Immune checkpoint inhibitors (ICI) mainly include anti-programmed cell death protein 1 (PD-1) antibodies (e.g., nivolumab, pembrolizumab, tislelizumab, etc.), anti-programmed Cell Death Protein-Ligand 1 (PD-L1) antibodies (e.g., atezolizumab, durvalumab, etc.), and anti-cytotoxic T Lymphocyte-Antigen 4 (CTLA-4) antibodies (e.g., ipilimumab, etc.). Typically, tumors directly or indirectly reduce the intensity and extent of the immune response through immune checkpoints to maintain the self-tolerance of tumor cells in their surrounding normal tissues and to evade immune detection. Specifically, targeted binding of anti-PD1, anti-PDL1, and anti-CTLA4 antibodies enhances the anti-tumor immune response and accelerates host-mediated destruction of malignant cells by promoting immune surveillance (1). ICI have been widely used to treat non-small cell lung cancer (NSCLC), metastatic melanoma, renal cell carcinoma, and other tumors (2, 3). Nonetheless, the incidence of adverse drug reactions is on the rise, especially the non-specific characteristics of neurological Immune-induced adverse events (NirAEs), which are challenging to recognize and treat (4).

Immune-induced adverse events (IrAEs) have the potential to affect any organ system. However, the gastrointestinal tract, endocrine glands, skin, liver, and lungs are the most frequently involved, with a lower incidence of NirAEs. However, it is associated with higher mortality (5). The most commonly reported symptom of NirAEs is headache. They may also involve the peripheral and central nervous system (6). Myasthenia gravis (MG) is an autoimmune disorder impacting the neuromuscular junction, commonly identified by symptoms like ptosis and diplopia. In severe cases, it may involve the respiratory and masticatory muscles, leading to dyspnea and dysphagia. Acetylcholine receptor antibodies (AChR-Abs) and anti-muscle specific kinase antibodies (anti-MuSK Abs) are highly diagnosis-specific, with detection rates of around 85 and 10%, respectively (7, 8). ICI-induced MG is more difficult to diagnose and is often combined with myositis and/or myocarditis, with a rapid progression of the disease, often leading to patient death (9). Early recognition and effective clinical management are crucial. We reviewed our institution’s database and searched the literature for relevant case reports to summarize the prognostic and clinical characteristics of 110 patients with MG in the context of receiving ICI.

Out of 961 unique articles identified in the literature, 96 publications, detailing 101 patients, met the inclusion criteria, with an additional 9 patients identified from PLAGH. Consequently, our final analysis encompassed a total of 110 patients; Median age was 72 years (range: 30–90 years), 67 were males. The most common type of cancer was melanoma (n = 34), followed by lung cancer (n = 31). 12 patients had a previous history of MG. Most patients received PD-1 inhibitors. 55 patients were diagnosed with MG combined with myositis and/or myocarditis. Among them, myositis was also diagnosed in 20 and myocarditis in 25; 10 had the triad of MG/myositis/myocarditis. For patients with the triad of MG/myositis/myocarditis, all patients had a rapid onset of illness after receiving the first or second cycle of ICI therapy. Almost all patients received steroids, and the remaining common treatments included intravenous immunoglobulin (IVIG; n = 9), acetylcholinesterase inhibitors (n = 5), and mechanical ventilation (n = 5). Eventually, 7 patients reported death.

9 patients from PLAGH were diagnosed with ICI-induced MG. The clinical data of the patients were summarized in Table 1. Their median age was 66 years (range: 49–79 years). 6 patients were male. The most common type of cancer was lung cancer (n = 4), followed by esophageal cancer (n = 2). None of the 9 patients had a previous history of MG, and all received PD-1 or PD-L1 inhibitors. 4 patients were treated with ICI combined with targeted therapy, three with ICI combined with chemotherapy, one with ICI combined with HDAC inhibitor, and one with ICI alone therapy. The PDL1-expression level on tumor cells was available for 5 patients: < 1% for 3%, 1%–49% for 1, and >50% for 1. Of these patients, 5 patients developed symptoms immediately after their first or second ICI. The median time from ICI initiation to first MG symptoms was 4 weeks (range: 2–15 weeks) (Figure 2).

The most common symptoms at first presentation were ptosis (n = 5) and dysphagia (n = 5), and the rest of the frequent symptoms included dyspnea and limb weakness and excluded exacerbation of symptoms due to progression of the primary tumor. Myocarditis was also diagnosed in 6 patients, myositis was diagnosed in 3 patients, and liver injury in 2 patients. 4 patients were found to have positive anti-AChR antibodies. 7 patients were detected with elevated creatine phosphokinase (CPK; median 2,208 IU/L, range: 380–9,994 IU/L). 2 patients had electromyography showing myogenic injury, and one patient had a muscle biopsy showing disseminated myofibrillar necrosis with type II myofibrillar atrophy. Computed tomography or magnetic resonance imaging was performed in 7 patients to rule out brain metastases or acute intracranial events. 3 patients had abnormal electrocardiograms on admission, demonstrating third-degree atrioventricular and right bundle branch blocks.

