Efgartigimod as Rescue Therapy for PD-1 Inhibitor–Associated Myasthenia Gravis, Myocarditis, and Myositis (MMM) Syndrome: A 2-Case Report and Literature Review

Introduction

Immune checkpoint inhibitors (ICIs) mainly activate CD8-positive T cells to produce antitumor effects in several advanced malignancies by targeting negative immune regulators, such as programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 [1], and lymphocyte activation gene-3 [2]. Despite ICIs having revolutionized tumor immunotherapy, they cause a higher frequency of immune-related adverse events (irAEs), including severe and fatal fulminant complications, which have resulted from the extensive use of ICIs [3]. For instance, myocarditis represents the most prevalent adverse cardiotoxicity related to ICI, manifesting as a spectrum of arrhythmias in the early stages [4–6]. Neuromuscular disorders, which predominantly consist of myositis, myasthenia gravis, demyelinating polyneuropathy, and overlap syndromes, account for 50% of neurological irAEs. To date, there has been an increasing number of case reports of the triple overlapping syndrome of myasthenia gravis, myocarditis, and myositis (MMM syndrome).

Managing irAEs involves assessing the severity of symptoms to determine if ICI therapy should be temporarily halted or permanently discontinued, along with administering high doses of glucocorticoids and other immunosuppressive therapies [7]. In managing neuromuscular and cardiac irAEs, such as MMM syndrome, current practices often draw from guidelines for myasthenia gravis and myocarditis, usually involving a combination of corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange. However, several reports have shown that in MMM syndrome, these measures are often slow or incomplete in reversing neuromuscular weakness and myocardial damage, with a substantial proportion of patients progressing to myasthenic crisis or even death. In addition, these regimens cause broad immunosuppression and can theoretically blunt the antitumor effects of ICIs [8]. Therefore, there is a clear unmet need for adjunctive therapies that can rapidly and selectively remove pathogenic autoantibodies while minimizing interference with antitumor immunity in severe and fatal irAEs.

Efgartigimod, a humanized immunoglobulin G (IgG1) Fc fragment, targets the neonatal Fc receptor (FcRn) to disrupt its interaction with IgG, resulting in decreased IgG recycling and increased degradation of total IgG, including pathological autoantibodies. With continued preclinical and clinical research, efgartigimod has shown encouraging prospects in treating autoimmune and infectious diseases [9,10]. Unlike systemic immunosuppressive therapies, such as corticosteroids, FcRn inhibition increases IgG clearance without affecting IgG production and appears to have limited effects on other immunoglobulin classes and immune effector pathways; Compared with IVIG or plasmapheresis, it provides a targeted pharmacological strategy to lower circulating IgG by accelerating IgG catabolism, and may be more amenable to repeat dosing as a potential maintenance approach [11]. This prompted us to speculate that efgartigimod could be a new supplementary method for treating ICI-related MMM syndrome and myasthenic crisis.

Here, we report the use of efgartigimod in 2 cases of the PD-1 inhibitor–associated MMM syndrome. This report aims to detail the clinical features, treatment, and results of 2 patients with MMM syndrome linked to PD-1 inhibitors who received adjunctive efgartigimod, and to investigate possible factors affecting treatment response.

Case Reports

CASE 1:

A 42-year-old man with metastatic pleural mesothelioma and liver cancer started combination therapy with paclitaxel (450 mg), nedaplatin (70 mg), and camrelizumab (200 mg). Three days after treatment initiation, he developed bilateral ptosis and diplopia. Five days after treatment initiation, he experienced generalized fatigue, myalgia, dysphagia, and progressive weakness of neck extension, resulting in impaired mobility and the need for a liquid diet.

His medical history was notable for thymoma infiltrating the left upper lung, for which he underwent thymectomy and left upper lobectomy 3 years earlier, followed by adjuvant chemotherapy. He had no prior history of neuromuscular disorders or eye-related symptoms and no history of heart disease.

