No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Health-Related Quality of Life and Treatment Targets in Myasthenia Gravis.
Abstract
Introduction:
The aim of this study was to determine factors affecting health-related quality of life (HRQOL) and to propose appropriate treatment targets for patients with myasthenia gravis (MG).
Methods:
We evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two-year follow-up data were obtained for 282 patients. Correlations between detailed clinical factors and the Japanese version of the 15-item MG-specific QOL scale score were analyzed.
Results:
In a cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P<0.0001), total dose of oral prednisolone during the last year (P=0.002), and Cushingoid appearance index (P=0.0004), showed significant negative effects on HRQOL, but the quantitative MG score and current prednisolone dose did not.
Conclusions:
Achieving minimal manifestations (MM) status or better with prednisolone ≤ 5 mg/day was found to exert a major positive impact on HRQOL in both the cross-sectional and 2-year follow-up patient samples and can be recommended as a treatment target.
... However, the remission rate is still low, at almost the same levels seen in the 1940-1960 period when no immunotherapies against MG were available. [1][2][3] Even today, many MG patients are burdened with residual symptoms and/or long-term side effects from chronic treatment. [4][5][6][7][8][9][10] In this review we summarize the significance of sequential surveys by the Japanese MG registry By these analyses, we have clarified the actual situation of MG patients, 2,3,5-10,15 determined major factors negatively affecting health-related QOL of patients, 2,3,5 recommended an appropriate treatment target to achieve sufficient QOL, 2,3 and proposed treatment strategies to enable MG patients to achieve the target early and live a normal lifestyle. ...
... The rate of patients with complete stable remission or pharmacologic remission is low. 2,3,8,17 Complete stable remission, even if achieved, usually cannot be maintained fully over multiple years, and the rate of stabilization is unlikely to be increased by the presently available treatments. Likewise, long-term pharmacologic remission cannot be achieved without intolerable side effects. ...
... Eventually, insufficiently reduced levels of oral corticosteroids have been a major factor that negatively affects patient QOL independently of MG symptoms. 2,3 Thus, according to analyses of clinical factors and patient QOL, the second guideline states "The first goal in MG treatment is a status of ...
The primary purpose of the Japanese myasthenia gravis registry (JAMG‐R) has been to research and promote high‐quality medical care for MG patients in Japan. We reviewed the findings of surveys performed by JAMG‐R over an approximately 10‐year period. The first goal for favorable quality of life (QOL) is a status of minimal manifestations (MM) or better with an oral prednisolone (PSL) dose of 5 mg/day or less (MM‐5 mg). Early and aggressive use of non‐oral fast‐acting treatment together with low‐dose oral PSL (the “EFT strategy”) is recommended to reduce disease severity with minimal oral steroid use so that the MM‐5 mg target can be met as soon as possible. We conducted the fourth largest multi‐center survey ever in 2021, obtaining detailed clinical information from 1,710 consecutive MG patients all over Japan, and compared the 2021 surveys to those from 2012 and 2015. The frequency of patients treated with EFT strategies showed a gradual increase, reaching 39% of the total MG patients in the 2021 survey. The current and maximum dose of PSL and the number of days at high‐dose (> 20 mg/day) PSL showed decreases. Survey results indicate that as EFT strategies have spread, the percentage of patients on MM‐5 mg has increased. We again confirmed that MM‐5 mg was associated with favorable QOL in the 2021 survey. Recent data regarding COVID‐19 suggests that it did not seriously impact the MG population in Japan; unfortunately, refractory MG, observed in 21% of patients, is still an unresolved problem.
... 7 Japanese patients with MG have been shown to be socioeconomically disadvantaged, with unemployment or unwilling job transfer found to be associated with several MG-related factors, including "insufficient control of symptoms." 9 In addition, there is evidence that disease severity and total dose of oral corticosteroids commonly used to treat gMG have significant negative effects on health-related quality of life in Japanese patients with MG. 10,11 Epidemiologic data indicate that the incidence of MG-particularly later-onset disease-has been increasing in Japan. 12,13 A nationwide survey conducted in 2006 identified almost 15,100 patients with MG in Japan (prevalence rate of 11.8 per 100,000), with elderly-onset (>65 y of age) MG accounting for 16.8% of cases compared with 7.3% in earlier studies. ...
... Their long-term use is associated with a range of adverse side effects and can negatively impact on quality of life in patients with MG. 10,11,17,[36][37][38][39] Conversely, achieving minimal manifestations status or better with a prednisolone dose of ≤5 mg/d has been shown to have a significantly positive effect on health-related quality of life in Japanese patients with MG. 10 The current analysis demonstrated that eculizumab treatment was associated with an increase over time in the proportion of patients who were treated with a low daily oral corticosteroid dose of ≤5 mg, the current target recommended in treatment guidelines for MG in Japan. 1 This is consistent with the results of a post-hoc analysis of immunosuppressant use in the REGAIN OLE, which showed that eculizumab treatment was accompanied by significant reductions in the mean daily dose of oral prednisone and other corticosteroids-almost half of patients decreased dosage or stopped their corticosteroid during the OLE. 32 Mean daily doses of azathioprine and mycophenolate mofetil were also significantly reduced during the OLE. ...
