Immune Checkpoint Inhibitor–Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases

Abstract

Background

The development of immune checkpoint inhibitors (ICIs) represents a paradigm shift in the treatment of cancers. Despite showing remarkable efficacy, these agents can be associated with life-threatening immune-related adverse events. In recent years, several cases of myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS) have been reported. However, given the rarity, the clinical features and outcomes of these cases remain poorly understood. We, therefore, attempted to systematically review and summarize all cases of IM3OS reported in the literature.

Materials and Methods

Studies reporting IM3OS were identified in Embase and MEDLINE. Only case reports and case series published in journals or presented at conferences were included. We conducted a systematic review according to the PRISMA Harms guidelines.

Results

A total of 60 cases were eligible. The patients’ median age was 71 years, and the majority (67%) were males; melanoma was the most common indication for ICIs (38%). The most-reported symptoms were fatigue (80%) and muscle weakness (78%). The median number of doses to the development of IM3OS was one. The average creatine kinase level was 9,645 IU/L. Cardiac arrhythmias occurred in 67% of patients, and 18% had depressed ejection fraction. Initial treatment consisted of immunosuppression with high-dose steroids and supportive therapies. Sixty percent of the patients died in hospital because of acute complications.

Conclusion

IM3OS can be associated with significant mortality and morbidity. Prospective studies are needed to understand the optimal approach to diagnose and manage these patients and to develop biomarkers to predict the occurrence and severity of this rare but serious condition.

Implications for Practice

Clinicians should suspect coexisting myositis and/or myasthenia gravis in all patients with immune checkpoint inhibitor-induced myocarditis, given their propensity to occur together. Early recognition and prompt treatment with the help of a multidisciplinary team might help improve the outcomes of this life-threatening condition.

Immune checkpoint inhibitors, Myositis, Myasthenia gravis, Myocarditis, Immune-related adverse events, Immune checkpoint inhibitor, Induced myocarditis, Overlap syndrome

Introduction

Immune checkpoint inhibitors (ICIs) represent a paradigm shift in cancer therapy and have revolutionized cancer care. ICIs targeting cytotoxic T-lymphocyte-associated antigen 4, programmed cell death protein 1 (PD-1) on T cells, or its ligand on tumor cells have been U.S. Food and Drug Administration approved for various solid tumors and hematologic malignancies. Despite showing impressive antitumor efficacy, these agents can, however, be associated with wide-ranging life-threatening inflammatory and autoimmune immune-related adverse events (irAEs). ICI-induced myocarditis is one such rare yet severe adverse event and has been reported in <1% of irAEs in clinical trials and institutional series [1].

Although most ICI-induced myocarditis cases tend to occur by themselves, several cases of overlap syndrome with myositis and/or myasthenia gravis have been described, primarily as case reports or small case series. Some researchers have reported the incidence of concurrent myositis and myasthenia gravis in up to 30%–40% and 10% patients with immune-related myocarditis, respectively [2]. However, given the rarity of concurrent myositis and myasthenia gravis, clinical presentation, treatment, and outcomes of these patients remain less clear. We, therefore, attempted to systematically review and summarize all cases of ICI-induced myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS) reported in the literature.

Materials and Methods

Protocol and Registration

The protocol was registered in PROSPERO International Prospective Register of Systematic Reviews (CRD42021242304).

Study Design

We conducted a systematic review according to the PRISMA Harms guidelines (supplemental online Table 1) [3].

Search Strategy

We searched MEDLINE and Embase on July 14, 2021, to identify studies reporting concurrent myocarditis with myositis and/or myasthenia gravis associated with ICIs. We limited our search to studies conducted in humans and published after the first ICI's approval in the U.S. in 2011. We did not apply any language restrictions. We searched the reference section of included articles for additional reports. Our search strategy is described in supplemental online Table 2.

Eligibility Criteria

We included case reports and case series published in journals or presented in conferences. We excluded pharmacokinetic/pharmacodynamic studies and randomized controlled trials. We also excluded case series without detailed patient-level data. The included studies reported patients who received an approved ICI (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, and durvalumab) either as a single-agent or in combination with other ICIs and developed concurrent ICI-induced myocarditis with myositis and/or myasthenia gravis.

