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Clinical characteristics and impairment of activities of daily living among patients with myasthenia gravis with differing degrees of muscle weakness: a real-world study of patients in the US and five European countries

BMC Neurology volume 24, Article number: 385 (2024) Cite this article

Abstract

Background

Real-world data were employed to determine clinical characteristics of patients with myasthenia gravis (MG) with differing degrees of muscle weakness, as defined using the Myasthenia Gravis Foundation of America (MGFA) classification system.

Methods

Data were drawn from the Adelphi MG Disease Specific Programme (DSP)™, a multinational (United States, France, Germany, Italy, Spain, United Kingdom) survey completed by physicians and their patients with MG in 2020. The association between MGFA class and impairment in activities of daily living (ADL) was tested using linear regression adjusting for sex and Charlson Comorbidity Index. Bivariate comparisons were performed for each individual item. A range of other clinical characteristics were also explored according to MGFA class.

Results

Among 1232 patients, those in MGFA class I had significantly lower ADL impairment versus class II or III/IV (adjusted for sex and Charlson Comorbidity Index) (p < 0.01). However, heterogeneity occurred within each MGFA class. Bulbar symptoms (impaired speech, difficulty swallowing, and/or difficulty chewing/choking on food) were reported in some class I patients (mild in 1.1–1.9% and moderate in 0.3–1.1% of patients) and class II patients (mild in 8.5–16.4%, moderate in 4.7–7.4%, and severe in 0.3–0.9% of patients), and shortness of breath was reported in some class I (mild in 0.5% of patients) and class II patients (mild in 9.8%, moderate in 4.8%, and severe in 0.3% of patients). Conversely, in 11.2–19.2% of class III/IV patients, bulbar symptoms and shortness of breath reported were only mild in severity. In line with this finding, despite significant correlations between MGFA class and several clinical characteristics, patients across every class were at risk of experiencing myasthenic crisis or hospitalization, experiencing comorbidities including anxiety and depression, and not being in remission.

Conclusions

Although MGFA class correlates with greater ADL impairment and presence of other clinical characteristics, there is variability between patients in each class in terms of symptoms experienced, overall disease burden, and the precise nature of ADL impairment.

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Background

Myasthenia gravis (MG) is a rare, chronic, autoantibody-driven disorder of the post-synaptic membrane at the neuromuscular junction, resulting in muscle weakness and fatigability. Ocular, bulbar, and limb skeletal muscles can be affected, resulting in a wide array of symptoms such as eyelid droop, difficulty speaking or swallowing, limb weakness, fatigue, and shortness of breath [1, 2].

A key feature of MG is the variable and fluctuating nature of symptoms, particularly muscle weakness and fatigability, which make it challenging to classify patients [1,2,3,4]. The Myasthenia Gravis Foundation of America (MGFA) classification system is widely utilized, and groups patients based on severity and localization of muscle weakness at the time of assessment [3, 5]. Patients are categorized as ocular (class I), mild (class II), moderate (class III), severe (class IV), or intubation with/without mechanical ventilation (class V). A deeper understanding of the clinical characteristics of patients within each MGFA class would be beneficial to fully appreciate the potential impact of MG symptoms on an individual patient.

Symptoms can impair a person’s ability to independently perform the routine tasks necessary to remain safe, healthy and clean, referred to as ‘activities of daily living’ (ADL) [6,7,8,9,10,11,12]. Correlation between MGFA class and impairment of ADL has been observed in a small study in Poland [13], and in the global MyRealWorld-MG study, though in the latter all data were patient-reported including MGFA class: patients either recalled the opinion of their clinician or conducted a self-assessment [12].

Our study objective was to evaluate and explore ADL impairment, alongside a wide variety of other physician-reported clinical characteristics, among patients with MG in different MGFA classes. To this end, we explored data from the Adelphi Real World (ARW) MG Disease Specific Programme (DSP)™, an established methodology for collecting real-world data for a specific disease using cross-sectional surveys with retrospective chart review. ARW DSP surveys are completed by large numbers of physicians and their patients across multiple countries, following recruitment by local fieldwork agents. This approach generates objective, impartial and comparable data which can be used to evaluate the impact of a disease on a wide range of outcomes.