Eighteen days after camrelizumab initiation, he was admitted to the oncology department. On the first day of admission (day 1), initial laboratory test results revealed markedly elevated high-sensitivity troponin I (3700.6 ng/L; reference range <26.2 ng/L), creatine kinase-MB (>300 ng/mL; range <6.6 ng/mL), total creatine kinase (>13 000 U/L; range 26–140 U/L), aspartate aminotransferase (1484 U/L; range 8–40 U/L), and alanine aminotransferase (560 U/L; range 5–35 U/L) (Figure 1). Electrocardiography showed sinus tachycardia, complete right bundle branch block, and T-wave abnormalities. Transthoracic echocardiography demonstrated no structural abnormalities.

On day 1, high-dose IV methylprednisolone (500 mg/day) and IVIG (30 g/day) were initiated.

Despite treatment, the patient’s respiratory status deteriorated. On day 4, he developed myasthenic crisis with severe hypercapnic respiratory failure (PaCO₂ 85 mmHg) and was transferred to the intensive care unit (ICU) for endotracheal intubation and mechanical ventilation. A tracheostomy was performed on day 10. He subsequently received steroid pulse therapy (500 mg/day for 6 days with gradual taper) and underwent plasma exchange (7 sessions per week).

Although cardiac biomarkers and creatine kinase levels declined significantly and sinus rhythm was restored, neuromuscular symptoms persisted, including severe bulbar weakness and ventilator dependence.

On day 11, serum anti-acetylcholine receptor (AChR) antibody was positive (2.973 nmol/L; range <0.5 nmol/L), while anti–muscle-specific receptor tyrosine kinase (MuSK), anti-titin, anti– voltage-gated calcium channel (VGCC), and anti-LRP4 antibodies were negative.

According to the Society for Immunotherapy of Cancer (SITC) clinical practice guidelines for adverse events related to ICI [12], soon after PD-1 inhibitor exposure, myocarditis was diagnosed based on a significant increase in high-sensitivity troponin I levels and new electrocardiographic abnormalities (sinus tachycardia, complete right bundle branch block, and T-wave alterations). Transthoracic echocardiography showed no alternative explanations for structural heart disease or elevated troponin levels. The concomitant myositis diagnosis was supported by pronounced myalgia and weakness, and creatine kinase and transaminases were significantly elevated in a pattern consistent with muscle damage. The diagnosis of myasthenia gravis was supported by typical ocular manifestations (ptosis, diplopia, dysphagia, cervical extensor weakness), rapid progression to hypercapnic respiratory failure requiring mechanical ventilation, plus serologically confirmed positive AChR antibodies and negative anti-MuSK and other tests for myasthenia gravis–related antibodies.

On day 11, adjunctive efgartigimod (800 mg weekly) was initiated for 4 consecutive doses. After the first infusion, ptosis improved, and the patient was intermittently removed from ventilatory support. Oral intake was resumed with a soft diet, and rehabilitation training was started. On day 22, he was successfully weaned from mechanical ventilation. He was transferred to the general ward on day 23.

After completion of 1 treatment cycle, anti-AChR antibody levels slightly decreased to 2.758 nmol/L. Steroids were tapered to 20 mg/day by day 32. The patient regained independent ambulation with assistive devices and was discharged on day 54.

During 90-day follow-up, he remained clinically stable on pyridostigmine bromide (60 mg twice daily) without relapse and did not require further efgartigimod treatment.

CASE 2:

A 68-year-old man with gastric cancer received neoadjuvant therapy with sintilimab (200 mg per dose, 2 doses). Five days after the second injection, he developed dizziness, fatigue, bilateral ptosis, diplopia, palpitations, dysphagia with coughing, dysarthria, and progressive dyspnea.

His medical history included sigmoid colon cancer treated surgically 3 years earlier, as well as 10-year histories of hypertension and diabetes mellitus. Before starting sintilimab therapy, the patient had no prior history of neuromuscular disorders or eye-related symptoms, and his baseline physical function was normal.