Study Selection

Two reviewers (A.K. and R.P.) initially screened the titles and abstracts for eligibility using Microsoft Excel (Microsoft, Redmond, WA). Full texts of citations deemed eligible were retrieved and further assessed for eligibility. All disagreements were resolved through consensus. We achieved complete consensus before inclusion.

Data Extraction

Study and patient characteristics, description of the ICI-induced myocarditis with myositis and/or myasthenia gravis, work-up, and outcomes were extracted by one author (A.K.) and checked for accuracy by a second author (R.P.).

Data Synthesis

We report aggregated data from case reports and case series. No inferential or predictive statistics were computed given limitations in sample size.

Results

After a review of 1,615 citations in MEDLINE and Embase, we included 36 case reports and 6 case series; this resulted in a total of 60 cases of IM3OS (Fig. 1).

Figure 1

Flow diagram describing the systematic search and study selection process.

Abbreviation: ICI, immune checkpoint inhibitor.

Completeness of Reporting Elements and Risk of Bias

All the included case reports and case series provided basic demographic information such as age and sex. Only 11 cases commented on the presence or absence of autoimmune disease at baseline; one patient has chronic lymphocytic lymphoma [4]. Laboratory data and outcome data were incomplete in most of the cases. Survival information was available for 48 cases. The risk of bias assessment is shown in supplemental online Table 3.

Clinical Characteristics

The characteristics of the included patients are described in Table 1. The median age of the patients was 71, and 67% (n = 40) of them were men. The most-reported symptom was fatigue (80%) and muscle weakness (78%). There was no consistent pattern of preexisting autoimmune conditions—only one patient had a prior autoimmune disease [5]. Twenty-two patients were reported to have concomitant myasthenia gravis [4, 6–18]. The median number of doses to the development of IM3OS was one. The mean creatine kinase (CK) level was 9,645 IU/L. Forty patients developed arrhythmias due to myocarditis and 11 patients had depressed ejection fraction (defined as less than 50% by echocardiography; Table 2).