... Their long-term use is associated with a range of adverse side effects and can negatively impact on quality of life in patients with MG. 10,11,17,[36][37][38][39] Conversely, achieving minimal manifestations status or better with a prednisolone dose of ≤5 mg/d has been shown to have a significantly positive effect on health-related quality of life in Japanese patients with MG. 10 The current analysis demonstrated that eculizumab treatment was associated with an increase over time in the proportion of patients who were treated with a low daily oral corticosteroid dose of ≤5 mg, the current target recommended in treatment guidelines for MG in Japan. 1 This is consistent with the results of a post-hoc analysis of immunosuppressant use in the REGAIN OLE, which showed that eculizumab treatment was accompanied by significant reductions in the mean daily dose of oral prednisone and other corticosteroids-almost half of patients decreased dosage or stopped their corticosteroid during the OLE. 32 Mean daily doses of azathioprine and mycophenolate mofetil were also significantly reduced during the OLE. ...
Introduction
Eculizumab, a terminal complement protein C5 inhibitor, is approved in Japan for the treatment of patients with anti‐acetylcholine receptor antibody‐positive (AChR Ab+) generalized myasthenia gravis (gMG) that is difficult to control with plasmapheresis or high‐dose intravenous immunoglobulin therapy.
Methods
This analysis of mandatory postmarketing surveillance in Japan assessed the safety and effectiveness of eculizumab in patients with AChR Ab+ gMG who had completed case‐report forms at 26 wk after eculizumab initiation up to the cutoff date of April 2021. Changes from baseline were assessed for Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) total scores overall, and MG‐ADL scores in patient subgroups according to sex, age at diagnosis and baseline, and baseline disease severity. The change in concomitant corticosteroid use was also evaluated.
Results
Data were available for 134 adults (67.2% female; mean age 51.9 y); the effectiveness‐analysis set comprised 126 patients. After 26 wk, 78% of patients were continuing eculizumab treatment. Adverse drug reactions were reported by 49 patients (37%) (most frequently headache [n = 10]). Improvements in MG‐ADL scores were seen regardless of sex; age at diagnosis (<50/≥50 y); baseline age (18 to <40/≥40 to <65/≥65 y); Myasthenia Gravis Foundation of America disease classification (IIa/IIb/IIIa/IIIb/IVa/IVb/V); or baseline MG‐ADL score (<6/≥6). Of patients receiving corticosteroids, the proportion receiving low doses (average ≤5 mg/d) increased from 7.0% before eculizumab initiation to 26.4% by Week 52.
Conclusion
Eculizumab was well tolerated and effective in treating AChR Ab+ gMG across a broad spectrum of adult Japanese patients with difficult‐to‐control gMG.
... In MG, as in other chronic diseases, patients' HRQOL is reduced. Quality of life improves with better control of the disease [9,17] and worsens with more severe disease [6,[17][18][19]. Other factors that reduce HRQOL are bulbar involvement [8,17,20], generalised disease, and refractory disease [7]. ...
... In MG, as in other chronic diseases, patients' HRQOL is reduced. Quality of life improves with better control of the disease [9,17] and worsens with more severe disease [6,[17][18][19]. Other factors that reduce HRQOL are bulbar involvement [8,17,20], generalised disease, and refractory disease [7]. ...
... Quality of life improves with better control of the disease [9,17] and worsens with more severe disease [6,[17][18][19]. Other factors that reduce HRQOL are bulbar involvement [8,17,20], generalised disease, and refractory disease [7]. In our study, we also found that disease severity according to the QMG scale prior to enrolment in the study was associated with HRQOL; however, MGFA classification did not affect the HRQOL of our patients, as this classification reflects the moment of greatest severity in the course of the disease but not the severity during the period of study [18,21]. ...
Health-related quality of life (HRQOL) in myasthenia gravis (MG) is frequently decreased. Further, there are many validated clinical scales and questionnaires to evaluate the clinical status in MG. We aimed to determine if there was an improvement in HRQOL following an intensive treatment for MG, identify which demographic and clinical features influenced patients’ HRQOL, and investigate if the questionnaire MG-QOL15 correlated with other evaluation scales. We recruited 45 patients with generalised MG who were starting immunomodulatory treatment with intravenous immunoglobulins and prednisone for the first time. At each visit, we administered several validated scales for MG. The mean MG-QOL15 score improved significantly at 4 and 6 weeks of the study. Additionally, the MG-QOL15 score correlated strong with the Myasthenia Gravis-Activities of Daily Living (MG-ADL) and the Neuro-QOL Fatigue and weakest with the Quantitative Myasthenia Gravis Scoring System (QMG). The QMG score prior to study enrolment was associated with HRQOL. We observed that HRQOL in MG improved after receiving an intensive immunomodulatory treatment and achieving better control of the symptoms. The questionnaire MG-QOL15 correlated positively with other clinical measures. As MG is a fluctuating condition, and some symptoms are difficult to examine, we direct physicians toward the use of scales and questionnaires composed of items perceived by the patient.