Methods

Study design and data source

ARW DSPs are cross-sectional surveys which also capture retrospective data from patients’ medical histories. A complete description of the methodology has been previously published and validated [14,15,16,17] (Supplementary Appendix 1). Patient inclusion is based on natural presentation, and physician- and patient-reported information is collected with a consistent approach across all countries, generating objective and impartial data.

The MG DSP recorded information about patients with MG in the United States (US) and five European countries (France, Germany, Italy, Spain and the United Kingdom [UK]) in June–September 2020.

Following informed consent, data were collected in three stages (Supplementary Appendix 1): (i) an online physician-completed survey about disease management; (ii) an online physician-completed patient record form (PRF) chart review about the next 1–10 consecutive consulting patients seen in clinical practice that met inclusion criteria; and (iii) a pen-and-paper patient self-completion (PSC) form.

Physicians were hospital- or office-based with a primary specialty of neurology, primary care or geriatrics, who had personally treated ≥ 1 patient with a confirmed diagnosis of MG in the prior 12 months, recruited by local fieldwork agents (with appropriate remuneration for their involvement).

This secondary analysis was performed using survey results for a subset of physicians and their patients. Patients eligible for the analysis were ≥ 18 years of age and were MGFA class I-IV.

In a PRF question about patient ethnicity, options were: White, African American, Hispanic/Latin, Asian – other, mixed race, South-East Asian, Afro-Caribbean, Asian-Indian subcontinent, Middle Eastern, Native American, or other. Due to small numbers in many categories, these were grouped as ‘White’ and ‘other’ for this analysis.

MGFA classification

Severity and localization of muscle weakness is determined using the MGFA classification system [3]. When completing the PRF form as part of the MG DSP, physicians were asked to confirm the patient’s class at the current time and were provided with a link to MGFA classification system definitions. For this analysis, patients were MGFA class I (ocular MG), class II (mild generalized MG), class III (moderate generalized MG) or class IV (severe generalized MG). Class V patients (those requiring intubation, with or without mechanical ventilation, except when employed during routine postoperative management; or use of a feeding tube without intubation) were excluded.

Class III and IV patients were merged into one category due to the small number of patients in each group. In addition, A and B sub-classes were merged for MGFA classes II to IV. Although these sub-classes were included as options in the survey, the two are difficult to distinguish (A is predominately limb/axial and B is predominately bulbar, but they ‘may also have lesser or equal involvement of [the other]’). It was decided to remove any ambiguity and focus instead on the ocular/mild/moderate/severe aspect of the classification system.

Assessment of ADL

The physician-completed PRF form included multiple questions designed to provide information about ADL of the patient on the day of the survey, as communicated by the patient to the physician during their consultation. For this analysis, these questions were reviewed to identify those most informative of patient ADL, using the ‘MG-ADL’ scale (which assesses the impact of MG on daily functions [11] but was not part of the ARW DSP survey) as guidance. Responses were combined post-collection to create a total score ranging from 0 to 22, with higher score indicating greater impairment. This was not a defined, validated tool.

Other clinical characteristics

The PRF chart review form included questions about patient disease characteristics (including concomitant conditions, as discussed in Supplementary Appendix 2), clinical history and current treatment.

In the PRF, remission was defined as follows. Complete Stable Remission (CSR): patient has been symptom-free and has not received any treatment for MG; Minimal Manifestations (MM): patient has no symptoms or functional limitations but some weakness on examination of some muscles; Pharmacological Remission (PR): patient has been symptom-free but continues to receive treatment for MG; or not in remission.

Charlson Comorbidity Index (CCI) was calculated post-survey using patient age and presence of comorbidities collected in the PRF (which was specifically designed to include all relevant comorbidities as options).

Ethical approval

The MG DSP survey obtained ethics approval from the Western Institutional Review Board (sponsor protocol number: AG8768). Data were collected in such a way that patients and physicians could not be identified directly; all data were aggregated and de-identified before receipt. Data collection was undertaken in line with relevant legislation and guidelines including European Pharmaceutical Marketing Research Association guidelines [18], the US Health Insurance Portability and Accountability Act 1996 [19] and Health Information Technology for Economic and Clinical Health Act legislation [20].

Data analysis

Demographic and clinical variables for the overall sample and for each of the three MGFA classes were presented.

A linear regression analysis was used to test the association between MGFA class and ADL scores while adjusting for sex and CCI. MGFA class was included as a categorical covariate and no interaction terms were used. Marginal means and standard errors were reported. For each individual item, bivariate comparisons were also performed to identify significant differences according to MGFA class.

Variables were compared using Analysis of Variance (for continuous variables), Fisher’s exact test (for dichotomous categorical variables), Kruskal-Wallace tests (for ordered categorical variables), or chi-squared tests otherwise.

There was no adjustment for multiple testing. Missing data were not imputed; therefore, the sample size of patients could vary from variable to variable.

All statistical analyses were performed using STATA v17 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).

Results

Patient population

Data were provided by 222 physicians relating to 1232 patients. Of these, 456 (37.0%) of patients were from the US, 128 (10.4%) from France, 102 (8.3%) from Germany, 152 (12.3%) from Italy, 244 (19.8%) from Spain, and 152 (12.3%) from the UK. Twenty six (2.1%) of patients were under the care of geriatricians, 893 (72.4%) neurologists and 315 (25.5%) general physicians. Half of patients were male and the majority were White (Table 1).

Severity and localization of muscle weakness (MGFA classification)

MGFA data were available for all patients. Overall, 367 (29.8%) of patients were MGFA class I (ocular MG), 579 (47.0%) were class II (mild, generalized MG), and 286 (23.2%) were class III/IV (moderate/severe, generalized MG). Mean age was significantly different between class I, class II and class III/IV (p < 0.001), though it was in the fifth decade in every group (Table 1). There were no significant differences in sex or ethnicity (Table 1).

ADL impairment

An ADL impairment score was calculated for 1202/1232 patients (for whom the physician competed the relevant sections of the survey). Patients in class I had a marginal mean (standard error) score of 1.9 (0.3), compared with 3.5 (0.3) in class II and 6.0 (0.5) in class III/IV (Fig. 1). Class I patients had significantly lower scores versus class II or class III/IV (adjusted for sex and CCI) (p < 0.01) (Fig. 1).

Across every item, there was a significant difference in the proportion of patients in each response category (i.e. symptom absent/mild/moderate/severe, or assistance required/not required) according to MGFA class (p < 0.001; Fig. 2). Full results of the regression analysis are provided in Supplementary Appendix 3. However, a range of ADL impairment scores was observed within each MGFA class (Fig. 2).

Fig. 1
figure 1

Mean score among patients by MGFA class, indicating the degree of physician-assessed ADL impairment. ADL, activities of daily living; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; n, number of patients. Figure shows marginal mean score by MGFA classification with 95% confidence intervals. Total score ranged from 0 to 22, with higher score indicating greater impairment. p-values are from linear regression analysis to test association between MGFA class and score while adjusting for sex and Charlson Comorbidity Index. The number of patients was n = 367 for MGFA class I, n = 579 for MGFA class II, and n = 286 for MGFA class III/IV

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Fig. 2
figure 2

Proportion of patients with or without (A–F) symptoms and (G–H) requirement for assistance. MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; n, number of patients. Figures show proportion of patients in MGFA class I, II, and III/IV for whom their physician reported (A–F) absence of symptom or presence of mild/moderate/severe symptom and (G–H) requirement or non-requirement for assistance. The number of patients was n = 367 for MGFA class I, n = 579 for MGFA class II, and n = 286 for MGFA class III/IV

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Table 1 Demographic characteristics of patients with MG, overall and stratified by MGFA Class
Full size table

Other clinical characteristics

There were statistically significant differences between patients in MGFA class I, class II, and class III/IV for a number of clinical characteristics, including those relating to the presence of comorbidities, remission status, experience of myasthenic crisis, MG-related hospitalization, and number/type of treatment lines received (Table 2).