ICIs were stopped for all patients. They all received corticosteroids, 5 with acetylcholinesterase inhibitors, 6 with immunoglobulins, and the rest of the treatments included rituximab and mycophenolate mofetil (MMF). Overall, MG symptoms improved in 8 and worsened in 1 patient. 3 patients reported death, and the cause of death was systemic organ failure, all due to the tumor. Six patients are currently alive.

We searched medical records and reviewed the literature for ICI-induced MG. NirAEs are less common, with incidence rates of only 1%–5% (10), with an incidence of 0.2% for irAE-MG. Compared with other irAEs, the mortality rates are high (11). According to meta-analyses of clinical trials, the incidence of any grade of irAE was 66 and 72% for PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, respectively. The incidence of severe irAE was 14 and 24% for PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, respectively (12, 13), and 0.3%–1.3% were lethal (14).

There were no differences in the clinical features and prognosis of ICI-induced MG between patients with previous MG episodes and those experiencing new-onset disease. The actual incidence of MG episodes following ICI in patients with a previous MG diagnosis remains unknown, primarily due to the absence of pertinent cohort studies. In addition, conventional studies often exclude individuals with a history of autoimmunity, posing challenges in evaluating the impact of ICI in substantial subject cohorts. The precise mechanism through which ICI induces MG remains currently unknown. It remains questionable whether patients with new-onset MG have subclinical autoimmunity that manifests only after exposure to ICI. Studies have demonstrated that CTLA-4 knockout mice can spontaneously develop MG (15). Furthermore, specific CTLA-4 genetic variants predispose individuals to MG, particularly in Caucasian and East Asian populations (16, 17). Overexpression of PD-1 is linked to favorable outcomes in autoimmune diseases, as it facilitates CD8 T cell depletion; however, PD-1 inhibitors may worsen symptoms in individuals with pre-existing MG (18). Currently, additional studies are required to validate these findings.

A review of 110 cases supports that ICI-induced MG is a life-threatening irAE that rapidly deteriorates shortly after ICI initiation. 32 patients presented with dyspnea requiring mechanical ventilation. In addition, we found that ICI-induced MG was often concurrent with myocarditis and/or myositis. 110 patients were grouped into a control group without other irAEs and an experimental group with other irAEs, such as myocarditis and myositis. The results showed a higher mortality in the MG combined myositis/myocarditis group. Our study supports that ICI-mediated MG and its overlapping syndrome occur early after the initiation of therapy and are associated with significant mortality.

ICI-induced MG have a 57%–83% positive rate of anti-AchR antibodies, in addition to the common neostigmine test and ice test, and some patients may be combined with hyper CPK and even positivity of myositis-associated antibodies, which often suggests that simultaneous combination of ICI-induced myositis may be possible. In our study, 70 patients were positive for anti-AchR antibodies, in addition to Anti-AchR, Anti-Striated muscle antibodies (antititin, anti-heart muscle, and anti-skeletal muscle autoantibodies) have been identified in both ICI-induced MG and myositis (19, 20), While myositis-specific autoantibodies tend to be negative (21–23). Müller-Jensen et al. studies have demonstrated that the presence of ICI-induced neuromuscular disease in cancer patients with 80 and 88% sensitivity and specificity, respectively, for the detection of these autoantibodies. Neuromuscular autoantibodies may serve as viable markers for the diagnosis and potential prediction of life-threatening ICI-induced neuromuscular diseases (24).

7 patients were treated with PD-1 combination with CTLA-4 inhibitor, six of whom had comorbid myositis and/or myocarditis, suggesting that the combination of the two drugs may be associated with a higher incidence of irAE. The reported incidence and distribution of irAE may vary by drug type, PD-1, PD-L1, CTLA-4, or combination. The incidence of serious irAE is as high as 27% with anti-CTLA4 compared to 16% with anti-PD1 and may increase to 55% when both therapies are used concurrently (25). Meanwhile, the incidence and severity of irAE are higher when CTLA-4 inhibitors are used alone or in combination with PD-1 or PD-L1 drugs, such as ipilimumab and nivolumab, regardless of the treatment of the primary tumor (26–28). A meta-analysis showed that the risk of irAE was elevated in solid tumors when ICI was added to chemotherapy, regardless of the drug (and tumor type) used (29).

