Efgartigimod Successfully Ameliorated Acute Exacerbation of Myasthenia Gravis with Anti-muscle-specific Kinase Antibodies

Abstract

We herein report two patients with anti-muscle-specific kinase (MuSK) antibody-positive myasthenia gravis who experienced rapid deterioration of weakness, particularly respiratory muscle weakness, necessitating non-invasive positive pressure ventilation (NIPPV) and were treated with efgartigimod. After treatment initiation, a rapid reduction in IgG levels and recovery from clinical symptoms were observed. NIPPV was no longer required two to three weeks after the first infusion of efgartigimod. These findings suggest that the reduction of IgG levels using efgartigimod is a good treatment option in patients with myasthenia gravis positive for anti-MuSK antibodies, even during the acute phase of the disease.

Introduction

Myasthenia gravis (MG) is an acquired autoimmune disorder of the neuromuscular junction, characterized by muscle weakness that worsens with repeated exercise (fatigability). Ocular symptoms, such as ptosis and diplopia, are usually the first manifestations of the disease, and weakness of the limb and neck muscles, dysarthria, and dysphagia are also common (1-3). In severe cases, respiratory disturbances require management using an artificial ventilation.

Autoantibodies directed against molecules in the postsynaptic membrane of the neuromuscular junction play an important role in the pathophysiology of MG (4). Indeed, up to 85% of patients with generalized MG are positive for antibodies against the acetylcholine receptor (AChR), and 40% of patients with generalized MG who are negative for anti-AChR antibodies test positive for antibodies against muscle-specific kinase (MuSK) (5,6). Anti-AChR antibodies consist of IgG1 and IgG3 isotypes and are capable of activating the complement cascade (6). Therefore, the binding of these antibodies to AChRs results in blockade of the neuromuscular junction and destruction of AChRs through the formation of a membrane attack complex (7). In contrast, anti-MuSK autoantibodies predominantly belong to the IgG4 isotype, which is unable to activate complements (5). Nevertheless, anti-MuSK autoantibodies are pathogenic because they inhibit MuSK activation and thereby induce declustering of AChRs, resulting in defects in synaptic transmission (8).

Efgartigimod is a first-in-class antibody fragment drug targeting the neonatal Fc receptor (FcRn). This prevents FcRn from recycling IgG back into the blood, leading to a reduction in the overall IgG levels (9). The drug was approved for use in patients with MG by the United States Food and Drug Administration in December 2021, Pharmaceuticals and Medical Devices Agency of Japan in January 2022, and European Medicines Agency in August 2022, based on the results of a randomized controlled trial that mainly involved patients positive for anti-AChR antibodies (10). Although a recent study of rozanolixizumab suggested that FcRn inhibitors are also effective in patients with anti-MuSK autoantibodies (11), the number of patients evaluated remains small.

We herein report two patients with MG with anti-MuSK antibodies who responded successfully to efgartigimod during the acute exacerbation phase of the disease, which had necessitated non-invasive positive pressure ventilation (NIPPV).

Case Reports

Patient 1

A 78-year-old woman developed a dropped head 8 months prior to admission to our hospital. As the dropped head gradually worsened, she was referred to the orthopedic department and underwent posterior cervical spinal fusion six months after the initial presentation. Despite continuous postoperative rehabilitation, upper limb weakness persisted. The patient was unable to raise her arms when she was referred to our hospital.

Upon admission, the patient was alert and well oriented. An examination revealed that the cranial nerve functions were intact, except for difficulty in swallowing. Manual muscle testing revealed severe weakness in the neck extensors and muscles in the proximal portions of the upper limbs. Weakness in the distal portions of the upper and proximal portions of the lower limbs was mild, whereas weakness in the distal portions of the lower limbs was normal. No diurnal fluctuations were observed. No muscle atrophy was observed. Deep tendon reflexes and multimodal sensory examination results were normal. Planter responses were flexor on both sides, and cerebellar signs were negative.

Although the results of nerve conduction studies were unremarkable, a repetitive nerve low-rate stimulation (3 Hz) test recording at the orbicularis oculi, trapezius, and abductor pollicis brevis muscles revealed a decrease in compound muscle action potentials (46%, 15%, and 21%, respectively), which was highly suggestive of MG. Radioimmunoassays revealed elevated anti-MuSK antibody levels (121 nmol/L; normal, ＜0.02 nmol/L). The results of other blood examinations were unremarkable, and anti-AChR antibodies were negative. Whole-body computed tomography with and without contrast enhancement revealed no tumor.

