Myocarditis, Myositis, and Myasthenia Gravis

Abstract

Background

Triple M syndrome is the combination of myocarditis, myositis, and myasthenia gravis secondary to immune checkpoint inhibitor (ICI) treatment. Traditionally managed with high-dose steroids, ICI myocarditis may benefit from early initiation of nonsteroidal immunosuppression.

Case Summary

A man with hepatocellular carcinoma presented with double vision and an elevated high-sensitivity troponin after receiving his first dose of tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor). He was diagnosed with steroid-refractory ICI myocarditis and treated with abatacept and ruxolitinib. Early recognition of triple M syndrome and initiation of nonsteroidal immunosuppression are described.

Discussion

Management of ICI myocarditis is evolving. Nonsteroidal immunosuppression may become an essential component of management as ICI use, and therefore occurrence of triple M syndrome, increases.

Take-Home Messages

If there is recent initiation of ICI therapy, elevated troponin, and concomitant ICI toxicities, providers should suspect ICI myocarditis despite negative cardiac magnetic resonance imaging. Nonsteroidal immunosuppression with CTLA-4 agonists may be effective in patients treated with CTLA-4 inhibitors.

Graphical Abstract

History of presentation

A 59-year-old man presented with double vision 19 days after his first dose of combination immune checkpoint inhibitor (ICI) therapy with tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor). He denied chest pain or heart failure symptoms. Physical examination was notable for inability to abduct the left eye, bilateral left upper quadrant visual field defects, right ptosis, and no evidence of volume overload.

Take-Home Messages

• •If there is recent initiation of ICI therapy, elevated troponin, and concomitant ICI toxicities, providers should suspect ICI myocarditis despite negative cardiac MRI.
• •Nonsteroid immunosuppression with CTLA-4 agonists may be effective in patients treated with CTLA-4 inhibitors.

Past medical history

Past medical history included hepatocellular carcinoma and chronic hepatitis B virus. Hepatocellular carcinoma was diagnosed 2 months prior via imaging and elevated α-fetoprotein in the setting of unexplained transaminitis. He was not a surgical candidate and received treatment via radioembolization with yttrium-90 followed by tremelimumab and durvalumab.

Differential diagnosis

The differential diagnosis included stroke, cranial nerve palsy, acute coronary syndrome, and triple M syndrome.

Investigations

Initial laboratory results revealed a high-sensitivity troponin (hs-troponin) of 1,875 pg/mL, creatine kinase (CK) of 5,049 U/L, aspartate aminotransferase (AST) of 292 U/L, alkaline phosphatase (ALT) of 148 U/L, C-reactive protein (CRP) of 8.0 mg/L, and B-type natriuretic peptide (BNP) of 13 pg/mL. Myasthenia gravis (MG) antibodies, including Ach-Ab blocking, binding, and modulating, and anti-MuSK were negative. Central nervous system imaging was unremarkable. Coronary computed tomography angiography revealed nonobstructive stenosis (Figures 1A to 1C). Echocardiography demonstrated an ejection fraction of 62% and an abnormal global longitudinal strain of −10.6% (Video 1).

Figure 1.

Coronary CTA With Mild Calcific Atherosclerosis of the LAD

Computed tomography angiography of the coronary arteries with curved multiplanar reconstruction and maximum intensity projection of the left anterior descending (A), left circumflex (B), and right coronary (C) arteries demonstrating mild calcific atherosclerosis in the proximal left anterior descending artery (yellow arrow).

Cardiac magnetic resonance imaging (MRI) performed on day 2 did not demonstrate evidence of myocarditis. There was no late gadolinium enhancement (Figures 2A to 2C). The myocardial T2 value was 49 ms (Figures 3A to 3C), native T1 value was 1,003 ms, and extracellular volume was 28% (Figures 3D to 3F).

Figure 2.

Cardiac MRI Without Evidence of Late Gadolinium Enhancement

Cardiac magnetic resonance imaging using phase-sensitive inversion recovery (PSIR) demonstrated no late gadolinium enhancement of the myocardium in the 4-chamber (A), 2-chamber (B), and 3-chamber (C) views. The pericardium that appeared to be enhancing is epicardial fat which was confirmed with fat saturated images.

Figure 3.

Cardiac MRI With Normal T1 and T2 Mapping

Cardiac magnetic resonance imaging with T2 (A to C) and T1 (D to F) mapping. (A to C) T2 maps demonstrated normal global T2 value of 49 ms in the short axis view at the base (A), mid (B), and apex (C). (D to F) T1 maps demonstrated normal global native T1 value of 1,001 ms in the short axis view at the base (D), mid (E), and apex (F). The calculated extracellular volume is within normal limits at 28% with a hematocrit of 44%.

Despite negative cardiac MRI, suspicion for myocarditis was high in the setting of recent ICI therapy and concurrent myositis and MG. Prednisone was initiated 1 mg/kg on day 3, and an endomyocardial biopsy was performed on day 6. The biopsy was positive for subacute necrosis with lymphohistiocytic infiltrates, confirming the diagnosis of myocarditis (Figures 4A to 4C).

Figure 4.

Endomyocardial Biopsy With H&E, CD68 (Histiocyte Marker), and CD3 (T Lymphocyte Marker) Staining

(A) Hematoxylin and eosin (H&E) staining demonstrated subacute necrosis with lymphohistiocytic infiltration. (B) CD68 staining was positive for interstitial histiocytes. (C) CD3 staining was positive for interstitial T cells. The CD68/CD3 ratio was high, which was consistent with ICI myocarditis.

Management

The troponin level initially responded to steroid therapy; however, attempts to wean high-dose steroids resulted in a rise in troponin (Figure 5). At this time, 2 nonsteroidal immune modulators, abatacept and ruxolitinib, were initiated. A one-time dose of abatacept 10 mg/kg was administered on day 10, and ruxolitinib 20 mg twice a day was started on day 11. He was discharged on a ruxolitinib taper.

Figure 5.

hs-Troponin Versus Hospital Day

An attempt to wean high-dose steroids on hospitalization day 9 resulted in a rise in troponin as measured by the high-sensitivity troponin (hs-troponin) test.

The patient reported dysphagia and coughing with oral intake on day 12. This was thought to be due to worsening MG in the setting of a prolonged steroid course. At this time, he had been on 400 mg/kg intravenous immunoglobulin for 5 days and was on 60 mg pyridostigmine twice daily. MG treatment was increased to pyridostigmine 90 mg twice daily, and steroids were tapered to prednisone 80 mg/day the following day to minimize the risk of steroid-induced MG exacerbation. Respiratory status was stable throughout the hospitalization.

Outcome and follow-up

On discharge (day 26 post steroid initiation and day 18 post nonsteroidal immunosuppression initiation), hs-troponin was 25 pg/mL, and MG symptoms had improved. Discharge medications included a prednisone taper, ruxolitinib taper (20 mg twice a day for 44 days followed by 10 mg twice a day for 14 days), and 90 mg pyridostigmine indefinitely pending MG symptoms. A 28-day mobile cardiac telemetry did not document any arrhythmias. β-Blockers were not started for arrhythmia prevention during the hospital course or after owing to the potential of worsening MG by blocking acetylcholine receptors. High-sensitivity troponin was within normal limits at 1-week follow-up. The patient reported persistent ophthalmoplegia, hoarseness, and fatigable weakness, and pyridostigmine was increased to 90 mg 3 times a day indefinitely pending symptomatic improvement. A surveillance liver MRI scan was significant for new satellite lesions concerning for hepatocellular carcinoma. Discussions are ongoing regarding reinitiation of yttrium-90 treatment as immunotherapy was now contraindicated.

Discussion

Triple M syndrome is an overlap syndrome characterized by myocarditis, myositis, and MG secondary to ICI treatment. ICI myocarditis occurs in approximately 1% of patients. Among cases of ICI myocarditis, 25% exhibit concurrent myositis, and 11% exhibit concurrent MG.¹ Despite its rarity, ICI myocarditis carries a 46% risk of major adverse cardiac events and up to 50% mortality.^2,3

Steroid-refractory ICI myocarditis in the present patient was successfully treated with triple therapy (steroids, abatacept, and ruxolitinib). Abatacept, a CTLA-4 fusion protein, binds to CD80/CD86 on antigen-presenting cells, blocking CD28 interaction and inducing T-cell anergy.⁴ This is the opposite mechanism of tremelimumab, and perhaps the direct reversal in mechanisms led to the rapid improvement in hs-troponin.

Major oncology guidelines classify ICI-related complications by organ system and severity.^5,6 All recommend high-dose steroids for myocarditis and intravenous immunoglobulin/pyridostigmine for MG, but differ on second-line immunosuppression. For example, the European Society for Medical Oncology advises immediate second-line therapy for complicated myocarditis (eg, instability, heart block, arrhythmias), whereas the American Society of Clinical Oncology recommends it only for steroid-refractory cases. No consensus exists on the preferred agent or dosing of nonsteroidal immunosuppression, highlighting the lack of data on nonsteroidal immunosuppression in triple M syndrome.

Despite an hs-troponin peak of 8,071 pg/mL and biopsy-confirmed necrosis, our patient had no symptoms of heart failure, arrhythmias, or MRI findings of myocarditis. There is no consensus on which biomarkers or imaging findings should guide ICI myocarditis treatment. A review found troponin elevation in 98%, B-type natriuretic peptide elevation in 88%, and abnormal transthoracic echocardiography findings in 49% of cases (wall motion abnormalities, decreased left ventricular systolic function). In addition, cardiac MRI met the Lake Louise criteria for myocarditis in just 47% of ICI myocarditis cases, suggesting that a negative cardiac MRI scan should not exclude myocarditis in the appropriate clinical context.⁴ Given its low sensitivity, if cardiac MRI is negative for myocarditis but clinical suspicion for ICI myocarditis remains high, an endomyocardial biopsy may be an appropriate next step to confirm the diagnosis.

Early initiation of nonsteroidal immunosuppression can potentially minimize steroid burden. This is particularly important in triple M syndrome, as high-dose steroids can worsen MG, creating a situation in which the treatment for one feature of triple M syndrome can worsen another. As a result, an increased focus on early nonsteroidal immunosuppression in triple M syndrome could improve morbidity and mortality by minimizing steroid use.

A 2023 study compared outcomes of ICI-associated myotoxicity when treated with high-dose steroids according to consensus guidelines versus early initiation of ruxolitinib and abatacept. Although the sample size was small (n = 40), the study demonstrated a 56.6% improvement in fatality with the early initiation of ruxolitinib and abatacept.² Ongoing clinical trials are looking at the effectiveness of abatacept for treatment of ICI myocarditis NCT05195645 and NCT05335928.^7,8

A key consideration when treating ICI myocarditis with abatacept includes its delayed onset of action. Standard dosing of abatacept (10 mg/kg every 2 weeks) can take several days to take effect. Ruxolitinib was added for its rapid (within hours) onset and similar ability to decrease T-cell activation.¹ In addition, there is no standard for tracking the efficacy of abatacept. Monitoring CD86 receptor occupancy (CD86RO) on circulating monocytes has been proposed with a target CD86RO >80%.⁷ This percentage has been suggested in case studies, but clinical trial validation is lacking.

Conclusions

This case demonstrated successful treatment of triple M syndrome with nonsteroidal immunosuppression (abatacept and ruxolitinib) in a patient on tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor). It also demonstrated the limitation of cardiac MRI in early diagnosis of ICI myocarditis. The number of patients treated with ICIs will continue to increase. From 2011 to 2023, the percentage of tumors eligible for ICI therapy increased from 1.5% to 55%, and tumor response to ICI therapy increased from 0.14% to 20%.⁸ As ICI use increases, the recognition of triple M syndrome will also increase. We need a better understanding of nonsteroidal immunosuppressive therapies in the care of complex overlap syndromes.

Visual Summary.

Case Timeline

Timeline	Events
Admission	A 59-year-old man with hepatocellular carcinoma presented with double vision 19 d after his first dose of tremelimumab and durvalumab. Admission laboratory results were significant for hs-troponin of 1,875 pg/mL, CK of 5,049 U/L, AST of 292 U/L, ALT of 148 U/L, CRP of 8.0 mg/L, and BNP of 13 pg/mL. Physical examination was notable for inability to abduct the left eye, bilateral left upper quadrant visual field defects, right ptosis, and no evidence of volume overload.
Day 2	Cardiac MRI was significant for no evidence of myopericarditis, normal left ventricular function, and normal left ventricular ejection fraction.
Day 3	Prednisone 1 mg/kg was initiated because of high suspicion for triple M syndrome in the setting of elevated hs-troponin, recent ICI use, and elevated creatine kinase (despite negative cardiac MRI).
Day 6	The patient underwent right heart catheterization with endomyocardial biopsy. The biopsy was positive for subacute necrosis with lymphohistiocytic infiltrate, and steroids were increased to methylprednisolone 1 g/day owing to uptrending hs-troponin.
Day 9	Methylprednisolone was decreased from 1 g/day to 500 mg/day.
Day 10	The day after weaning steroids hs-troponin uptrended. The patient received 1 dose of abatacept 10 mg/kg and was continued on methylprednisolone 500 mg/day.
Day 11	The patient was started on ruxolitinib 20 mg twice a day.
Day 12	The patient reported dysphagia and coughing with oral intake. MG treatment was increased to pyridostigmine 90 mg twice daily, and steroids were tapered to prednisone 80 mg/day to minimize the risk of steroid-induced MG exacerbation.
Day 27	The patient was discharged on a prednisone taper, ruxolitinib taper (20 mg twice a day for 44 d followed by 10 mg twice a day for 14 d) and pyridostigmine 90 mg/day. The 1-wk outpatient hs-troponin was normal.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Echocardiogram with Abnormal Global Longitudinal Strain

Echocardiogram on day 6 of hospitalization was significant for a normal left ventricular ejection fraction of 62% and abnormal global longitudinal strain of −10.6%.