Table 1

Demographic parameters, presenting features, and outcomes of included cases

Author, year	Age	Sex	Indication	ICI	Presenting signs/symptoms	Other irAEs	In-hospital outcome	Best response on ICI?
Ang, 2021	74	F	Melanoma	anti-PD-L1 (agent unclear)	Bilateral shoulder girdle pain/stiffness, fatigue, subjective reduction in effort tolerance	—	Alive	Complete response
Arangalage, 2017	35	F	Melanoma	Nivolumab plus ipilimumab	Dyspnea	Thyroiditis	Alive	—
Arora, 2020	70	M	Melanoma	Nivolumab plus ipilimumab	Palpitations, double vision, right ptosis, presyncope	—	Dead	—
Arora, 2020	79	M	Melanoma	Pembrolizumab	Blurred vision, diplopia, fatigue, lower extremity weakness, diffuse pain	—	Dead	—
Arora, 2020	61	F	Breast cancer	Durvalumab plus tremelimumab	Right eyelid ptosis and hepatitis. During hospital stay, patient developed episodes of chest pain, dizziness, dyspnea	—	Dead	—
Arora, 2020	69	M	Bladder cancer	Pembrolizumab	Diffuse body pain and weakness	—	Dead	—
Arora, 2020	67	F	Melanoma	Nivolumab plus ipilimumab	Diffuse body weakness, dyspnea, dysphagia, hepatitis	Hepatitis	Dead	—
Arora, 2020	83	M	Melanoma	Nivolumab	Marked fatigue, weakness, chest pain and orthopnea. Initially diagnosed as pericarditis and colchicine and naproxen started but presented in a few days with chest tightness, dysphagia, and left eye ptosis	—	Dead	—
Arora, 2020	89	M	Lung cancer	Pembrolizumab	Disconjugate gaze, dysphagia, blurred vision, and imbalance.	—	Dead	—
Behling, 2017	63	M	Melanoma (uveal)	Nivolumab	Moderate pain in the proximal muscle groups of the upper limbs and a slight worsening of a pre-existing dyspnea under chronic obstructive pulmonary disease that had started 10 days after the first infusion of nivolumab	—	Dead	—
Bukamur, 2019	88	F	Lung cancer	Nivolumab	Muscle aches and proximal weakness	—	Alive	—
Charles, 2019	33	M	Hodgkin's lymphoma	Nivolumab	Patient was admitted for an acute interstitial pneumonia associated with hepatitis and cutaneous eruption. He progressed to multiorgan failure.	Pneumonitis, hepatitis, rash	Dead	—
Chen, 2018	43	M	Thymoma	Nivolumab	Moderate chest pain, dyspnea and generalized myalgias without fever, rash, diplopia, or dysphagia.	—	Dead	—
Chen, 2020	69	F	Lung cancer	Camrelizumab	Shortness of breath and weakness of muscle.	Thyroiditis	Dead	—
Fazal, 2020	82	M	Melanoma	Nivolumab	Two weeks of neck stiffness, head drop and gradually increasing fatigue with orthopnea, hypoxia, and dysarthric speech. On examination a unilateral left-sided ptosis, with normal extra-ocular muscle movements. Weakness of orbicularis oculi, neck extensors and flexors.	—	Dead	—
Fazel, 2019	78	F	Melanoma	Nivolumab plus ipilimumab	Diplopia and bilateral proximal muscle weakness/myalgias (greater in the lower extremities), and decreased vibratory sensation in the distal extremities	—	Dead	—
Fuentes-Antras, 2020	75	M	Lung cancer	Pembrolizumab	Severe asthenia, myalgia, profuse sweating, and palpitations which aggravated with diplopia and blurred vision.	Thyroiditis	Dead	Complete response
Fukasawa, 2017	69	F	Lung cancer	Nivolumab	General malaise and double vision	—	Alive	—
Hellman, 2019	84	M	Bladder cancer	Pembrolizumab (with epacadostat)	Drooping of both of eyes, difficulty walking, feeling “imbalanced,” generalized weakness, and mild dysphagia	—	Dead	—
Imai, 2019	70	M	Lung cancer	Pembrolizumab	Fever 2 weeks after receiving the second dose, followed by syncope and muscle weakness and tenderness	—	Dead	—
Jeyakumar, 2020	86	M	Cutaneous SCC	Cemiplimab	Decreased vision in the left eye and a 48-hour history of severe fatigue accompanied by lower back and bilateral hip pain.	—	Dead	—
Johnson, 2016	65	F	Melanoma	Nivolumab plus ipilimumab	Atypical chest pain, dyspnea, and fatigue 12 days after receiving the first dose of nivolumab.	—	Dead	—
Johnson, 2016	63	M	Melanoma	Nivolumab plus ipilimumab	Fatigue and myalgias	—	Dead	—
Kadota, 2019	78	M	Melanoma	Pembrolizumab	—	—	Dead	Partial response
Kadota, 2019	80	M	Melanoma	Nivolumab	—	MG	Alive	Stable disease
Kadota, 2019	63	M	Melanoma	Nivolumab	—	—	Dead	—
Kadota, 2019	65	F	Melanoma	Nivolumab plus ipilimumab	—	—	Dead	—
Kadota, 2019	63	M	Melanoma	Nivolumab plus ipilimumab	—	—	Dead	—
Konstantina, 2019	58	F	Thymoma	Pembrolizumab	Fever, rash, and oral ulcers	—	Dead	—
Konstantina, 2019	30	F	Thymoma	Pembrolizumab	Chest pain and proximal muscle weakness	MG	Dead
Liang, 2021	77	M	Chordoma	Sintilimab and anlotinib.	Acute chest tightness, shortness of breath, and profuse sweating. Bilateral droopy eyelids 5 days later.	—	Alive	—
Lie, 2019	79	M	Mesothelioma	Nivolumab	Severe proximal limb and truncal weakness, dyspnea, and generalized fatigue.		Alive	Progressive disease
Lipe, 2020	49	F	Thymoma	Pembrolizumab	The most common presenting symptoms were dyspnea, ptosis, diplopia, and fatigue	—	Alive	—
Lipe, 2020	67	M	Lung SCC	Durvalumab	—	—	Alive	—