Although treatment with prednisolone was initiated at 5 mg/day and gradually increased, the patient developed dyspnea and required NIPPV 17 days after admission. Muscle weakness in the proximal portion of the limbs and body, particularly the respiratory muscles, rapidly worsened, and administration of efgartigimod (10 mg/kg infusion of efgartigimod alpha, once a week for 4 weeks) was initiated the next day.

Seven days after the administration of the first infusion of efgartigimod, serum IgG levels decreased from 1,047 mg/dL to 626 mg/dL (Fig. 1). The IgG level finally decreased to 252 mg/dL one month after the initiation of efgartigimod treatment. In contrast, the levels of IgA and IgM before and 1 month after treatment were not significantly different from those of IgG (260-206 mg/dL for IgA and 186-153 mg/dL for IgM). The Quantitative Myasthenia Gravis (QMG) (12) score improved from 16 to 10 before treatment and 7 days after treatment. Two weeks after treatment, the patient no longer required NIPPV and was able to raise her arms fully (Fig. 2A). Head drop, the initial manifestation of the disease, was absent at that time. Furthermore, a significant improvement in the repetitive nerve stimulation (3 Hz) test results in the trapezius muscle was observed two weeks after the initiation of efgartigimod treatment (Fig. 2B). The drug was well-tolerated, with a complete blood count and normal aspartate aminotransferase and alanine aminotransferase levels.

Figure 1.

Serial changes in the serum IgG concentration, QMG score, and respiratory function (%VC) after the initiation of efgartigimod treatment in Patients 1 and 2. Along with the reduction in the levels of IgG, both patients showed recovery in terms of the QMG score and %VC. QMG: Quantitative Myasthenia Gravis, VC: vital capacity

Figure 2.

Improvement of muscle strength (A) and repetitive nerve stimulation findings (B) before and 2 weeks after the initiation of efgartigimod treatment in Patient 1. (A) Although she could not raise her arms when she was referred to our hospital, she was able to fully raise her arms two weeks after the treatment. (B) A repetitive nerve low-rate stimulation (3 Hz) test recording at the trapezius muscle revealed a significant decrease in compound muscle action potentials (46%) before treatment, whereas it was no longer observed after treatment.

Five months after admission to our hospital, her symptoms had stabilized with prednisolone (10 mg/day) and tacrolimus (3 mg/day).

Patient 2

A 70-year-old man developed double vision 2 months prior to admission to our hospital. Dyspnea appeared two weeks later, and NIPPV was offered at another hospital. As a blood examination revealed positivity for anti-MuSK antibodies, the patient was transferred to our hospital for a further investigation and treatment of MG. On admission, the patient was alert and well oriented. An examination revealed an intact cranial nerve function, except for diplopia, which appeared when gazing at the right side. Manual muscle testing revealed mild weakness of the neck flexor muscles; however, muscle weakness was not detected in any of the four limbs. In contrast, thoracic movement decreased, and vital capacity was 43% of the predictive value. The physical examination results for sensation, deep tendon reflexes, and plantar responses were unremarkable. No muscle atrophy was observed.

Nerve conduction studies revealed normal findings, whereas a repetitive nerve low-rate stimulation (3 Hz) test recording of the frontalis muscle revealed a decrease in compound muscle action potential (21%). The concentration of anti-MuSK antibodies was 12 nmol/L, whereas that of the anti-AChR antibodies was not elevated. Whole-body computed tomography with and without contrast enhancement revealed no tumor. However, emphysema, which was considered to be due to smoking, was detected in the lungs.

Despite prednisolone being initiated from 5 mg per day, the patient still required continuous NIPPV. Therefore, we started administering efgartigimod (10 mg/kg infusion of efgartigimod alpha, once a week for 4 weeks) 5 days after admission to our hospital. One month after the first infusion of efgartigimod, serum IgG levels decreased from 1,035 mg/dL to 88 mg/dL (Fig. 1). In contrast, the levels of IgA and IgM before and 1 month after treatment were not significantly different from those of IgG (121-79 mg/dL for IgA and 170-138 mg/dL for IgM).

As his respiratory symptoms gradually improved, he no longer required NIPPV three weeks after the initiation of efgartigimod therapy. However, the vital capacity examined 25 days after the initiation of efgartigimod treatment was still 70% of the predictive value. The forced expiratory volume in 1 second at that time was 62% (normal, ＞70%) of the predictive value, indicating that obstructive lung disease resulting from smoking was present even before the initiation of MG symptoms.

