Changes in Demographic and Clinical Characteristics of MuSK Myasthenia Gravis

ABSTRACT

Background

Over the last two decades, an increasing number of late‐ and very‐late onset myasthenia gravis cases (VLOMG) with acetylcholine receptor antibodies (AChR‐MG) have been reported, whereas demographic studies on muscle‐specific tyrosine kinase antibodies MG (MuSK‐MG) are lacking. We investigated whether the proportion of patients with MuSK‐MG with onset ≥ 50 years has increased and whether these patients show distinct clinical characteristics.

Methods

We retrospectively enrolled consecutive patients with MuSK‐MG onset ≥ 16 years followed between 1980 and 2025 at our tertiary center. Demographic characteristics and maximum disease severity, classified according to Myasthenia Gravis Foundation of America classification, were analyzed. Patients were stratified into three age‐at‐onset subgroups.

Results

Overall, 120 patients were included. A significant increase in the median age at MuSK‐MG onset was observed, from 36 years (IQR, 23–45.75) in the 1980s to 47 years (IQR, 29–69) in the 2013–2025 period (p = 0.033). Patients with onset ≥ 50 years increased from 2/17 (11.8%) to 19/39 (48.7%) (p = 0.015), including 12 VLOMG cases. Males increased from 23.5% to 35.9%. Maximum MG severity decreased over time, with a remarkable reduction of respiratory crises (p = 0.004), with no significant differences across age‐at‐onset groups.

Conclusions

Demographic changes observed in AChR‐MG also occur, though less prominently, in MuSK‐MG.

1. Introduction

MuSK‐antibody‐positive myasthenia gravis (MuSK‐MG) is a rare subtype of MG characterized by distinctive pathogenesis and clinical characteristics [1]. MuSK‐Abs are detected in up to 70% of MG patients without acetylcholine receptor autoantibodies (AChR‐Abs) [2]. MuSK‐MG has traditionally been considered a relatively homogeneous disease in terms of demographic characteristics, and genetic susceptibility. To date, studies performed in cohorts from different countries confirmed a marked female predominance, a typical clinical phenotype characterized by cranial and bulbar weakness, the lack of thymus abnormalities, and the association with HLA DQB1*05, DRB1*14, DRB1*16 haplotypes [3]. Nationwide studies have reported a lower frequency of MuSK‐MG in Northern compared with Southern Europe, with higher incidence and prevalence rates observed in Turkey [4] and Italy [5], as well as in the Netherlands [6] compared with Norway [7]. Since the recognition of this MG subtype, an age of onset peak among women in the late 30s has been reported [1], together with a female‐to‐male ratio ranging between 3:1 and 9:1 [2].

MG epidemiology has changed through the last decades with an increasing rate of AChR‐MG elderly patients. However, there are few data regarding epidemiological changes in MuSK‐MG [8, 9].

The aim of this study was to investigate changes of demographic and clinical characteristics among MuSK‐MG patients across a 45‐year period, and to determine whether these changes are associated with differences in clinical characteristics according to age of onset.

2. Materials and Methods

2.1. Study Population

In this single‐center retrospective study, we enrolled consecutive MuSK‐MG patients with age at onset ≥ 16 years seen between January 1980 and December 2025 at the Neurology Unit of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. In the whole population MuSK‐Abs were tested by radioimmunoassay (RIA) at diagnosis or in serum samples stored at −80°C. In some patients, who were double seronegative on RIA, MuSK‐Abs were detected by an in‐house live‐cell based assay (L‐CBA), when it became available [10]. Repetitive nerve stimulation (RNS) and/or single‐fiber electromyography (SF‐EMG) were performed in all patients.

All data were extracted from our medical records. In the whole patient population, we analyzed demographic characteristics (age of onset, sex), date of onset, severity and distribution of muscle weakness according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification at maximum disease severity [11]. We subdivided patients into three groups based on age at onset: early‐onset MG (EOMG, 16–49 years), late‐onset MG (LOMG, 50–64 years) and very‐late onset MG (VLOMG, ≥ 65 years).

2.2. Statistical Analysis

Descriptive statistics were used to summarize all variables. Qualitative variables were expressed as absolute counts and percentages, quantitative variables were presented as median, interquartile range, and range. Shapiro–Wilk test was employed to assess the distribution of the data. Fisher's exact test and χ ² test were utilized for comparing qualitative variables, as appropriate. Unpaired T‐test and Mann–Whitney test were performed for analyzing quantitative differences, as required. Statistical analyses were performed using GraphPad Prism 8.4.3.

2.3. Ethics

The study was approved by the Ethics Committee of Catholic University (protocol #26739/13) and was performed in accordance with the Declaration of Helsinki and its later amendments. All patients gave informed consent to participate in the study.

3. Results

This retrospective study included 120 consecutive MuSK‐MG patients (females 89/120%–74%) with onset between January 1980 and December 2025. Median age at disease onset was 41 years (IQR 28.25–57.75; range 16–80). Seventy‐eight (65%) patients were younger than 50 years of age at presentation, 27 (22.5%) cases had LOMG and 15 (12.5%) VLOMG. The median age at onset steadily increased from 36 years [IQR 23–45.75] in the 80s to 47 years [IQR 29–69] in the 2013–2025 period (p = 0.033). The number of patients with onset age ≥ 50 years increased from 2/17 (11.8%) in the first decade to 19/39 (48.7%) (p = 0.015); of these patients, 12 belonged to the VLOMG subgroup (Figure 1A).

FIGURE 1.

Demographic and clinical characteristics of MuSK‐MG cohort. The distribution of MG subtypes according to age of onset across the four decades demonstrates a significant increase in patients with MuSK‐MG onset ≥ 50 in the last decade (p = 0.015) (A). Females were prevalent in the three subgroups, particularly in the EOMG (58/78–74.4%) and LOMG group (22/27–81.5%), while in the VLOMG males increased to 6/15 (40%) (B). Male frequency increased from 23.5% (4/17) in the decade 1980–1990 to 35.9% (14/39) in the decade 2013–2025 (C). The distribution of maximum MG severity across the four decades reveals a marked decline in respiratory crises in the last decade (p = 0.004), whereas the proportion of patients with mild to moderate disease (Class II–III) remained stable over time (D). EOMG: early‐onset myasthenia gravis; LOMG: late‐onset myasthenia gravis; MGFA: Myasthenia Gravis Foundation of America; VLOMG: very‐late onset myasthenia gravis.

Female predominance was significant in the EOMG and LOMG groups (58/78, 74.4%, p < 0.0001; 22/27, 81.5%, p = 0.0015). On the other hand, the male proportion increased up to 40% among VLO cases (6/15) (Figure 1B). Moreover, the male frequency increased from 23.5% (4/17) in the decade 1980–1990 to 35.9% (14/39) in the period 2013–2025 (Figure 1C). Demographic and clinical characteristics according to age at onset are reported in Table 1.

TABLE 1.

Demographic and clinical characteristics of MuSK‐MG cohort according to age of onset.

	EOMG (N = 78)	LOMG (N = 27)	VLOMG (N = 15)
Female, n (%)	58 (74.4%)***	22 (81.5%)**	9 (60%)
Age at onset (years) Median (IQR)	32.5 [25–40]	58 [55–62]	72 [68–74]
Max MGFA class during disease course
I	2 (2.6%)	1 (3.7%)	2 (13.3%)
II	12 (15.4%)	6 (22.2%)	1 (6.7%)
III	39 (50%)	10 (37.0%)	8 (53.3%)
IV	10 (12.8%)	4 (14.8%)	1 (6.7%)
V	15 (19.2%)	6 (22.2%)	3 (20.0%)

Note: Female predominance was statistically significant in the EOMG and LOMG groups, whereas no significant sex predominance was observed in the VLOMG group. The distribution of the maximum MGFA class during the disease course did not differ significantly among the three age‐at‐onset groups. *p < 0.05; **p < 0.01; ***p < 0.001.

Abbreviations: EOMG, early‐onset myasthenia gravis; LOMG, late‐onset myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; VLOMG, very‐late‐onset myasthenia gravis.