Lipe, 2020	77	M	Urinary bladder cancer	Pembrolizumab	—	—	Dead	—
Lipe, 2020	81	F	Renal cell carcinoma	Nivolumab and ipilimumab	—	—	Alive	—
Lipe, 2020	75	M	Chondroma	Pembrolizumab	—	—	Alive	—
Lipe, 2020	66	F	Renal cell cancer	Nivolumab plus ipilimumab	—	—	Alive	—
Lipe, 2020	74	F	Melanoma	Nivolumab plus ipilimumab	—	—	Dead	—
Liu, 2020	71	M	Melanoma	Nivolumab	Exertional dyspnea and diplopia.	—	Alive
Martinez-Calle, 2018	67	F	Multiple myeloma	Pembrolizumab	Malaise and dyspnea on minimal exertion.	—	Dead	—
Matsui, 2020	69	M	Bladder cancer	Pembrolizumab	Myalgia with slight elevation of CK after first dose which was believed to be due to exercise. Five days after the second dose, patient presented with bilateral diplopia, ptosis, and decreased deep tendon reflexes. Dysesthesia in bilateral hands and feet. Weakness in bilateral iliopsoas and neck muscles	—	Dead	—
Mehta, 2016	79	M	Lung cancer	Nivolumab	Back pain and generalized weakness causing gait instability for two weeks and dyspnea for three days. Patient was hypotensive on presentation and had S3 gallop.	—	N/A	—
Monge, 2018	79	M	Prostate cancer	Nivolumab	Blurred vision and pain and stiffness in the upper back. On examination, Eye was within normal limits and there was tenderness in trapezius muscles and decreased motor strength in arms and neck	—	Alive	—
Nasr, 2018	79	M	Gastric adenocarcinoma	Pembrolizumab	Ten-day history of increasing left ptosis, blurry vision and diplopia. Physical examination revealed complete bilateral ptosis and bilateral external ophthalmoplegia	—	Dead	CT showed partial response
Rota, 2019	71	M	Renal cancer	Nivolumab	Dropped head, limb weakness progressing to inability to walk.	—	Dead	—
Saibil, 2019	67	M	Melanoma	Nivolumab plus ipilimumab	Three-day history of increasing fatigue, weakness, and dyspnea. On presentation, he also complained of feeling presyncopal. In the emergency room, he was bradycardic.	—	Dead	—
Sessums, 2020	74	M	Bladder cancer	Atezolizumab	Patient initially presented to an outside institution with dyspnea and underwent cardiac catheterization with stent placement to the left anterior descending artery but dyspnea continued. Dysphonia, diplopia, dysphagia, ptosis and proximal muscle weakness	—	Dead	—
Shah, 2019	73	M	Bladder cancer	Nivolumab plus ipilimumab	Mild jaw and throat discomfort when swallowing, followed by significant generalized weakness and myalgia, with bilateral ptosis and extraocular muscle weakness	—	Alive	—
Shirai, 2018	83	M	Melanoma	Pembrolizumab	Fatigable weakness and muscle pain 25 days after receiving pembrolizumab. Physical examination revealed bilateral ptosis, diplopia, weakness of neck flexor and extensor, and bilateral thigh myalgia.	MG	Alive	CT after 5 weeks showed stable disease
So, 2019	55	F	Melanoma	Nivolumab	Stiff neck, myalgia, ptosis, dysphagia, dyspnea, progressive ophthalmoplegia, and limb weakness	—	Alive	—
Swali, 2020	77	M	Melanoma	Pembrolizumab	Acute weakness, fatigue, and drooping eyelids.	MG	Alive	Disease progression in brain after few months
Szuchan, 2019	70	F	Thymic cancer	Pembrolizumab	1st admission: Exertional dyspnea. 2nd admission: Dyspnea, orthopnea, and weakness	MG	Alive	improvement with significant decrease or resolution of all measurable sites of metastatic disease in the lungs
Todo, 2020	63	M	Bladder cancer	Pembrolizumab	Grade 3-diarrhea, Grade 3-erythema multiforme with pruritus and left ptosis with diplopia.	MG, colitis, rash	Alive	Complete remission after a single dose of pembrolizumab
Tomoaia, 2020	63	F	Lung cancer	Nivolumab	Dyspnea, progressive fatigue and lethargy six days after the dose of nivolumab. Cardiac arrest on the day of admission.	MG	Dead	—
Valenti-Azcarate, 2019	66	M	Lung cancer	Nivolumab plus ipilimumab	Binocular diplopia, fatigue, mild dyspnea, and upper back pain.	MG	Alive	—
Veccia, 2016	65	M	Lung cancer	Nivolumab	Horizontal diplopia and mild ptosis of the right eye, without other neurologic signs 27 days after the dose of nivolumab. Ten days later, patient developed symmetric proximal muscle weakness, especially to the upper limbs.	MG	Dead	—
Witham, 2017	74	M	Melanoma	Nivolumab plus ipilimumab	Exertional dyspnea, fever, diplopic images, and muscle weakness. Neurological examination revealed bulbar deviation and ptosis on the left side.	—	N/A	—
Xing, 2017	66	M	Lung cancer	Sintilimab	Fatigue, myalgia, and tender muscles in both the upper and lower extremities four days after second dose of sintilimab followed by shortness of breath and progressive muscle weakness eight days later.	Myasthenic crisis	Alive	CT scan done after 2 months of sintilimab treatment showed disease progression
Yanase, 2020	59	M	Renal cell cancer	Nivolumab plus ipilimumab	Bilateral ptosis and malaise, and left eyeball adduction, descent, and taste were also impaired.	—	Alive	Partial response of metastatic lung disease

Note: —, unavailable/unreported data.

Abbreviations: CK, creatine kinase; CT, computed tomography; F, female; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; M, male; MG, myasthenia gravis; N/A, not available; SCC, squamous cell cancer.

Table 2

Summary of patients described in the case reports/case series

Parameter	Single-agent ICI therapy (n = 47)	Dual-agent ICI therapy (n = 13)	Overall (n = 60)
Age, years, median (range)	72 (30–89)	65 (35–78)	71 (33–89)
Male	34	6	40
Female	13	7	20
Indication for ICI
Melanoma	14	9	23
Lung	10	2	12
Bladder	6	1	7
Other	17a	1b	18c
Prior autoimmune disease
Yes	1	0	1
No	8	2	10
Unknown	38	11	49
Concomitant myasthenia gravis	13	3	16
Median number of doses to development of symptoms	1	1	1
Average creatine kinase (IU/L)	7,662.3	11,628.3	9,645.3
Arrhythmias
Yes	31	9	40
No	3	0	3
Unknown	13	4	17
Depressed ejection fraction
Yes	8	3	11
Treatment strategies
Steroids	47	13	60
Infliximab	2	3	5
Tacrolimus	0	1	1
Mycophenolate	6	2	8
Plasmapheresis	4	3	7
ATG	1	2	3
IVIG	13	5	18
Rituximab	1	0	1
In-hospital outcomes
Alive	21	2	23
Died	25	10	35
Unknown	1	1	2

Single-agent ICI therapy refers to single agent anti-programed cell death 1 (ligand 1) therapy such as pembrolizumab or nivolumab. Dual-agent ICI therapy refers to ipilimumab + nivolumab or durvalumab + tremelimumab.

^a Cutaneous SCC 1, gastric 1, Hodgkin's lymphoma 1, mesothelioma 1, multiple myeloma 1, prostate 1, renal 4, thymoma 4, thymic carcinoma 1, chondroma 1, chordoma 1.

^b Breast 1.

^c Cutaneous SCC 1, gastric 1, Hodgkin's lymphoma 1, mesothelioma 1, multiple myeloma 1, prostate 1, renal 4, thymoma 4, thymic carcinoma 1, chondroma 1, chordoma 1, breast 1.

Abbreviations: ATG, antithymocyte globulin; ICI, immune checkpoint inhibitors; IVIG, intravenous immunoglobulin; SCC, squamous cell cancer.

Electrodiagnostic Tests

Electromyography (EMG) and/or nerve conduction studies were reported in 11 cases [4, 7, 9, 11, 19–25]. Most cases reported proximal muscle myopathic patterns with moderate to severe muscle injury. EMG was reported as within normal limits in three cases [7, 23, 24]. Repetitive nerve stimulation (RNS) studies are the most frequently used electrodiagnostic test for myasthenia gravis and is considered to be positive (i.e., abnormal) if the decrement in the compound muscle action potential amplitude with electrical stimulation 6 to 10 times at low rates (2 or 3 Hz) is greater than 10 percent. Single-fiber electromyography is less widely available but is the most sensitive diagnostic test for myasthenia gravis [26]. Electrodiagnostic test results were not consistently described in the case reports; only three cases detailed the electrodiagnostic test findings in which the diagnosis was considered to be myasthenia gravis [4, 11, 21].

Serologic Testing for Myasthenia Gravis

Although the majority of patients with myasthenia gravis have detectable autoantibodies against the acetylcholine receptor (AChR) or against another target on the surface of the muscle membrane (muscle-specific receptor tyrosine kinase [MuSK] or low-density lipoprotein receptor-related protein 4), some have antibodies against other skeletal muscle proteins such as titin and/or ryanodine (so-called “anti-striated muscle antibodies”) [26]. Less than 10% of patients can have seronegative myasthenia gravis, in which patients have negative standard assays for both AChR antibodies and MuSK antibodies. Results of the antibody testing were not consistently described in the case reports. All three cases in which electrodiagnostic testing suggested myasthenia gravis had positive anti-AChR antibodies [4, 11, 21]. Todo et al. described a case of seronegative myasthenia gravis, although electrodiagnostic testing was reported to be negative [27]. Anti-AChR antibodies were reported to be positive in the majority of cases in which concurrent myasthenia gravis was diagnosed [4, 6, 7, 10–12, 21, 28].

Cardiac Imaging

Eleven cases had cardiac magnetic resonance imaging (MRI) with features suggestive of myocarditis [4, 14, 20, 29–33]. Although a full description of MRI findings was not available in all cases, Arora et al. described evidence of myocardial edema and late gadolinium enhancement in the subepicardial midinferior wall consistent with acute myocarditis in one case. Only a slight myocardial gadolinium uptake was described by Witham et al. [33]. Two cases did not show any evidence of myocarditis: one of the cases had cardiac MRI performed 8 days after starting immunosuppression when cardiac biomarkers had already improved [4].

Histological Findings

Eighteen cases reported muscle biopsy results, with most cases describing myofiber necrosis and atrophy with lymphocytic (predominantly CD8 + T cell) and macrophage infiltrates [5, 9, 11, 12, 20, 21, 23, 24, 34–39]. One case reported negative inflammatory cell infiltration or necrosis [24]. Fifteen cases had cardiac biopsies [10, 12, 13, 18, 22, 24, 31, 33–36, 39, 40]. Most cases described lymphocytic infiltrate (which was positive for T-cell markers, both CD4 and CD8) with CD68 positive macrophages. Variable extent of myocyte injury was described; only six cases [10, 12, 13, 24, 34, 35] described both myocyte injury, and inflammatory infiltrate consistent with the Dallas criteria for myositis and the World Heart Federation criteria for the diagnosis of acute myocarditis [41, 42]. Fukasawa et al. reported the expression of human leukocyte antigen (HLA)-ABC and HLA-DR on myocardial cells in addition to the CD4 and CD8 T-cell infiltrations [13]. Some cases also described early interstitial fibrosis and endocardial fibrosis in areas of inflammatory infiltration, likely representing healing response [18, 33, 35]. Two case reports specifically described negative staining for CD20 expressing B lymphocytes [35, 39].

Treatment

Treatment consisted of two strategies: immunosuppression and supportive therapy. Corticosteroids were the most used primary immunosuppressive therapy (100%), with mycophenolate and cyclophosphamide being the most common steroid-sparing agent. Although upfront plasmapheresis and intravenous immunoglobulin (IVIG) were used in most patients with concurrent myasthenia gravis, these autoantibodies directed therapies were not limited to patients with myasthenia gravis (Table 2; supplemental online Table 4). Adjunctive immunosuppressive therapies were used primarily after failing initial steroids (82%, 18 out of 22 patients in which the case reports described the sequence of drug therapy).

Clinical Outcomes and Follow-up

Of the 58 patients with known survival, 35 (60%) patients died in the hospital because of acute complications. None of the survivors (n = 23) were rechallenged with ICIs in our series.

Discussion

We report the most extensive case series of IM3OS to date. In our study, most cases presented early, melanoma was the most common underlying malignancy, and the case fatality rate was high.

Although rare, ICI-related myocarditis is a life-threatening complication of ICI therapy, with mortality ranging from 25% to 50%. [2, 43] Although most cases of ICI-related myocarditis occur in isolation, concurrent development of myositis and/or myasthenia gravis has been reported in up to 30%–40% of cases [44]. Although the underlying mechanisms for the overlap of myositis/myasthenia gravis and myocarditis in ICI-treated patients remain unclear, molecular mimicry and the critical role of PD-1 signaling pathways in regulating autoimmune responses in these tissues might be responsible [45, 46]. Given the high rates of co-occurrence of these three conditions, it is essential to screen patients for the other two adverse events when one of these overlapping adverse events is seen. Work-up for ICI-induced myocarditis involves a high index of suspicion, electrocardiographs, and cardiac cytolysis biomarkers such as troponins and CK-MB [47]. Diagnosis is based on excluding acute coronary syndrome with a negative coronary angiography and tissue characterization with cardiac MRI and/or endomyocardial biopsy [45, 47]. Although the diagnosis of myocarditis has been historically based on histologic demonstration of myocardial inflammation and myocyte injury, these criteria might not be applicable in the immunotherapy era [48, 49]. Furthermore, because many cases of myocarditis in our series only reported inflammatory infiltrate without myocyte injury, the question remains whether the demonstration of myocyte injury is essential for ICI-treated patients. Further research is needed to refine the diagnostic criteria for myocarditis in ICI-treated patients and to develop and validate noninvasive imaging techniques such as cardiac MRI in these patients [49].

ICI-induced myositis tends to have a broad spectrum ranging from mild symptoms to life-threatening complications [50]. In a study based on the World Health Organization pharmacovigilance database, Allenbach et al. identified 465 cases of myositis with an overall incidence of <1%. Most patients were elderly with a median age of 70, slightly favoring males (56.4%). Median onset for myositis was the shortest among rheumatic irAEs (arthritis, myositis, sarcoidosis, Sjogren's syndrome, scleroderma, and polymyalgia rheumatica) (median 31 days; range 19.2–57.8), with the highest fatality rate (24%), especially when associated with myocarditis (57%) [50]. In our study, most of the cases developed symptoms of myositis within a median of one ICI dose. The most common presenting symptoms included myalgia, proximal limb weakness, and myasthenia symptoms. Most cases were rapidly progressive, contrasting the relatively indolent onset in primary autoimmune polymyositis [51]. All cases reported elevated CK levels. There have been several cases of CK-negative myositis with ICIs [52, 53]. Aldolase/CK discordance has been hypothesized to be due to high aldolase levels in regenerating myocytes, which tend to be preferentially involved in myositis [54]—aldolase level, therefore, should be checked even if CK levels are normal in the right setting.

ICI-induced myositis can be associated with myasthenia gravis in up to 40% of patients, which can present with visual, bulbar, or respiratory symptoms [44]. Given the relatively high incidence, patients presenting with immune-related myositis or myocarditis should be screened early for myasthenia gravis, given the risk of myasthenic crisis and adverse outcomes. In contrast to classical myasthenia gravis, immune-related myasthenia gravis tends to be life-threatening with higher rates of respiratory paralysis and death [55]. Despite the high morbidity and mortality, the diagnosis of immune-related myasthenia gravis is challenging given the lower positivity rates of RNS and anti-AChR autoantibodies (both approximating 60%) and a higher incidence of seronegativity [55]. Although the presence of thymoma is a crucial component of the pathogenesis of classical myasthenia gravis (and a potential diagnostic clue), it is not relevant to immune-related myasthenia gravis [55].

ICI-induced myositis has been described to be associated with CD8+ T lymphocytes and macrophage infiltration (some resembling granulomas) with myofiber necrosis mimicking necrotizing myositis [56]. Matas et al. reported marked necrosis, macrophagy, muscle regeneration with perivascular inflammatory infiltrates, and a significant component of macrophagic cells on a pathologic review of muscle biopsy from nine patients [56]. ICI-induced myocarditis shares similar features with a predominance of T cells (especially CD8+ T cells). These findings have led to the use of T-cell targeted therapies with significant benefit in patients with steroid-refractory ICI-induced myocarditis [57–59]. However, Balanescu et al. recently reported complement deposition within capillaries (pericapillary C4d) in two cases of ICI-induced myocarditis, suggesting a component of antibody-mediated injury [60]. This perhaps explains successes of using therapies directed against antibody-mediated autoimmunity such as IVIG and plasmapheresis in a few case reports of IM3OS [61, 62].

All cases of IM3OS in our series were treated with high-dose corticosteroids as per the current guidelines for immune-related myocarditis [63]. In addition to the steroids, most patients with concurrent myocarditis and myasthenia gravis received upfront IVIG and plasmapheresis, given concerns regarding paradoxical exacerbation of myasthenia symptoms with steroids alone [28, 64]. However, some case reports employed IVIG and plasmapheresis even without myasthenia, highlighting the uncertainty in our understanding of the pathogenesis of myocarditis and myositis overlap syndromes. In addition to steroids and IVIG/plasmapheresis, other immunosuppressive drugs such as tacrolimus, infliximab, mycophenolate mofetil, or antithymocyte globulin were used as adjunctive therapies in patients without rapid improvement on steroids.

Finally, we found significant in-hospital mortality in cases with IM3OS, with mortality rates approaching 60%. This underscores the importance of a high index of suspicion for concomitant myocarditis in patients presenting with ICI-induced myositis and/or myasthenia gravis (or vice versa) to avoid delays in the diagnosis and treatment. High morbidity and mortality associated with IM3OS probably explain why none of the included patients were rechallenged with ICIs. Additionally, given the high mortality with IM3OS, patients might benefit from an upfront initiation of adjunctive immunomodulatory treatments, although this needs to be studied in prospective studies.

Limitations

Our study has several limitations. Owing to variability in the data available from case reports, there were missing data on clinical features, diagnostic studies, hospital course, and outcomes of some patients, subjecting our results to reporting bias. Given the reasons mentioned above, we relied on the case reports’ authors to adjudicate the diagnosis of concurrent myasthenia gravis. Some laboratory data parameters could not distinguish whether the lack of reporting reflected normal results versus the test not being conducted. Because our sample size was potentially nonrepresentative, we did not estimate any accuracy parameters.

Conclusion

Our study shows that IM3OS tends to develop early with ICI treatment and can be associated with significant morbidity and mortality. Prospective studies are needed to determine the biomarkers to predict the occurrence and severity of IM3OS and the optimal approach to diagnose and manage ICI-treated patients with this potentially life-threatening complication.

Author Contributions

Conception/design: Ranjan Pathak, Anjan Katel

Administrative Support: Anjan Katel

Collection and/or assembly of data: Ranjan Pathak, Anjan Katel, Erminia Massarelli, Victoria M Villaflor, Virginia Sun, Ravi Salgia

Data analysis and interpretation: Ranjan Pathak, Anjan Katel, Erminia Massarelli, Victoria M Villaflor, Virginia Sun, Ravi Salgia

Manuscript writing: Ranjan Pathak, Anjan Katel

Critical revision and final approval of manuscript: Ranjan Pathak, Anjan Katel, Erminia Massarelli, Victoria M Villaflor, Virginia Sun, Ravi Salgia

Disclosures

Erminia Massarelli: Merck, AstraZeneca, Eli Lilly & Co. (C/A); Vicky Villaflor: AstraZeneca, Bristol-Myers Squibb, Genentech (C/A), Takeda (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Author notes

No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact [email protected]. For permission information contact [email protected].

Disclosures of potential conflicts of interest may be found at the end of this article.