He became independent in activities of daily living and was discharged 1 month after admission to our hospital, and he remained stable with the administration of prednisolone (9 mg/day) 2 months later. The drug was well-tolerated, with a normal complete blood count and normal aspartate aminotransferase and alanine aminotransferase levels.

Discussion

Patients with anti-MuSK antibody-positive MG show some peculiar features compared to those with anti-AChR antibodies (1-3). In particular, a high frequency of bulbar symptoms and respiratory muscle weakness, which leads to respiratory insufficiency, may result in critical conditions (1,2). In addition, patients with anti-MuSK antibodies tend to show muscle atrophy, and some are refractory to conventional immunotherapy (3). These findings suggest that appropriate immunotherapy leading to remission induction is required at an early stage of the disease.

Recently, efgartigimod has been introduced for the treatment of MG. It causes a reduction in the overall levels of IgG, including pathogenic autoantibodies such as anti-AChR and anti-MuSK antibodies, by enhancing the intracellular degradation of IgG through inhibition of the IgG recycling pathway mediated by FcRn (9). A phase 3 trial involving 167 patients, consisting of 129 patients with anti-AChR antibodies, 6 with anti-MuSK antibodies, and 32 without these antibodies, demonstrated that efgartigimod was effective in patients with MG (10). However, the primary efficacy endpoint, defined as the proportion of responders in terms of the Myasthenia Gravis Activities of Daily Living (MG-ADL) score (13) during the first treatment cycle, was assessed only in the anti-AChR antibody-positive group. As for the group positive for anti-MuSK antibodies, all six were considered MG-ADL responders in the first treatment cycle although 3 were assigned to the placebo group. Therefore, further information on the use of efgartigimod for anti-MuSK antibody-positive MG is required.

In addition, the efficacy of efgartigimod in patients with rapid exacerbation of MG symptoms has not been clarified because the eligibility criteria for the phase 3 trial required patients to be on a stable dose of at least one treatment, including acetylcholinesterase inhibitors, corticosteroids, and non-steroidal immunosuppressive therapies (10).

In the present report, we describe the efficacy of efgartigimod in two patients with rapidly developing MG who tested positive for anti-MuSK antibodies. Plasma exchange (PE) and intravenous immunoglobulin (IVIg) are currently the first choices for the treatment of myasthenic crisis (14). Previous studies have indicated that PE is more favorable than IVIg in patients with anti-MuSK antibodies, because PE can rapidly reduce pathogenic IgG4 (15,16). However, PE is an invasive procedure that requires specialized equipment and technicians. The mechanism of action of efgartigimod on MG is similar to that of PE, as it also reduces IgG, including pathogenic IgG4. Therefore, efgartigimod may be beneficial for anti-MuSK antibody-positive MG both in terms of effectiveness and convenience. Considering the advantages and disadvantages of PE, IVIg, and efgartigimod for the treatment of MG (10,14-17) (Table), we adopted efgartigimod for our patients.

Table.

The Characteristics of PE, IVIg, and Efgartigimod for the Treatment of MG (10, 14-17).

	PE	IVIg	Efgartigimod
Mechanism of action	Removal of	Multiple mechanism,	Reduction of IgG
	pathogenic antibodies	including neutralization
		of pathogenic antibodies
Special equipment/technician	Necessary	Unnecessary	Unnecessary
Severe complication	Hypotension/shock	Thromboembolic events	Uncommon
	Anaphylaxis	Acute renal failure
	Catheter-related infection
Efficacy on anti-MuSK	Effective	Less effective	Probably effective
antibody-positive cases

IVIg: intravenous immunoglobulin, MG: myasthenia gravis, MuSK: muscle-specific kinase, PE: plasma exchange

Although weakness, particularly in the respiratory muscles, developed rapidly and necessitated respiratory support by NIPPV at the time of admission to our hospital, clinical recovery was evident even one week after the first infusion of efgartigimod in both patients. A previous study demonstrated that serial studies on serum anti-MuSK antibody levels closely correlated with clinical severity (18). In addition, anti-MuSK antibody titers sharply decreased in patients who responded well to early steroid therapy or PE (18). These findings suggest that reducing IgG levels using efgartigimod is a good treatment option for patients with MG who are positive for anti-MuSK antibodies, even during the acute phase of the disease. The fact that IgG4 is the main isotype of anti-MuSK antibodies may be attributable to a good response to efgartigimod because IgG4, unlike the IgG1 and IgG3 isotypes of anti-AChR antibodies, does not activate complement (5,6). Further clinical trials and real-world data are required to validate our findings.

The authors state that they have no Conflict of Interest (COI).

Financial Support

This work was supported in part by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour, and Welfare of Japan (23FC1009).