Notwithstanding these correlations, a proportion of patients in every MGFA class had clinical characteristics reflective of less-than-optimal disease control (Table 2). For example, many patients in class I or II (i.e. ocular MG and mild generalized MG, respectively) were not considered to be in remission (7.4% and 12.1%, respectively), had experienced a myasthenic crisis (9.1% and 21.0%, respectively) or hospitalization (34.5% and 47.7%, respectively) at some point since diagnosis, and/or experienced comorbid depression (12% and 14.3%, respectively) or anxiety (13.6% and 17.4%, respectively).

Table 2 Clinical characteristics of patients with MG, overall and stratified by MGFA Class
Full size table

Discussion

Results of this multinational, real-world survey completed by physicians treating 1232 patients with MG revealed that ADL impairment broadly increased with increasing MGFA classification, i.e. the site and degree of muscle weakness. This concurs with the findings of previous studies in which MG-ADL score correlated with MGFA class [12, 13] or other measures of MG severity [21,22,23]. As context for the difference in ADL impairment between MGFA classes in this study, a 2-point change in the validated MG-ADL score between consecutive assessments was previously deemed to indicate clinical improvement [23]. However, direct comparisons should not be drawn, as in this study, MG-ADL score was not collected, ADL impairment was captured at a single point in time with no follow-up, and statistical analysis techniques were designed to identify significant differences across the three MGFA class groups but not to precisely pinpoint where these differences lie.

However, our data also highlight the heterogeneity observed within each MGFA class, including the presence and severity of defined ocular and bulbar symptoms, as well as the requirement for assistance with oral hygiene or arising from a chair. All data were physician-reported, based upon patient consultations at the time of the survey as well as review of patient medical records.

Unlike previous publications, our study also explored a breadth of survey data to examine any differences between MGFA classes and to further elucidate the heterogeneous nature of ADL impairment and clinical impact experienced by people with MG. Although statistically significant differences were observed between patients in MGFA class I, II, and III/IV, differences were not clinically meaningful in all cases. For example, although CCI differed significantly, in every group the mean was < 1, a value which is generally considered low [24,25,26]. The mean number of hospitalizations within the prior 12 months also remained < 1 in every MGFA class.

In contrast, the proportion of patients who had ever experienced a myasthenic crisis differed significantly according to MGFA class, with a clinically meaningful difference in rates (9.1%, 21.0% and 41.1% in class I, II and III/IV, respectively). There were also substantial differences in the proportion of patients in remission (7.4%, 12.1% and 40.6% in class I, II and III/IV, respectively were not in remission) and the use of non-steroidal immunosuppressants (23.6%, 38.7% and 51.1% in class I, II and III/IV, respectively), corticosteroids (22.1%, 29.5% and 44.5% in class I, II and III/IV, respectively), and intravenous immunoglobulin (0.9%, 5.5% and 12.0% in class I, II and III/IV, respectively). The mean number of concomitant conditions ranged from 1.3 to 2.1; although this is a relatively small difference, studies have shown that the addition of each chronic condition increases health care utilization and cost [27] and that the presence of ≥ 3 conditions in total is associated with poorer outcomes compared with 1–2 [28]. We conclude that these variables appear to be correlated with the site and degree of muscle weakness in a clinically meaningful manner, reflecting differences in both disease burden and treatment approaches.

Despite these clinical characteristics differing by MGFA class, in line with our analysis of ADL the data also highlight the heterogeneity observed within each MGFA class and demonstrate that patients across every class still experienced adverse outcomes. Myasthenic crisis, hospitalization, and comorbidities including anxiety and depression were still experienced by a number of those in class I or II.

Taken together, these results highlight the variability between patients assessed as having the same degree of muscle weakness, in terms of the symptoms experienced, their disease burden, and the impact on their ADL. They also highlight the impact of poor disease control on a patient’s lived experience, across every MGFA class. This finding also aligns with the many studies that demonstrate the impact of MG on health-related quality of life more generally, including both qualitative [29, 30] and quantitative [31] studies highlighting the many challenges of living with the condition.

