Abstract
Background:
Myasthenia gravis (MG) is a rare autoimmune neuromuscular disease characterized by fluctuating muscle weakness and a variable clinical course. While sex differences in MG onset and progression are well documented, the extent to which these disparities affect quality of life (QoL)—particularly through fatigue and psychological burden—remains unexplored.
Objectives:
To systematically evaluate gender differences in QoL among MG patients and assess whether psychological factors and fatigue contribute to these disparities.
Design:
A systematic review and meta-analysis were conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines.
Data sources and methods:
Searches were performed in PubMed, Embase, and PsycINFO from inception through February 2025. Eligible studies included adult MG patients with QoL outcomes stratified by gender. QoL scores were synthesized using a random-effects model. Psychological and fatigue-related variables were examined qualitatively.
Results:
Twelve studies (N = 4744; 2889 women, 1855 men) met the criteria for the systematic review, and five studies (N = 3765) were included in the meta-analysis. Women consistently reported lower QoL compared to men. The initial pooled analysis showed a moderate but non-significant effect (Hedges’ g = 0.319, p = 0.0812; I² = 94.96%). Sensitivity analysis (excluding an outlier study) reduced heterogeneity (I² = 0%) and revealed a significant gender effect (Hedges’ g = 0.440, p < 0.001), with women experiencing significantly poorer QoL. Psychological comorbidities—particularly depression and anxiety—and higher levels of fatigue were more prevalent among female patients and consistently associated with lower QoL.
Conclusion:
Women with MG experience significantly reduced QoL, partially attributable to higher fatigue and psychological burden. These findings underscore the need for gender-sensitive approaches in MG management, including routine psychological screening and fatigue interventions. Future research should adopt standardized assessment tools and explore the impact of hormonal life stages on MG outcomes.
Trial registration:
PROSPERO CRD420251011446.
Plain language summary
Researchers Beeching et al. conducted a systematic review and meta-analysis of the scientific literature, examining the quality of life (QoL) in patients with Myasthenia Gravis (MG), a rare neurological condition that causes muscle weakness and fatigue, making everyday activities more challenging. This study focused on gender differences in QoL and explored how psychological factors and fatigue, two key aspects that tend to affect women more than men, influence the quality of life in MG patients, offering a deeper understanding of gender-related differences. The results suggest that there are disparities in QoL between men and women with MG, with women reportedly experiencing lower QoL. However, the limited number of studies the researchers managed to include in the analysis prevents drawing any definitive conclusions. Very few studies also explored the role of psychological factors and fatigue in predicting QoL, but those that did found that both of these aspects had a negative impact on QoL in MG. Future studies should prioritize collecting gender-sensitive outcomes and using a standardized set of tools to assess QoL, fatigue, and psychosocial factors. This would enhance comparability, ensure more reliable data, and help establish a foundation for tailored psychotherapeutic interventions in MG.
Introduction
Neurological diseases pose a substantial global burden, ranking as the leading cause of disability and the second leading cause of death worldwide. 1 Notably, autoimmune and neuroimmunological conditions exhibit striking sex-based disparities, with significant differences in both incidence and disease trajectory between males and females.2,3 Gender differences are especially pronounced in rare diseases, where women are frequently diagnosed later and experience distinct trajectories in both physical and psychological outcomes. 4
Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness due to impaired neuromuscular transmission. 5 It is the most prominent autoimmune disorder of the neuromuscular junction 6 and its prevalence has been steadily on the rise over the past 50 years, currently affecting 150–200 people per one million worldwide. 5
At onset, MG primarily affects ocular, facial, and throat muscles—although symptoms may be generalized even in the early stages—resulting in drooping eyelids (ptosis), double vision (diplopia), and difficulty swallowing (dysphagia).7,8 However, as the severity of this disorder increases, skeletal muscles become affected as well, to the point where, in the most extreme of cases, patients require intubation and ventilation to stay alive. 9
In MG, auto-antibodies targeting acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), or related components of the neuromuscular junction lead to disrupted synaptic signaling and muscle dysfunction. 10
A bimodal distribution is observed in MG, with women more commonly developing the condition in early adulthood (before the age of 40), whereas men are predominantly affected later in life (after the age of 50). 5 This pattern is likely influenced by hormonal factors, particularly the immunomodulatory role of estrogen. 11 Estrogen has been shown to enhance autoimmune activity, which may contribute to the higher prevalence of MG and other autoimmune diseases in females. 12
In women with MG, hormonal fluctuations associated with menstruation, pregnancy, and menopause can complicate disease management by exacerbating hallmark symptoms such as fluctuating muscle weakness, ptosis, diplopia, dysphagia, and fatigue, particularly during periods of immune and hormonal instability,13–16 increasing disease burden and influencing treatment response. 14
Women with MG are also more likely to experience comorbid autoimmune conditions, such as thyroid disease and systemic lupus erythematosus, 17 which complicate symptom management and contribute to worse quality of life (QoL) outcomes. Psychosocial factors, particularly a higher prevalence of anxiety and depression, may further amplify the disease burden in female patients.
Despite growing attention to the clinical aspects of MG, relatively fewer studies have investigated how sex differences can impact a patient-reported outcome such as QoL.
Moderate to severe fatigue is one of the primary examples of how MG can affect the livelihoods of those who endure it. 18 We must consider however, that fatigue is a nonspecific symptom, and therefore it can often disguise itself into various other disorders, such as chronic stress, depression, or hormonal imbalances, 18 which increase the chances of misdiagnosis, at least in the early phases of clinical disease manifestation. 19
MG is not only characterized by debilitating physical symptoms but it can also present limited psychological well-being, 20 an aspect of the disease that has only recently been addressed systematically by the literature. 21 Many people who suffer from chronic illnesses experience feelings of helplessness and frustration typical of depression, 22 which has been shown to increase behaviors such as poor treatment adherence 23 and suicide 24 in this population.
Depression, anxiety, and fatigue are common comorbidities in MG,18,25 which have also been recognized to disproportionately affect women in the general population,26–28 potentially contributing to poorer QoL.
Given these clinical and psychosocial challenges, gender may play a pivotal role in shaping how patients experience and adapt to MG. Yet, the extent to which these factors contribute to differences in QoL between men and women remains unexplored.
In this context, we conducted a systematic review and meta-analysis to assess gender differences in QoL among patients with MG. A secondary objective was to examine whether psychosocial factors and fatigue help explain observed disparities. We hypothesized that (i) women with MG report poorer QoL than men, (ii) this difference is partially mediated by higher levels of fatigue and psychological distress, and (iii) these findings would support the need for the integration of gender-sensitive psychological care in MG management.
Advancing understanding of gendered experiences in MG could inform more holistic, equitable approaches to treatment and care.
Methods
Eligibility criteria
To be included in the review, studies were required to involve adult patients (⩾18 years) diagnosed with MG, be published in English, and report means and standard deviations (SDs) of QoL outcomes assessed using standardized QoL instruments, with data disaggregated by gender.
Studies that reported results on neuromuscular or autoimmune conditions other than MG and articles that had QoL outcomes in MG without providing separate means and SDs for men and women were excluded, as well as reviews and published abstracts.
Electronic sources and search
In accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement, 29 an electronic search of the literature published in English through January and February 2025 was carried out using PubMed, Embase, and PsycINFO. The search string was based on the Medical Subject Headings (MeSH) terms such as “myasthenia gravis” and “gender” and “quality of life.” The full list of search terms can be found in Supplemental Table 1.
The search was carried out between January 1, 2025 and February 24, 2025 and it generated 96 findings, across the three databases. The last time the databases were checked was March 1, 2025.
Study selection and quality assessment
Abstracts and full texts of articles were assessed by two independent authors (F.B. and A.L.). Data were independently extracted from each original publication and inserted in two separate databases, including the first author’s name, the country in which the study was carried out, the type of study design, the year of publication, the duration of the study in months, the sample size, the female sample, the male sample, patient characteristics, and QoL outcomes. Any disagreements that occurred were resolved by consulting a third author (G.C.R.), to reach a general consensus.
Assessment of the quality of publications based on the risk of bias was evaluated with the modified versions of the Newcastle–Ottawa Scale (NOS) adapted for cross-sectional studies, for cohort studies, and for case–control studies. The cross-sectional and cohort NOS are divided into three sections that evaluate three quality parameters (selection, comparability, and outcome). The case–control version of the NOS instead investigates selection, comparability, and exposure. Two independent raters (F.B. and A.L.) conducted the quality assessment consulting a third rater (G.C.R.) if necessary. The risk of bias assessment is represented in Figure 1.
Risk of bias assessment histogram.
Data items
The outcome domain this review sought to explore was QoL in men and women with MG. Of the 12 studies that received an acceptable evaluation in terms of quality, only 5 were chosen for the meta-analysis, as they were the only ones who provided means and SD for QoL for the two genders. Within the meta-analysis, 3765 patients were studied collectively, 2348 females and 1417 males. The selected outcome measure was the mean difference of QoL scores in men and women, as the analysis was conducted over observational studies (cohort, cross-sectional, and case–control). While tabulating the study characteristics, we did not convert any values to compensate for missing data. All relevant means and SDs for males and females were tabulated using Excel and checked before being submitted for analysis.
The remaining studies were examined within our systematic review to display fatigue and psychological variables that could impact QoL in MG, and how their scores compared between men and women.
Meta-analysis
A random-effects model was carried out using the NCSS 2025 and the publication bias and funnel plot were obtained using Comprehensive Meta-Analysis (CMA) software (Biostat Inc., Englewood, NJ 2022). Firstly, we calculated the effect size of each study to see the difference in means of QoL between men and women. The heterogeneity of the obtained effect sizes was assessed by performing the I2 index. A forest plot for QoL was generated to assess asymmetry between men and women. We inserted results as standardized mean differences. Due to the high heterogeneity, we subsequently performed a sensitivity test by using the leave-one-out technique, which drastically reduced the levels of heterogeneity of the studies. Finally, we calculated the publication bias (Egger’s test) and produced a funnel plot. The final conclusions of our study were therefore drawn from an analysis of the studies remaining after the sensitivity test.
Results
Ninety-six studies were identified in the initial search. Following the removal of 41 duplicate records and 15 due to irrelevance, non-original content, or written in a language that was not English, we were left with 37 studies. Of these articles, 22 were excluded, as they did not divide outcome scores between men and women.
We screened 15 articles, which spanned a period of 12 years (2012–2024) and were published worldwide (United States, Serbia, France, Italy, China, India, Netherlands, Taiwan, Malaysia, Denmark, Germany). Of these, three did not pass the quality assessment (Supplemental Table 2). Thus, 12 articles (Table 1) were considered for the systematic review, and 5 of these (Table 2) were subjected to quantitative analysis, due to a lack of data on QoL in men and women provided as means and SDs in the remaining 7 studies. The PRISMA flow chart for study selection is shown in Figure 2, while the PRISMA checklist can be accessed in Supplemental Table 3.
List and features of the studies included in the systematic review.
MG-ADL, Myasthenia Gravis Activities of Daily Living Profile; MGFA, Myasthenia Gravis Foundation of America clinical classification; MG-QoL-15r, 15-item Myasthenia Gravis Quality of Life Scale revised version; N/A, not available; QMG, Quantitative Myasthenia Gravis Clinical Score; SF-36, 36-Item Short Form Survey Instrument.
List and features of the studies included in the meta-analysis.
MG-ADL, Myasthenia Gravis Activities of Daily Living Profile; MGFA, Myasthenia Gravis Foundation of America clinical classification; MG-QoL-15r, 15-item Myasthenia Gravis Quality of Life Scale revised version; N/A, not available.
Flowchart of evaluation process for the systematic review and meta-analysis.
All studies included in the systematic review adopted an ecological design (case-control = 1; cohort = 3; cross-sectional = 8) and primarily focused on the associations between MG and QoL. The predictors of QoL levels included: depression (n = 5), anxiety (n = 4), and fatigue (n = 3). Within the meta-analysis, we included the total QoL scores assessed in five studies that compared men and women.
Study designs and sample sizes
The studies included in this review vary widely along different dimensions. Most are cross-sectional studies,30–37 but there are also two cohort studies,38,39 and one case–control study. 40 The study duration ranged from 1 month 30 to 47 months. 34
Sample sizes were also not consistent, with some studies evaluating large populations32,34 and others focusing on smaller groups,33,37 with a range of sample sizes going from 1815 32 participants to 35. 37 This variability in study design, duration, and sample size illustrates the many different approaches that have been applied to explore QoL outcomes in MG.
Baseline characteristics
The gender distribution was part of our inclusion criteria; therefore, in each of these 12 studies, the number of women and men participants was stated. Of the 4744 participants included in this systematic review, 2889 were women, and 1846 were men.
All studies reported the age mean and SD or median and interquartile range (IQR) of the complete sample except Dong et al., 32 ranging from 40.74 ± 17.8 33 to 62.4 ± 13.9, 36 but only seven studies reported age means and SD or medians and IQR for men and women.31,32,34,36,38,39,41
Data on disease duration are available in seven studies,30–34,36,37 with disease duration ranging from 3 to 20 years. However, the different lengths in disease durations in men and women are reported only in five studies.31,32,34,36,41
All studies assessed MG disease severity. The number of studies that reported the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification 42 was three.33,38,40
MGFA is a qualitative measure that classifies MG patients according to disease severity into five different categories (I: ocular muscle weakness; II: slight muscle weakness experienced outside of ocular muscles; III: moderate muscle weakness outside of ocular muscle weakness, which can be of any severity; IV: severe muscle weakness outside of ocular muscle weakness along with ocular muscle weakness of any kind; V: intubation). 42
Eight of the remaining studies31,32,34–37,39,41 quantified the level of disease severity either with the Myasthenia Gravis Activities of Daily Living Profile (MG-ADL), 43 and one 30 utilized the Quantitative Myasthenia Gravis (QMG) Clinical Score. 44 The MG-ADL scale assesses the impact of MG on daily functioning. It has eight items, with a total score that ranges from 0 to 24. Higher total scores indicate greater disability levels. 43 The QMG is a 13-item disease severity evaluation scoring system for physicians. The overall score ranges from 0 to 39. Higher scores indicate more severe symptoms. 44
The studies that used quantitative disease severity measures for men and women were four.31,32,34,39 Disease severity, reported on the MG-ADL scale, was found to be significantly higher in women compared to men (6.75 ± 4.47 vs 6.15 ± 4.54, respectively; p < 0.01) by Dong et al., 32 Wilcke et al. (4.8 ± 3.7 vs 3.0 ± 3.0, respectively; p = 0.032), 39 Lee et al. (6.72 ± 3.95 vs 5.02 ± 3.57, respectively; p < 0.001), 34 and Ruiter et al. (4.9 ± 3.7 vs 3.1 ± 2.9, respectively; p < 0.001). 36
Quality of life
QoL was most commonly assessed using the 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL-15) 45 or its revised version (MG-QoL-15r) 45 in eight studies.31–34,36,37,39,41 Both are validated tools derived from the original 60-item MG-QoL scale, designed to capture the psychological, physical, and social impact of MG. The MG-QoL-15r consists of 15 items scored from 0 to 2, yielding a total score ranging from 0 to 30, where higher scores indicate poorer QoL. 45
The remaining studies that measured QoL30,38 utilized the 36-Item Short Form Survey Instrument (SF-36). 46 The SF-36 is a health survey that measures physical and mental health across 36 items in 8 domains. The range of scores of the SF-36 is 0 to 100, with higher scores indicating lower levels of disability. 46 QoL was evaluated in females and males in six studies.31–34,36,48
Camdessanché et al. carried out a cross-sectional online MG patient survey that involved 255 participants. 31 Their aim was to collect information on how MG patients perceived their illness, and the ways in which they proposed to improve treatment. The sample was composed of 187 women and 59 men (the rest of the participants did not declare their gender), with an age range of 41–67 years. Along the MG-QoL-15r scale, 45 the median score for women was 15/30 points (IQR = 9–20), while men scored 11/30 (IQR = 6–16). The study did not report any correlations between gender and QoL and the results were not presented with a mean and SD, therefore we could not include this study in our meta-analysis.
Dong et al.’s cross-sectional study was conducted among 1815 subjects (1194 women and 621 men). 32 The authors used the MG-QoL-15r and the findings revealed that, on average, female patients reported lower QoL scores on the scale compared to males (44.49 ± 29.10 vs 49.32 ± 29.18; p < 0.001), which in this case meant that QoL was worse for women, as the authors of this study reversed the scores of each item and then summed them to obtain total item scores. In this particular study, a higher score on the MG-QoL-15r indicated better QoL. Additionally, the authors reported that QoL was adversely affected by the number of comorbidities, with women seeing a faster decline than males as comorbidities grew (p < 0.05). Furthermore, an active lifestyle (p < 0.001), unemployment (p < 0.001), and disease exacerbations (p < 0.001) were all important determinants of QoL.
Kumar et al. evaluated the QoL of MG patients who were receiving the best possible treatment and had a stable course of the condition. 33 The MG-QoL-15 scale 45 was used to assess QoL in 50 MG patients (24 women and 26 men). The mean score on the MG-QoL-15 was higher for women compared to men, but the difference between the scores was not statistically significant (12.96 ± 10.6 vs 7.96 ± 7.6, respectively; p = 0.067). In fact, these authors reported that QoL was not significantly impacted by factors such as age, gender, thymectomy status, thymoma, or steroid therapy. Only a small number of patients reported having difficulties driving or participating in hobbies because of MG, and none experienced severe difficulties with personal grooming in public places despite the severity of the disease.
Lee et al. examined QoL in MG patients comparing demographic and disease-related data in a total of 1315 patients (827 women and 488 men). 34 The results revealed that women were generally younger (50.3 ± 14.30 vs 61.6 ± 12.69, respectively; p < 0.001), had an earlier onset of symptoms (5.5 ± 9.77 vs 3.7 ± 10.06, respectively; p = 0.0026), and were more likely to have thymoma and undergo thymectomy (38% vs 18%, respectively; p < 0.001) in MG. QoL, as measured by the MG-QoL-15 scale, 45 was significantly worse in women compared to men (24.53 ± 14.74 vs 18.44 ± 13.65, respectively; p < 0.001). However, this disparity in QoL was eliminated in women who had undergone thymectomy, as their scores were comparable to those of men, regardless of thymectomy status.
Ruiter et al. assessed fatigue in 420 participants with MG using an online survey. 36 There were positive associations with female gender, body mass index (BMI), disease severity, and depressive symptoms, and fatigue prevalence and intensity rose dramatically with disease severity. QoL, measured with the MG-QoL-15, was significantly worse in women compared to men with MG (23.6 ± 12.0 vs 18.2 ± 12.3, respectively; p < 0.001).
Wilcke et al. evaluated factors affecting QoL in individuals with MG to explore gender differences. 39 They conducted a retrospective and prospective analysis of 165 patients (80 women and 85 men). The study used the MG-QoL-15 scale and found that women with MG had significantly poorer QoL compared to men (19.7 ± 12.4 vs 13.0 ± 13.0, respectively; p = 0.024).
Psychological factors
Five studies30,31,34–36 investigated the presence of depressive symptoms in MG patients. Assessments were conducted using validated tools such as the Hamilton Depression Rating Scale (HDRS), 47 the Hospital Anxiety and Depression Scale (HADS), 48 and the Neuro-QoL (Quality of Life in Neurological Disorders) depression item bank. 49
The HDRS, a 17-item questionnaire, measures depression levels. The total score range is from 0 to 52. Higher scores indicate higher levels of depression. Score intervals correspond to: absence of depression (⩽7), mild depression (8–16), moderate depression (17–23), and severe depression (⩾24). 47
The HADS is a 14-question screening tool, 7 items assessing depressive symptoms and 7 items assessing anxiety symptoms. The range score for depression or anxiety is 0–21. Score intervals correspond to: no depression/anxiety (⩽7), minor depression/anxiety (8–10), moderate depression/anxiety (11–15), severe depressive/anxious symptoms (⩾16). 48
The depression item bank of the Neuro-QoL consists of eight items that measure depression levels in responders. Total scores range from 8 to 40. Higher scores correspond to higher levels of depression. 49
Anxiety was measured by four cross-sectional studies,30,31,35,36 and evaluations we carried out using HADS, 48 or in one case 30 with the Hamilton Anxiety Rating Scale (HARS). 50 The HARS is a 14-item scale that analyzes the severity of anxiety levels in responders. The total score range is between 0 and 56, with higher scores indicating higher levels of anxiety. Score intervals correspond to: absence of anxiety (<7), mild anxiety (8–17), mild to moderate anxiety (18–24), and severe anxiety (25–30). 50
Basta et al. and Liu et al. did not assess differences between men and women.30,35 However, Basta et al. found that higher levels of anxiety and depression were psychological predictors of poor QoL in MG (p = 0.001), 30 and Liu et al. reported that the possibility of exhibiting PTSD symptoms in MG was positively correlated with higher anxiety (p = 0.029) and depression (p = 0.006) scores. 35
Camdessanché et al. reported the median and IQR scores of men and women in their sample along the HADS-anxiety (HADS-a) and HADS-depression (HADS-d) self-report measures, 48 including the percentage of their sample that fell into the following categories: no anxiety/depression, possible anxiety/depression, and probable anxiety/depression. 31 The median score along the anxiety scale for women was 9 (possible anxiety), while for men it was 6 (no anxiety), with 31.6% of the female sample being classified as probably having anxiety, compared to 20.3% of the male sample. Depression seemed to have a more even distribution between men and women, with the median scores of the sample being 7 for women and 6 for men, indicating no depression, but those who were classified as probable depression were 24.7% of the female sample and 16.9% of the male sample.
Lee et al. found that depression, measured with the Neuro-QoL depression item bank, was significantly higher in women compared to men (1.31 ± 1.19 vs 0.96 ± 1.09, respectively; p < 0.001) and it correlated significantly with poorer QoL (p < 0.001), 34 while Ruiter et al. found no significant differences between men and women along the self-report HADS-d scores (5.6 ± 3.7 vs 5.2 ± 3.7, respectively; p = 0.276), but the results of a multivariate regression analysis showed a significant positive correlation between female gender, BMI, disease severity, and depressive symptoms (p < 0.001). 36
Fatigue
Three cross-sectional studies31,34,36 investigated fatigue levels in men and women by applying the Neuro-QoL fatigue item bank 49 or the Checklist Individual Strength fatigue subscale (CIS-f). 51 The fatigue item bank of the Neuro-QoL consists of eight items that investigate levels of fatigue. Total scores range from 8 to 40. Higher scores correspond to higher levels of fatigue. 49
The CIS-f is an eight-item measure that investigates subjective levels of fatigue. It has a total score range between 8 and 56. Higher scores indicate higher levels of fatigue. A score of > 35 on the CIS-f indicates that the responder suffers from severe fatigue. 51
Camdessanché et al. reported the median and IQR scores of men and women in their sample along the Neuro-QoL fatigue item bank, 49 including the percentage of their sample that fell into the following categories: no problems, mild problems, moderate problems, and severe problems. 31 The percentage of the female sample with moderate and severe problems was 55.4%, while the percentage of males that were part of the same categories was 31.7%.
Fatigue levels were significantly higher in women compared to men, according to Lee et al. (19.03 ± 7.03 vs 14.57 ± 7.98, respectively; p < 0.001), 34 using the Neuro-QoL fatigue item bank, and Ruiter et al. (40.9 ± 11.6 vs 32.8 ± 13.6, respectively; p < 0.001), 36 using the CIS-f, both studies showing a significant positive relationship between fatigue and QoL.34,36
Meta-analysis
The PubMed, Embase, and PsycINFO search initially yielded 96 studies, but, after screening, only 5 studies were selected for quantitative analysis, which included a total of 3765 patients with MG (females = 2348; males = 1417). QoL outcomes between female and male patients with MG across these five studies32–34,36,39 were inserted into a random effects model which showed a larger effect size (g = 0.319) but without statistical significance (p = 0.0812).
However, the heterogeneity analyses carried out with Cochran’s test (Q = 79.411; p = 0.001) and I² (94.96% with a confidence interval between 90.93%, and 97.20%) suggested that a substantial proportion of the variation in the results was due to differences between the studies rather than sampling error.
Considering that one study in particular 32 seemed to be completely unaligned compared to the others, we decided to conduct a sensitivity analysis by leaving this study out. Removing it drastically decreased heterogeneity values (Q = 0.474, p = 0.9245, and I2 = 0%) in the analysis carried over the remaining four studies.33,34,36,39
Out of a total number of 1950 observations, the overall effect size across all four studies was g = 0.440 with a 95% confidence interval and a p < 0.001, indicating that QoL was significantly overall lower in women compared to men. Single effect sizes of each of the four studies and forest plot are shown in Figure 3.
Effect sizes for each of the four studies (Kumar et al., 2016; Lee et al., 2018; Ruiter et al., 2021; Wilcke et al., 2023) and forest plot.
We carried out an analysis of the publication bias, which revealed Egger’s test = 3.62 with a p = 0.068, which did not indicate strong evidence of bias. The funnel plot is shown in Figure 4.
Funnel plot.
Discussion
This systematic review and meta-analysis aimed to investigate whether gender differences influence QoL in MG patients and to what extent psychological factors and fatigue help explain these disparities. Our hypotheses were that: (i) women with MG report poorer QoL than men, (ii) this disparity is partly mediated by higher psychological distress and fatigue, and (iii) these findings would support the need for gender-sensitive care models in MG.
The results of our meta-analysis confirm the first hypothesis: female gender is associated with significantly worse QoL in MG, with a moderate effect size (Hedges’ g = 0.44, p < 0.001) across four studies. Although initial heterogeneity was high, sensitivity analysis—excluding an outlier study—revealed a consistent and robust pattern across the remaining studies.
Specifically, the study by Dong et al. 32 likely differed significantly due to a methodological deviation in how the MG-QoL-15r questionnaire was administered and scored. Unlike the other studies, the authors did not use the questionnaire in its original format. Instead, they reversed the scoring of each item, summed the reversed scores, and then normalized the total by dividing it by the maximum possible subscale score and multiplying by 100 to produce a 0–100 scale. This methodological discrepancy likely explains the outlier status of this study in our pooled analysis.
On the other hand, Kumar et al. 33 and Camdessanché et al. 31 did not report a significant difference in QoL levels between men and women. Differences in study outcomes may be attributed to several factors, including variations in sample size, study design, and patient population characteristics. For instance, smaller cohorts may lack the statistical power to detect gender-related differences, especially when stratifying by disease subtype, age of onset, or hormonal stage. In addition, retrospective versus prospective study designs can influence the reliability of symptom reporting and diagnostic criteria used, potentially leading to inconsistent findings.
Furthermore, differences in geographic, genetic, or environmental factors may contribute to variations in disease expression across study populations. Some studies may also not account for hormonal stages (e.g., premenopausal vs postmenopausal) or comorbid conditions, which are increasingly recognized as relevant modifiers in autoimmune diseases, including MG.
By acknowledging these methodological differences, we aim to contextualize our findings within the broader literature and emphasize the importance of carefully designed, stratified studies to better understand the role of gender in MG.
The findings from the broader literature supported our secondary hypothesis: fatigue and the investigated psychological symptoms, depression, and anxiety, disproportionately affect women with MG and appear to be important contributors to their reduced QoL.
Several studies reviewed showed that women with MG had significantly higher rates of depression and anxiety than men. For example, Lee et al. 34 and Ruiter et al. 36 found that depression and fatigue were significant predictors of reduced QoL in women. Camdessanché et al. 31 further showed that a higher proportion of women reported probable depression and anxiety, though these findings were not linked statistically to QoL in that study.
Importantly, fatigue was consistently higher in female patients, and its negative impact on QoL was well-documented. These findings support our secondary aim: fatigue and psychological burden are key explanatory variables of gender disparities in QoL.
Several biological and psychosocial factors may contribute to these gender differences: hormonal influences, particularly estrogen, may heighten immune reactivity and influence the onset, severity, and symptom fluctuations in MG; life-course hormonal events—such as menstruation, pregnancy, and menopause—can amplify fatigue and mood disturbances, further lowering QoL.52–54. Moreover, comorbid autoimmune conditions (e.g., thyroid disease, systemic lupus erythematosus) are more prevalent in women with MG 17 and may increase symptom burden. 55
Women with MG have a significantly higher risk of developing comorbid autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and autoimmune thyroid disorders.32,56,57 This higher prevalence is thought to be influenced by sex hormones, particularly estrogen, which plays a key role in modulating immune responses. 14
Estrogen enhances the survival and activation of B cells, thereby increasing the production of autoantibodies.58,59 Additionally, it promotes a Th2-dominant immune profile and suppresses the Th1 response, which is generally more protective against autoimmunity.14,60 These hormonal influences may underlie both the increased susceptibility to autoimmune diseases in women and the exacerbation of MG symptoms.
Comorbid autoimmune conditions can intensify the symptom burden in MG by contributing to greater neuromuscular weakness, fatigue, and overall disease severity, thereby negatively affecting prognosis and QoL.57,61,62
We propose that MG in women should be understood within a biopsychosocial framework, considering both the physiological impact of the disease and the intersecting psychological and hormonal stressors that women may face at different life stages. For instance: pregnancy and postpartum periods may exacerbate fatigue and depressive symptoms, complicating disease management. On the other hand, menopause, with its associated decline in estrogen, may also intensify musculoskeletal and mood symptoms, compounding MG-related difficulties.
Our findings suggest the integration of gender-sensitive assessment into the routine care of MG, particularly for evaluating QoL, fatigue, and psychological well-being. Moreover, health professionals should be aware that women may require more comprehensive support due to both biological and psychosocial vulnerabilities. Clinical guidelines should consider hormonal transitions as modifiers of MG symptoms and treatment responses.
Hormonal fluctuations across distinct life stages—such as pre-menopause, pregnancy, and post-menopause—have been shown to significantly influence the immune system and, consequently, the course of autoimmune diseases like MG. 14
For instance, many women with MG report symptom worsening during menstruation, 13 while others experience stabilization or improvement during the immunosuppression that occurs during the second and third trimesters of pregnancy. 63
Including participants across hormonal stages allows for a more nuanced understanding of sex-based differences in disease pathogenesis, symptom burden, and QoL. This approach may also inform more personalized treatment strategies for women with MG, considering how hormonal status could influence therapeutic response and disease progression.
Another relevant aspect regards the routine use of structured screening tools for depression, anxiety, and fatigue with consistent QoL scales like the MG-QoL-15r 45 to facilitate comparison across studies and patients. Interventions such as the cognitive behavioral therapy approach, fatigue management programs, physiotherapy, and peer support may be particularly beneficial for female MG patients and should be explored in future trials.
Based on our findings, we suggest several hypotheses for future research: (i) Hormonal fluctuations modulate symptom severity and QoL in women with MG, requiring life-stage-specific interventions. (ii) Targeted treatment of fatigue and psychological symptoms will improve QoL more significantly in women than men. (iii) Integration of psychological care can mitigate long-term QoL disparities in MG patients, particularly in women diagnosed at a younger age.
This review is not without limitations. The number of studies eligible for meta-analysis was small (n = 4), and although sensitivity analysis improved homogeneity, this limits the generalizability of the findings. Additionally, there was variability in study designs, sample sizes, and QoL measurement tools, introducing potential bias. Female participants were overrepresented in most studies, which may limit gender balance in the pooled results. Many studies lacked longitudinal data, making it difficult to assess how QoL evolves over time or across life events.
In this review, stratification based on treatment type (symptomatic vs immunosuppressive) was not considered. This factor could indirectly influence QoL outcomes in women with MG, as certain medications, particularly glucocorticoids and pyridostigmine, are known to cause physical64,65 and psychological 66 side effects in MG patients. Future analyses should account for treatment regimens to more accurately assess QoL differences in MG patients also stratified by gender.
Another potentially relevant factor not addressed in this review is the serological status of neuromuscular junction antibodies. To our knowledge, no studies to date have found a significant association between serological status—such as AChR, MuSK, or seronegative status—and MG-QoL-15r outcomes. However, serological status has been associated with differences in disease severity, 38 which is a well-established predictor of QoL in MG. 67 Future studies should explore this relationship more directly by comparing QoL and disease burden across different antibody profiles to further elucidate their role in shaping patient-reported outcomes.
Despite these limitations, the strengths of our review include: a comprehensive synthesis of both quantitative and qualitative findings across 12 studies. To our knowledge, this is the first meta-analytic quantification of gender differences in MG-related QoL A critical, gender-focused framework that integrates biological, psychological, and social dimensions of illness. Through the critical examination of these studies, we aimed to enhance the understanding of how gender differences shape the perception of the experience of illness and the challenges faced by patients with MG, as well as which types of measurements are applied to gather this information within the literature.
Conclusion
In conclusion, this systematic review and meta-analysis demonstrates that women with MG experience significantly lower QoL than men, and that this difference is partly driven by higher psychological distress and fatigue levels. Our results support the implementation of gender-sensitive, holistic care approaches in MG management and call for longitudinal, life-stage-focused research to further elucidate these disparities. Understanding how gender shapes the lived experience of MG is essential for improving outcomes, tailoring treatments, and ensuring equitable care.
Supplemental Material
sj-docx-1-tan-10.1177_17562864251344742 – Supplemental material for Female gender and quality of life outcomes in myasthenia gravis: a systematic review and meta-analysis
Supplemental material, sj-docx-1-tan-10.1177_17562864251344742 for Female gender and quality of life outcomes in myasthenia gravis: a systematic review and meta-analysis by Francesca Beeching, Alessandro Lecchi and Gianna Carla Riccitelli in Therapeutic Advances in Neurological Disorders
Footnotes
Acknowledgements
The authors of this review would like to thank Stefano Damato, PhD student at the Dalle Molle Institute for Artificial Intelligence Studies of Lugan, for assistance with data analysis.
Declarations
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References
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