During the study period, severe disease forms (MGFA Class IV and V) affected 15 (12.5%) and 24 (20%) patients, respectively. Maximum MG severity decreased over time, with a remarkable decline of Class V (p = 0.004), while the rate of mild and moderate disease (Class II–III) did not change significantly (Figure 1D). Only five (4.2%) patients had purely ocular symptoms for the whole course of disease (minimum follow‐up 5 years), with predominant symmetrical ophthalmoparesis and severe ptosis. Notably, three out of these five cases were older than 60 at presentation, and in three cases MuSK‐Abs were negative by RIA and detected only by L‐CBA. Clinical characteristics and maximum disease severity did not significantly differ in the three patients' subgroups (Table 1).

4. Discussion

Our study shows a significant increase of MuSK‐MG cases older than 50 at the disease onset, in the 2013–2025 period, with a trend towards male predominance among elderly patients.

Although in AChR‐MG, patient subgrouping by age at onset is based on distinct immunological and genetic profiles, such differences have not been explored in MuSK‐MG.

Based on our findings, maximum disease severity improved compared to previous decades and appears not related to age of onset.

Ocular MG associated with MuSK‐Abs is very rare [12]. However, in the last period we observed five cases with persistently ocular symptoms, three of these cases were older than 60 at presentation and two were positive only by L‐CBA. These findings support the use of CBA in RIA‐negative elderly patients with MG symptoms confined to the ocular muscles.

In contrast to AChR‐MG, a bimodal pattern of incidence and the onset of the disease in patients older than 65 are less common in MuSK‐MG [12], although reported in recent studies from China and Japan [8, 9]. In 2020, Deymeer described a cohort of 38 MuSK‐MG patients (82% were females), median age at onset was 34, and five patients were 50 year‐old or older at the disease onset [4]. In a Spanish cohort of 25 MuSK‐MG patients, eight belonged to the LO and four to the VLO group [13]. Our data show recent demographic changes that mirror, to a lesser extent, those observed in AChR‐MG [14]. Recognizing these demographic changes is crucial for optimizing diagnostic approaches and, above all, for personalized therapeutic strategies across different age groups. In MuSK‐MG, corticosteroids are typically used as first‐line treatment, and the efficacy of rituximab is generally acknowledged. However, the use of these agents in elderly patients is challenging because of the high rate of comorbidities that increase the risk of adverse events and reduced tolerance [14]. Neonatal Fc receptor inhibitors proved to be effective and well‐tolerated in MuSK‐MG, with a potential use also as rescue therapy in elderly patients [15, 16]. Based on our data, the increasing proportion of elderly patients may pose greater diagnostic and therapeutic challenges. Aging of the general population, the improvement of diagnosis and the better acknowledgement of the disease are likely the predominant factors contributing to these findings. However, we cannot exclude that other environmental factors are involved in this changing demographic scenario [17, 18].

Author Contributions

Silvia Falso: conceptualization, investigation, writing – original draft, methodology, validation, visualization, formal analysis, writing – review and editing, data curation. Sofia Marini: investigation, data curation, writing – review and editing. Martina Marini: investigation, data curation, writing – review and editing. Federico Habetswallner: investigation, data curation, writing – review and editing. Amelia Evoli: writing – review and editing, conceptualization, investigation, methodology, validation, visualization, formal analysis, project administration, data curation, supervision, writing – original draft. Raffaele Iorio: conceptualization, investigation, methodology, validation, visualization, writing – review and editing, funding acquisition, formal analysis, project administration, data curation, supervision, resources, software, writing – original draft.

Conflicts of Interest

S.F. has received consultancy fees and speaker honoraria from Alexion, Argenx, UCB. S.M. has received speaker honoraria from Alexion and UCB. A.E. has received consultancy fees and speaker honoraria from Grifols and UCB. R.I. has received consultancy fees and speaker honoraria from Alexion, Argenx, Amgen, UCB, Merck, Johnson&Johnson, Lundbeck, and Dianthus Therapeutics. The remaining authors have no conflicts of interest.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.