Due to the number of survey respondents, in this study, patients in MGFA class III and IV were merged into a single group. Further studies with a larger number of individuals could explore the differences between patients in these two groups, and also between A and B sub-classes of each MGFA class, to establish whether this explains some of the variability observed.

These results confirm that muscle weakness is generally connected to functional status, specifically symptoms that would impair a patients’ ability to speak, eat, and see, as well as the ability to perform tasks such as tooth brushing and arising from a chair without assistance. Ocular symptoms such as ptosis and diplopia restrict a wide variety of activities such as driving, reading, or use of a computer, and – combined with difficulty talking – impede communication with others; difficulty chewing and swallowing affects nutritional intake and may eventually necessitate gastrostomy in more severe cases; and shortness of breath constrains physical exertion and everyday activities, in some cases necessitating ventilation. However, this connection is not entirely linear, and physicians should assess functional status on a case-by-case basis. MG is often referred to as “the snowflake disease” as it differs greatly from person to person [32]. Accordingly, a holistic and personalized treatment approach would benefit patients, taking into account not only disease subtype, weakness distribution, and severity but also factors such as patient characteristics and comorbidities [1].

A very small percentage of patients in MGFA class I displayed symptoms usually associated with generalized MG or required help with oral hygiene or rising from a chair, though in at least some cases this may be related to age and/or comorbidities. There were also a small number of people who had not received any lines of maintenance treatment. They might have received acute therapies and/or surgery but not yet started maintenance treatment, have only just received a diagnosis of MG and not yet begun treatment, have refused treatment, or have been confronting barriers to access such as a lack of insurance coverage.

Of note, the study was performed in June–September 2020, just after the COVID-19 pandemic, which is known to have had a particularly detrimental impact on people with rare diseases and those with MG in particular. Studies have highlighted negative effects on psychosocial health as well as reduced access to care and support [33,34,35].

Comparisons may be drawn between patients with MG and those with other diseases with similar characteristics, such as unpredictable and fluctuating cycles of relapsing/remitting symptoms. ADL is impaired in patients with systemic lupus erythematosus [36,37,38,39], multiple sclerosis (MS) [40, 41], and myositis [42], often associated with measures of disease severity, increased symptoms, or disability. For MS, it has been suggested that incorporation of ADL tasks into clinical practice and clinical trials may be more valuable than the classical neurological examination [43].

The key strength of the study was the inclusion of a broad, multinational patient population. As this was a real-world study, it had the potential to highlight areas of concern not addressed in clinical trials, which by design include a small proportion of the consulting population due to stringent eligibility criteria [44] and involve high adherence [45]. Unlike some prior studies [12], MGFA class was determined by the treating physician, and not by the patient.

There are also some study limitations. Formal validation or verification of the methodology utilized to assess physician-reported ADL impairment has not been performed. Stratification of results based on autoantibody status (i.e., acetylcholine receptor, muscle specific kinase, low-density lipoprotein receptor–related protein 4, or seronegative) was not performed. Though there were no formal patient selection verification procedures, the DSP is not a true random sample of physicians/patients; participation is influenced by willingness and frequency of physician consultations (though the instruction to complete surveys for the next 1–10 patients with MG is representative of a physician’s real-world classification of their patients). As with all surveys, recall bias may influence physician responses (though data were collected during appointments, when physicians would be expected to have access to medical records, reducing the likelihood of bias). As missing data were not imputed, the base of patients for analysis could vary between variables.

It should be noted that the MGFA classification system is designed to identify subgroups of patients with MG who share distinct clinical features or severity of disease that may indicate different prognoses or responses to therapy, and not to measure outcome [3]. In addition, MG-ADL (which was utilized as a guide to which survey questions best reflected patient ADL) score can be affected by non-specific patient life events and factors such as presence of comorbidities, age, or family or employment responsibilities. Such aspects are not controlled for in a real-world study, thus accurately reflecting the reality of patients’ lives. Our results should be interpreted with these factors in mind.