Myocarditis and NirAEs are life-threatening initial irAEs, and clinicians should be more cautious in evaluating ICI rechallenge in these patients. Therefore, more evidence is needed to assess the safety and efficacy of rechallenge. Pembrolizumab and nivolumab were the most frequently utilized ICI in various studies, serving as both primary and secondary therapies. Moreover, these agents share similar three-dimensional structures and effector mechanisms; nevertheless, pembrolizumab exhibits a higher affinity for recombinant human PD-1 compared to nivolumab (30). Kan et al. demonstrated an enhanced response in four melanoma patients treated initially with nivolumab and subsequently with pembrolizumab (31). In a cohort encompassing diverse cancer types, predominantly melanoma and lung cancer, Simonaggio et al. reported a modest improvement in overall response rate with anti-PD-1 or anti-PD-L1 inhibitors. This finding suggests that, within the context of successful and well-tolerated primary treatment, which may support re-treatment with the same drug or drug group, the initial response to ICI treatment could serve as a crucial predictor of re-challenge efficacy (32, 33). Currently, prior or combined radiotherapy, chemotherapy, or targeted therapy is regarded as a promising strategy to enhance the effectiveness of both primary and secondary immunotherapy. Research by Niki et al., Watanabe et al., and Xu et al. has indicated that patients who exhibited a positive response to a second ICI received intermittent treatment with radiotherapy, chemotherapy, or targeted therapy, particularly in patients with NSCLC (34–36).

9 patients in MG symptomatic remission could be rechallenged with ICI without compromising ICI efficacy at a reduced dose of steroids, prophylaxis with pyridostigmine, and/or IVIG after carefully evaluating available treatment options. There needs to be adequate literature on the impact of rechallenge on survival, irAE recurrence, and the incidence of new irAE. Despite the risk of recurrent irAE, initiating ICI after discontinuation for prior MG may be partially safe with careful clinical monitoring and aggressive prevention. An investigation on the safety of rechallenge revealed that the recurrence rate of irAE varied based on the organ involved in the initial irAE. It was lower in patients re-initiated with the same ICI drug or ICI combination compared to those re-initiated with a different ICI drug or ICI combination (p = 0.02). The median duration of ICI discontinuation to re-initiation and the severity of the initial irAE were not predictive of recurrent irAE after ICI re-initiation (37). Previous literature shows that periodic irAE is not as severe as the first one and that patients continue to respond to medication after the episode (38).

As shown in the current study, ICI-induced MG is often combined with myositis and/or myocarditis and is significantly associated with poor prognosis (39). We observed that patients with combined myositis and/or myocarditis had a significantly shorter time to disease onset after the first or second dose of ICI treatment than patients with MG alone. This trend toward early onset of disease may indicate that flares and/or progression in the myositis and/or myocarditis group were more rapid in patients with poorer outcomes. Although ICI toxicity may occur at any time during treatment, Our findings align with prior studies indicating that fatal ICI toxicity often manifests early, potentially within 4 weeks of treatment initiation or shortly after the initial dose (40). Other studies have confirmed troponin as a possible predictor and have used elevated creatinine and decreased urea and hemoglobin as early biomarkers in dying patients (41).

ICI-related MG hardly resolves spontaneously and requires immediate hospitalization once detected. In terms of treatment, patients require immediate discontinuation of ICI. The current study found that this group of patients responds poorly to acetylcholinesterase inhibitor therapy unless symptoms are nonprogressive and mild, but high-dose methylprednisolone shock combined with IVIG or plasma exchange has been recommended as an important therapeutic measure in studies of ICI-related MG treatment. It can be used to alleviate myasthenia gravis crisis. In addition, a combination of immunomodulators such as MMF, rituximab, and infliximab may be considered in addition to the above treatment options. Patients with overlap syndrome have a potentially fatal risk of rapid progression to serious adverse events, and the main interventions currently available for this group of patients include recognition of the triad, airway support, administration of high-dose methylprednisolone, and ensuring early involvement of the multidisciplinary team.

The fact that ICI-induced MG is a relatively uncommon complication limits the study. There are no established diagnostic standards for diagnosing MG, myositis, and myocarditis. In particular, MG can be diagnosed in some patients who are negative for AChR antibodies. The results of our study will help clinicians familiarize themselves with the clinical features of ICI-induced MG. They will help them to make an early diagnosis of the disease and intervene promptly. In addition, our findings offer a safety signal for patients with no available alternatives in advanced stages that may help clinicians balance each patient’s advantages and disadvantages.

Although ICI-induced MG is rare, it often involves the respiratory muscles, leading to dyspnea and high mortality. Moreover, most patients remain symptomatic after treatment, seriously affecting their quality of life. In addition, half of the patients with ICI-induced MG often have a combination of myositis and/or myocarditis, which contributes to the rapid deterioration of the patient’s disease. Therefore, it is essential to recognize this possible complication as early as possible in patients treated with ICI, and the necessity of a multidisciplinary strategy and multimodal active treatment should also be recognized.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

YQ: Conceptualization, Data curation, Formal analysis, Methodology, Software, Supervision, Writing – original draft, Writing – review & editing. SC: Conceptualization, Data curation, Formal analysis, Methodology, Software, Supervision, Writing – original draft, Writing – review & editing. QG: Conceptualization, Data curation, Formal analysis, Methodology, Software, Supervision, Writing – original draft, Writing – review & editing. TZ: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. YLi: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. ZD: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. YLv: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. XD: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. YH: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing. ZL: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing.