Introduction

Myasthenia gravis (MG) is a neuromuscular junction disorder characterized by fluctuating muscle weakness, affecting the quality and safety of life1. MG is caused by the production of antibodies targeting different postsynaptic components of the neuromuscular junction, including acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4)2,3,4. Immunoglobulin G (IgG) autoantibodies against the AChR are positive in 80–85% of MG patients5,6.

Myasthenic crisis (MC), defined as respiratory insufficiency requiring invasive or non-invasive ventilation, is a life-threatening manifestation of MG, which occurs in approximately 15%-20% of patients7,8,9. To improve early recognition and intervention of life-threatening events, the concept of impending MC (IMC) is introduced, that refers to rapid clinical worsening potentially leading to MC over days to weeks in the opinion of the treating physician7.

Intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), modulating IgG levels, are the mainstay for the management of IMC7. However, limitations in plasma donations directly impact the availability of IVIg and PLEX10. In addition, these approaches can be associated with some severe adverse reactions and a substantial burden to patients11,12,13,14,15. Immunoadsorption (IA), another type of plasmapheresis, can selectively remove immunoglobulin from plasma without requiring transfusion of another patient’s plasma16,17, which has been proved to be equally effective compared with PLEX treatment in patients with MC18. However, the side effects and complications of IA related to the procedure itself could not be avoided19,20, and widespread application of IA systems has been limited by the complexity of the procedure and economic reasons21. Hence, it is urgent to develop chemically synthesized or recombinantly generated drugs used in rescuing IMC.

The neonatal Fc receptor (FcRn) prevents the degradation of IgG in lysosomes and prolongs their half-life to ensure IgG homeostasis22. Efgartigimod, a human IgG1-derived Fc fragment, has a significantly higher affinity for FcRn compared with endogenous IgG, and its treatment results in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers13. Efgartigimod has been proved to be well tolerated and efficacious in patients with generalized MG (GMG)23,24. Case reports also indicated the efficacy of efgartigimod in the treatment of MC and IMC25,26,27,28. Thus, the present study aimed to compare the efficacy of efgartigimod and IVIg in rescuing IMC.

Methods

Participants and study design

This is a single-center, retrospective cohort study, conducted at the First Hospital of Shanxi Medical University, Shanxi Province, China. This study has been approved by the Institutional Ethics Committee of the First Hospital of Shanxi Medical University (NO.KYLL-2024-243) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all individual participants included in the study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

We identified GMG patients with episodes of IMC between January 1, 2020 and June 30, 2024 in our center. Patients were included if they met all the following criteria: AChR antibody-positive GMG patients who were 18 years or older received efgartigimod or IVIg treatment for IMC7; patients were classified as IIIb or IVb according to the Myasthenia Gravis Foundation of America (MGFA) Classification29 before efgartigimod or IVIg treatment; patients maintained a minimum follow-up of 4 weeks post-treatment. Patients were excluded if they were co-administered with PLEX, rituximab, or eculizumab for rescuing IMC, were treated with IVIg, PLEX, or efgartigimod in one month before the diagnosis of IMC, received rituximab or eculizumab within 6 months, undergone thymectomy within 3 months, received high-dose glucocorticoid therapy within 1 month, or had severe comorbidities influencing the clinical assessment. Patients were allowed to use cholinesterase inhibitors, oral corticosteroids, or other nonsteroidal immunosuppressant drugs.

Interventions and data collection

Included patients had been administered weekly intravenous infusions of efgartigimod at a dosage of 10 mg/kg, consisting of at least one dose, or received IVIg at a dose of 0.4 g/kg per day for five consecutive days, forming the efgartigimod group and IVIg group, respectively. Information including sex, age at admission, age at onset, disease duration, MGFA classification, thymoma, thymectomy, seropositivity for anti-AChR, anti-titin and anti-RyR antibodies, cholinesterase inhibitors and immunosuppressive treatment at enrollment, and scores of Myasthenia Gravis activities of daily living (MG-ADL)30, Myasthenia Gravis Composite (MGC) scale31, quantitative Myasthenia Gravis (QMG)32, and the revised 15-item Myasthenia Gravis Quality of Life (MG-QOL15r) questionnaire33 were collected.

Outcomes

The primary outcome was determined as the mean change in MG-ADL score from baseline (the initial dose of efgartigimod or IVIg) to week 1 and 4 after treatment, respectively, for the efgartigimod group compared with the IVIg group. Secondary outcomes included the following: (1) the mean difference in MGC score change between the two groups; and (2) the proportions of MG-ADL responders (defined as ≥ 2-point reduction in MG-ADL score from baseline values)34 and MGC responders (defined as ≥ 3-point reduction in MGC score from baseline values) at week 1 and week 431. Safety was assessed based on medical records during the hospitalization to monitor the adverse events (AEs) and serious AEs (SAEs).

Statistical analyses

Normally distributed continuous variables were summarized as mean ± standard deviation (SD), and non-normally distributed continuous variables were summarized as median (interquartile ranges). Categorical variables were shown as number (percentage). The normality of continuous data was evaluated by the Kolmogorov–Smirnov test. Baseline characteristics between the two groups were compared using the Student’s t-test or Mann–Whitney U-test for continuous variables and Fisher’s exact test or chi-square test for categorical variables. Baseline and post-intervention scores of MG-ADL, MGC, QMG, and MG-QOL15r in each group were compared by paired samples t-test or Wilcoxon’s signed rank test. The changes in the MG-ADL and MGC scores between the two groups were assessed using the Student’s t-test or Mann–Whitney U-test. The proportions of MG-ADL and MGC responders were compared using Fisher’s exact test. All significance tests were two-sided. A P value < 0.05 was considered to be statistically significant. Statistical Package for Social Sciences (SPSS) software 24.0 (IBM, Armonk, NY, United States) and GraphPad Prisma Software 6.0 (Inc., San Diego, CA, United States) were used for statistical analyses and graphic drawings, respectively.

Results

Demographic and clinical features

During the study period, a total of 370 MG patients in our center were screened. Of them, 9 IMC patients treated with efgartigimod and 10 patients treated with IVIg fulfilled the inclusion and exclusion criteria and were enrolled in this study (Fig. 1). The mean age for all participants was 58.68 ± 16.34 years and 57.89% (11/19) were female. The mean disease duration of all participants was 13.16 ± 19.43 months. In the efgartigimod group, five patients were treated with efgartigimod weekly for 4 consecutive weeks and three for 2 consecutive weeks, and one received a single dose. All the 19 participants had been assessed with MG-ADL and MGC scales at baseline, week 1, and 4. Four scales including MG-ADL, MGC, QMG, and MG-QOL15r were applied in each patient in the efgartigimod group at baseline, week 1, 2, 3, and 4. The demographic and clinical characteristics at baseline are shown in Table 1. There were no significant differences in sex, age at admission, age at onset, disease duration, MGFA classification, autoantibody profile, pyridostigmine and immunosuppressive treatment at enrollment, and the mean scores of MG-ADL and MGC between the two treatment groups (P > 0.05).

Fig. 1
Fig. 1
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The workflow for enrollment in both treatment groups. MG, myasthenia gravis; MC, myasthenic crisis; IMC, impending myasthenic crisis; MGFA, Myasthenia Gravis Foundation of America Classification.

Table 1 Baseline clinical characteristics and MG relevant scores in both treatment groups.
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Efficacy

The mean scores of MG-ADL, MGC, QMG and MG-QOL15r at baseline, week 1, 2, 3, and 4 in the efgartigimod group and those of MG-ADL and MGC at baseline, week 1, and 4 in the IVIg group are shown in Table 2 and Fig. 2. In each group, post-treatment scores were significantly decreased compared with baseline ones (P < 0.05).

Table 2 The mean scores of the MG-ADL, MGC, QMG and MG-QOL15r at baseline and during follow-up in both treatment groups.
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Fig. 2
Fig. 2
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The changes in the MG-ADL score (A), MGC score (B), QMG score (C) and MG-QOL15r score (D) in the efgartigimod group during the follow-up compared with baseline. MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite scale; QMG, quantitative Myasthenia Gravis; MG-QOL15r, the revised 15-item Myasthenia Gravis Quality of Life questionnaire. Error bars show standard error. * P < 0.05, ** P < 0.01, *** P < 0.001, ns, not significant.

For the primary outcome, the efgartigimod group had a greater reduction in the MG-ADL score at week 1 (mean difference, -3.67; 95% confidence interval [CI], − 7.03 to − 0.31; P = 0.035) and week 4 (mean difference, − 4.31; 95% CI, − 7.16 to − 1.47; P = 0.005; Fig. 3A).

Fig. 3
Fig. 3
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The comparisons of changes in the MG-ADL score (A) and MGC score (B) at week 1 and week 4 after treatment between the two groups. MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite scale. Error bars show standard error. * P < 0.05, ** P < 0.01, ns, not significant.

The reduction in the MGC score was greater in the efgartigimod group than in the IVIg group at week 1 (mean difference, − 7.76; 95% CI, − 15.74 to 0.22; P = 0.056) and week 4 (mean difference, − 5.72; 95% CI, − 13.09 to 1.65; P = 0.120; Fig. 3B), but the differences did not reach statistical significance.

The proportions of MG-ADL and MGC responders were comparable between the efgartigimod and IVIg groups at week 1 (88.89% vs. 70.00% in MG-ADL, P = 0.582; 88.89% vs. 70.00% in MGC, P = 0.582). At week 4, all 19 patients were MG-ADL and MGC responders.

Safety

One patient in the efgartigimod group had an upper respiratory infection with fever after the third dose, which was relieved in 6 days with oral ibuprofen treatment. No other AEs or SAEs were documented in medical records.

Discussion

In the present study, efgartigimod provided rapid and clinically meaningful improvement with acceptable safety profiles in GMG patients with IMC. The reduction in the MG-ADL score was significantly greater in the efgartigimod group than in the IVIg group at week 1 and 4.

IMC, exemplified by a rapid worsening of clinical symptoms within a very short time period, is a severe and life-threatening state of disease. Early identification of IMC and rapid symptom improvement are important for preventing patients from developing MC and reducing disease mortality7,35. The ADAPT phase 3 trial showed that most GMG patients treated with efgartigimod had a clinically meaningful improvement in MG-ADL within 2 weeks of starting treatment, demonstrating that efgartigimod was an efficacious and fast-acting treatment option24. Similarly, most of our IMC patients treated with efgartigimod were MG-ADL responders and they achieved significant reduction in the scores of MG-ADL, MGC, QMG and MG-QOL15r at week 1. Case reports also presented similar results that MG patients in a state of IMC, MC or refractory MC who responded to IVIg or PLEX poorly were successfully rescued by add-on efgartigimod treatment25,27,28. Overall, these results suggested rapid therapeutic effect of efgartigimod and indicated that efgartigimod could be a rescue therapy for IMC or MC patients.

IVIg is one of the standard rescue therapies for IMC36. One mechanism of IVIg’s therapeutic action is to cause high IgG peak concentrations and saturation of FcRn receptors, competing with endogenous IgG for FcRn and leading to unspecific IgG clearance13,37. Efgartigimod, as a human IgG1-derived Fc fragment, is modified at five residues using ABDEG technology to increase its affinity for FcRn at both physiological and acidic pH38,39,40,41. Animal experiments proved that the FcRn-antagonizing potency of efgartigimod exceeded that of IVIg in cynomolgus monkeys13. In addition, unlike animal studies13,37, IVIg is usually infused at a daily dose of 0.4 g/kg for 5 consecutive days in clinical practice, which may further hinder its rapid efficacy. Our results also showed a greater reduction in the MG-ADL score in the efgartigimod group than in the IVIg group at week 1 and week 4, which further supported the advantages of efgartigimod.

In the present study, both efgartigimod and IVIg showed acceptable safety profiles. One of the patients treated with efgartigimod experienced an upper respiratory infection. The prevalence of infection (11.11%) in the efgartigimod group was lower than that in the ADAPT trial (46%)24. Participants received efgartigimod treatment for up to 4 doses with a very short follow-up period in the present study, which might account for the difference. In contrast, patients in the efgartigimod group in the ADAPT trial were treated for more than 4 doses24. These findings indicated that short-term treatment with efgartigimod was safe in GMG patients with IMC.

The efficacy of PLEX and IA in the treatment of MC has been proved18,42,43,44. However, previous studies also confirmed PLEX (20%-46%)43,44 and IA (13–50%)16,45 had a higher rate of complications when compared with IVIg (2–14.79%)44,46. The most serious adverse effects of PLEX, IA, IVIg were the cardiovascular complications, infectious complications, acute renal failure and thromboembolic events, which usually occurred during the long-term infusion or procedure16,43,47,48. In contrast, these adverse effects were rarely observed under efgartigimod treatment24, which may be related to the advantage that the infusion of efgartigimod is a relatively simple fast process. The direct comparison of clinical safety between efgartigimod and other rescue treatments needs further performed in larger cohorts of IMC or MC patients.

This current study has several limitations. First, the sample size was relatively small, which may be the reason for the lack of significant difference in change in MGC score between the two groups and in addition increased the sampling error. Secondly, this retrospective study omitted some key information, for example, the QMG and MG-QOL15r scores in the IVIg group. Another limitation was that the efgartigimod group did not all receive the same dosing regimen, which may influence the results of comparison between the two groups. Last, the observational design led to confounding bias and selection bias. Baseline MG scores were higher in the efgartigimod group than in the IVIg group, although the differences were not significant. As severe patients may benefit to a greater extent from treatment, it could lead to a significant reduction in MG-ADL score in the efgartigimod group. As a result, randomized clinical trials with larger sample size are anticipated to validate the results of our study.

Conclusion

Our study showed the rapid effect and safety of efgartigimod in treating IMC. The reduction in the MG-ADL score was significantly greater in the efgartigimod group than in the IVIg group at week 1 and 4. These findings suggest that efgartigimod is a treatment option for IMC in addition to IVIg and PLEX.