Conclusions

In conclusion, although MGFA class correlates with ADL impairment and other clinical characteristics, there remains variability between patients of the same MGFA class in terms of the symptoms experienced, the precise nature of ADL impairment, and overall disease burden. It is, therefore, important to consider the individual experiences of each patient, taking into account more than just MGFA class.

Data availability

All data, i.e. methodology, materials, data and data analysis, that support the findings of this survey are the intellectual property of Adelphi Real World. All requests for access should be addressed directly to Gregor Gibson at gregor.gibson@adelphigroup.com.Gregor Gibson is an employee of Adelphi Real World.

Abbreviations

ARW:

Adelphi Real World

ADL:

Activities of daily living

CCI:

Charlson Comorbidity Index

DSP:

Disease Specific Programme

MG:

Myasthenia gravis

MG-ADL:

Myasthenia gravis activities of daily living

MGFA:

Myasthenia Gravis Foundation of America

MS:

Multiple sclerosis

n:

Number of patients

PRF:

Patient record Form

PSC:

Patient self-completion form

UK:

United Kingdom

USA:

United States of America

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Acknowledgements

Not applicable.

Funding

Janssen Scientific Affairs, LLC did not influence the original survey through either contribution to the design of questionnaires or data collection. The analysis described here used data from the Adelphi Real World Myasthenia Gravis DSP. The DSP is a wholly owned Adelphi Real World product. Janssen Scientific Affairs, LLC is one of multiple subscribers to the DSP.

Publication of survey results was not contingent on the subscriber’s approval or censorship of the manuscript.

Author information

Authors and Affiliations

  1. Janssen Scientific Affairs, LLC, Titusville, NJ, USA

    Jacqueline Pesa & Zia Choudhry

  2. 800 Ridgeview Drive, Horsham, PA, 18074, USA

    Jacqueline Pesa

  3. Adelphi Real World, Bollington, UK

    Jonathan de Courcy, Sophie Barlow, Gregor Gibson, Emma Chatterton & Shiva Lauretta Birija

  4. Macclesfield, UK

    Bethan Hahn

  5. HSHS Medical Group Multispecialty Care - St. Elizabeth’s, O’Fallon, IL, USA

    Raghav Govindarajan

Authors
  1. Jacqueline Pesa
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Contributions

Conceptualization: JP, ZC, JdC, GGStatistical analysis: SBData curation, analysis and interpretation: JP, ZC, JdC, SB, GG, EC, SLB, BH, RG Writing (original draft): BH Writing (review & editing): JP, ZC, JdC, SB, GG, EC, SLB, BH, RG.

Corresponding author

Correspondence to Jacqueline Pesa.

Ethics declarations

Ethics approval and consent to participate

The MG DSP survey obtained ethics approval from the Western Institutional Review Board (sponsor protocol number: AG8768). Using a checkbox, patients provided informed consent to take part in the survey. Data were collected in such a way that patients and physicians could not be identified directly; all data were aggregated and de-identified before receipt. Data collection was undertaken in line with relevant legislation and guidelines including European Pharmaceutical Marketing Research Association guidelines [18], the US Health Insurance Portability and Accountability Act 1996 [19] and Health Information Technology for Economic and Clinical Health Act legislation [20].

Consent for publication

Not required.

Competing interests

JP and ZC are employees of Janssen Scientific Affairs, LLC. JdC, SB, GG, EC and SLB are employees of Adelphi Real World. RG is on the advisory board for Argenx, UCB and Janssen and serves as speaker for Argenx and Alexion. BH received payment as a contractor from Adelphi Real World for their involvement in this manuscript, and also receives payment as a contractor from Janssen (Pharmaceutical Companies of Johnson & Johnson), Amiculum Limited, and McCann Health Medical Communications.

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Pesa, J., Choudhry, Z., de Courcy, J. et al. Clinical characteristics and impairment of activities of daily living among patients with myasthenia gravis with differing degrees of muscle weakness: a real-world study of patients in the US and five European countries. BMC Neurol 24, 385 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-024-03869-9

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Keywords

BMC Neurology

ISSN: 1471-2377

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