On the first day of admission (day 1), his laboratory test results indicated high levels of hypersensitive troponin I (3891 ng/L, range <26.2 ng/L), creatine kinase-MB (>300 ng/mL, range <6.6 ng/mL), creatine kinase (11994 U/L, range 26–140 U/L), and transaminases (aspartate transaminase 498 U/L, range 8–40 U/L; alanine transaminase 226 U/L, range 0–40 U/L) (Figure 2). Electrocardiography revealed sinus bradycardia with abnormalities, first-degree atrioventricular block, right bundle branch block combined with left anterior fascicular block, and clockwise rotation. Echocardiography demonstrated no significant abnormalities. Following informed consent from the patient, corticosteroid treatment (methylprednisolone 140 mg/day for 9 days, followed by gradual reduction) and IVIG (10 g/day for 4 days) were initiated on day 1. Despite the reduction in troponin I and creatine kinase levels, the weakness in the neck and respiratory muscles persisted, with hemodynamic instability and respiratory failure. The patient was subsequently transferred to the ICU and underwent endotracheal intubation for mechanical ventilation support. Fiberoptic bronchoscopy revealed alimentary remnants in the airways; therefore, antibiotic therapy with piperacillin-tazobactam was initiated. The etiological results of bronchoalveolar lavage fluid confirmed Klebsiella pneumoniae. On day 27, he anti-titin antibody level was 2.287 nmol/L (reference value <1), while the other antibodies (anti-MuSK, anti-AchR, and anti-VGCC) were negative (Table 1).

According to the SITC clinical practice guidelines for adverse events related to ICI [12], the diagnosis of myocarditis was based on a marked high-sensitivity troponin I elevation with new conduction abnormalities (first-degree atrioventricular block and double-bundle block: right bundle branch block plus left anterior bundle block), with no marked echocardiographic abnormalities. Given the patient’s concurrent infections, we considered sepsis-related myocardial injury; however, the extent of troponin elevation, as well as the new conduction disease and temporal relationship with PD-1 inhibitor exposure, supported immune-related myocarditis as the primary diagnosis. Severe elevation of creatine kinase, elevated transaminases, and progressive proximal/cervical weakness supported concomitant myositis. Myasthenia gravis overlap syndrome was considered because the patient presented with a characteristic eyeball phenotype (bilateral ptosis, diplopia, dysphagia with cough, dysarthria) that progressed to ventilatory failure requiring mechanical ventilation. Because anti-titin antibody alone cannot diagnose myasthenia gravis, in this case, the diagnosis was made based on clinical serological overlapping phenotypes in the presence of immune checkpoint inhibitor exposure.

Given that the patient had a confirmed new-onset infection, it was unsuitable to initiate steroid pulse therapy. Instead, an empirical treatment of efgartigimod for myasthenia gravis (800 mg weekly for a total of 4 doses) was administered. Following the attainment of infection control, a steroid pulse of 500 mg daily for 3 days was initiated on day 36, with a subsequent gradual reduction, and the immunosuppressant tacrolimus (0.5 mg twice daily) was initiated. Plasmapheresis commenced on day 56 (4 times per week). On day 74, the patient’s myasthenia gravis–like symptoms exhibited minimal improvement, diplopia resolved, and the eyelids could briefly open. The patient’s ability to be temporarily disconnected from the ventilator increased to 6 hours per day. Treating this patient was challenging until this point. At the last available follow-up after hospital discharge, the patient remained alive but with persistent limb weakness and continued to require intermittent ventilatory support; no definite relapse of myocarditis was observed.

Discussion

We report 2 patients with PD-1 inhibitor–associated MMM syndrome in whom efgartigimod was used as adjunctive rescue therapy after an inadequate response to conventional immunomodulation. We found that MMM syndrome can rapidly progress to myasthenic crisis with severe respiratory failure despite early initiation of conventional immunomodulatory therapy. Among our 2 patients, the patient with anti-AChR antibody positivity experienced rapid neuromuscular recovery and was weaned from mechanical ventilation, whereas the patient with anti-titin antibody positivity showed improved muscle strength but had a slower and incomplete neuromuscular response. This supports the hypothesis that the autoantibody profile and baseline disease severity may influence reactivity.

MMM syndrome represents a significant clinical challenge. A recent study summarizing reporting trends and outcomes of irAEs in VigiBase (2008–2023) focused on life-threatening toxicities [13]. It highlighted that MMM syndrome occurred in 6.6% of cases and exhibited the highest overlap among irAEs (up to 30%), significantly higher than other overlap syndromes. Risk factors include thymic cancer, advanced age, and ICI combination therapy. We found that MMM syndrome do not occur concurrently [14] and can easily develop into a rapidly progressive, fatal, and refractory myasthenia crisis. While the overall fatality for irAEs has generally decreased since 2020, cases involving myasthenia remain severe. The clinical presentation, treatment, and outcomes of patients with this triad are not well-defined due to its rarity.

To better understand the clinical context and outcomes of this syndrome, we performed a comprehensive literature review following PRISMA guidelines. We systematically searched PubMed/MEDLINE for English-language articles from January 2011 through July 2024 using combinations of keywords such as “immune checkpoint inhibitor”, “myocarditis”, “myositis”, and “myasthenia gravis”, focusing on case reports and small case series. After removing duplicates and excluding reports with insufficient clinical detail, a total of 75 patient cases met our inclusion criteria for analysis. Data from these 75 cases were extracted and are summarized in Tables 2 and 3. This literature review process and selection of cases were conducted in a PRISMA-style manner to enhance clarity and reproducibility of the methodology.

In the literature review, we identified 75 reported patients with immune-related MMM syndrome associated with ICI therapy (Table 2). The mean patient age was 68.9±12.4 years and two-thirds were men; melanoma, urological cancers, and lung cancer accounted for most underlying malignancies. Most patients received PD-1/PD-L1 monotherapy, and symptoms typically appeared within 2 to 4 weeks after ICI initiation.

Regarding treatment, all patients (75/75, 100%) received systemic corticosteroids, and 45 (60.0%) underwent steroid pulse therapy. In addition, IVIG was administered in 48 patients (64.0%) and plasma exchange in 29 (38.7%), often in combination (Table 3). Despite this aggressive conventional immunosuppression, only 36 patients (48.0%) achieved complete remission, while 8 (10.7%) remained mechanically ventilator-dependent and 31 (41.3%) died. These data highlight that, even with high-dose corticosteroids, IVIG, and plasma exchange, outcomes of MMM syndrome are frequently unsatisfactory and mortality remains high.

From a therapeutic perspective, it is important to place efgartigimod in the context of existing treatment options for MMM syndrome. In our pooled cohort and in previously reported cases, almost all patients received high-dose corticosteroids, and many also underwent IVIG and/or plasma exchange, yet mortality remained high and many survivors had persistent neurological deficits (Tables 2, 3). High-dose corticosteroids are widely available and remain the backbone of current management; however, their clinical benefit on myasthenic weakness and myocarditis is usually delayed, becoming apparent only after several days to 1 to 2 weeks, and they are accompanied by well-known systemic toxicities, including infection, hyperglycemia, osteoporosis and steroid myopathy, as well as a potential attenuation of antitumor immunity. In addition, evidence regarding the use of efgartigimod in ICI-related immune-mediated adverse events has begun to accumulate. Recent case reports have described substantial neurological improvement in patients with ICI-associated myasthenia gravis with myositis and in pembrolizumab-induced MMM syndrome after treatment with efgartigimod in combination with high-dose corticosteroids and conventional rescue therapies such as IVIG and plasmapheresis [15,16]. Another report documented favorable outcomes in a patient with ICI-induced polyradiculoneuropathy and cardiomyopathy treated with efgartigimod [17]. Although these observations are limited to single cases, they support the concept that FcRn blockade may serve as a rational salvage option for severe, antibody-mediated irAEs that are refractory to standard immunosuppression.

Researchers have found that efgartigimod safely, rapidly, and continuously reduces total IgG levels. In randomized trials of generalized myasthenia gravis, 4 weekly infusions of efgartigimod produced a 61% to 85% reduction in total IgG and a 40% to 70% reduction in anti-AChR antibody titres, accompanied by clinically meaningful improvements in myasthenia gravis activities of daily living scores and quantitative myasthenia gravis scores, and a predominantly mild adverse-event profile [18–20]. These effects are quantitatively comparable to those achieved after a median of 6 sessions of plasma exchange, but they are obtained without the need for central venous access or large-volume exchanges and with preservation of albumin levels [21]. Our decision to use efgartigimod was driven by refractoriness to standard rescue therapies in case 1 and limitations of steroid escalation due to active infection in case 2. Compared with plasmapheresis, efgartigimod provides sustained IgG reduction without invasive procedures or large-volume exchanges, which is advantageous in critically ill patients. These mechanistic and practical features support its role as a complementary rather than redundant therapeutic option. Beyond these general considerations, efgartigimod is unlikely to benefit all patients with MMM syndrome to the same extent, and our 2 cases illustrate potential determinants of response.

Both patients initially received standard first-line therapies, including high-dose corticosteroids, IVIG, and plasma exchange. However, clinical responses were suboptimal, which prompted the use of adjunctive efgartigimod. In case 1, despite biochemical improvement after conventional therapies, severe bulbar weakness and ventilator dependence persisted. Following initiation of efgartigimod, the patient showed rapid neurological recovery and was successfully weaned from mechanical ventilation by day 22. In contrast, in case 2, the patient exhibited a slower and incomplete clinical response, with prolonged ventilator dependence, although cardiac enzymes and creatine kinase levels declined substantially. These contrasting outcomes suggest that autoantibody profiles may influence responsiveness to FcRn inhibition. Case 1 was anti-AChR-positive and demonstrated quick clinical improvement, whereas case 2 was anti-titin-positive and showed only partial recovery. Anti-AChR antibodies are predominantly IgG1/IgG3 subclasses that are efficiently reduced by FcRn blockade and primarily cause functional neuromuscular transmission failure. In contrast, anti-titin antibodies are associated with thymoma-related, late-onset, and structurally severe disease, which may be less reversible despite IgG reduction. Anti-titin antibodies are strongly associated with thymoma, late-onset myasthenia gravis (over 50 years old), and more severe, structurally destructive disease [22–25], and may therefore identify a subgroup in which rapid IgG depletion alone is insufficient to reverse established muscle damage. In contrast, classical anti-AChR antibodies are predominantly IgG1 and IgG3 isotypes that are efficiently recycled via FcRn and mediate neuromuscular transmission failure through complement activation and functional blockade of the receptor, mechanisms that are mechanistically well suited to FcRn inhibition. It is therefore plausible that efgartigimod will have the greatest effect in patients whose weakness is driven by reversible, antibody-mediated dysfunction, whereas those with extensive structural damage, complex autoantibody profiles, or advanced comorbidities may show more modest clinical gains despite reductions in IgG levels. Taken together, these observations suggest that individual patient characteristics, particularly antibody specificity, titre, associated thymic pathology, and baseline disease severity, may influence responsiveness to efgartigimod in MMM syndrome. Future studies should incorporate systematic immunological profiling and explore personalized treatment algorithms that align FcRn inhibitors, IVIG, plasmapheresis, and B-cell- or complement-targeted agents with distinct serological and clinical phenotypes.

Nevertheless, our cases provide preliminary evidence that efgartigimod may be a useful adjunct in selected patients with severe ICI-related MMM syndrome, particularly in disease with anti-AChR antibody positivity. Larger prospective studies are warranted to define optimal timing, patient selection and long-term safety.

Conclusions

Efgartigimod as an adjunctive treatment might be a promising rescue option for severe MMM syndrome associated with PD-1 inhibitors when high-dose corticosteroids, IVIG, and plasmapheresis are not sufficiently effective. Our cases indicate that patients with anti-AChR antibody positive disease might experience more clinical benefits than those with titin-predominant phenotypes. Future studies are needed to assess the criteria for patient selection, the ideal timing, and safety concerns.