the title
- Salem JE, et al. (2019) Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis.Cited for: That abatacept has been reported in severe ICI-associated myocarditis — the published record behind one of the four agents SITC lists for corticosteroid non-response. A single case report; it establishes existence, not efficacy.Supporting text: the title