... More recently, MG-specific quality of life instruments, including the 60-item MG quality of life scale (MG-QOL60) [9], a shortened version of MG-QOL-60, MG-QOL15 [10], and its revised version, MG-QOL15r [11], have become increasingly popular for measuring MG patients' physical and psychological functions. According to studies where MG specific HRQoL instruments were applied, factors including the severity of disease, dose of prednisone, levels of anxiety and depression could have impact on MG patients' well-beings as well [12,13]. ...
... When analyzing, nine items originally assigned to measure mobility were divided into two sub-scales. Items 4, 6, and 8 were allocated to indicate social quality of life (QoL) and items 5, 7, 10, 12, 13, 15 to physical QoL [13]. The Chinese version of all scales listed above has been validated and shown to have adequate reliability and validity [23][24][25]. ...
... Moreover, similar to other studies in different countries (e.g., Cutter et al., 2019 in the US [37], Cioncoloni et al., 2016 in Italy [41]), abilities of Chinese patients with MG to perform daily activities (measured by MG-ADL) also had positive impact on their HRQoL. Although prednisone has been proved as an effective therapeutic treatment in patients with MG [42], it was also found that its adverse effects in both long-term and short-term can negatively impact on HRQoL [13] and that total dose of oral prednisolone during the last 1 year had a significant negative effects on patients' HRQoL [43] In our study, reduced overall and physical HRQoL are more closely associated with patients who were under prednisone treatment during the time of survey. However, such findings should be interpreted with cautions since they only show association, rather than causality, between the current use prednisone and HRQoL. ...
Abstract Background Myasthenia gravis (MG), a chronic neuromuscular disorder, can adversely affect patients’ health-related quality of life (HRQoL), especially in women. The study aimed to evaluate the difference in HRQoL of women and men MG patients and explore the factors that mediate the relationship between gender and HRQoL. Methods A cross-sectional study was conducted among 1815 patients with MG in China. The revised 15-item MG quality of life scale (MG-QOL15r) was used to access patients’ HRQoL in overall, physical, social and emotional domains. Socio-demographic information, diagnosis and treatment history, comorbidities, social support, active lifestyle and the MG activities of daily living scale (MG-ADL) were recorded and compared between women and men using the Student’s t-test and Pearson’s Chi-square test. Multivariable regression analyses were conducted to identify independent contributors to HRQoL, especially those affecting different gender. Results On average, female patients with MG reported a lower MG-QOL15r score than the males (44.49 ± 29.10 vs 49.32 ± 29.18). The association between gender and patients’ HRQoL interacted with the number of comorbidities across the overall, physical and social domains of patients. As the number of comorbidities increased, the scores of HRQoL decreased and it was faster among females than the males (p
... 5,[14][15][16][17] During assessments of associations between MG-QOL15 and detailed clinical information from our survey in 2010 to validate the scale, we noticed several important points warranting clarification in order to improve the QOL of MG patients. 5 In addition to a 2010 survey, 5,18 we carried out further multicenter surveys in 2012 6,[19][20][21] and 2015, [22][23][24] and obtained detailed quantitative data and some longitudinal clinical information from a total of 1890 patients with established MG. By analyzing such data, we clarified the actual condition of MG patients, 5,6,18-21 determined major factors that negatively affect patient QOL, 5,6,18 recommended an appropriate treatment target to achieve good QOL, 5,6 and proposed treatment strategies to enable MG patients to achieve the target early and live a normal lifestyle. ...
... 5 In addition to a 2010 survey, 5,18 we carried out further multicenter surveys in 2012 6,[19][20][21] and 2015, [22][23][24] and obtained detailed quantitative data and some longitudinal clinical information from a total of 1890 patients with established MG. By analyzing such data, we clarified the actual condition of MG patients, 5,6,18-21 determined major factors that negatively affect patient QOL, 5,6,18 recommended an appropriate treatment target to achieve good QOL, 5,6 and proposed treatment strategies to enable MG patients to achieve the target early and live a normal lifestyle. 22 Herein, we introduce our findings and current thinking about MG treatment. ...
... 5 In addition to a 2010 survey, 5,18 we carried out further multicenter surveys in 2012 6,[19][20][21] and 2015, [22][23][24] and obtained detailed quantitative data and some longitudinal clinical information from a total of 1890 patients with established MG. By analyzing such data, we clarified the actual condition of MG patients, 5,6,18-21 determined major factors that negatively affect patient QOL, 5,6,18 recommended an appropriate treatment target to achieve good QOL, 5,6 and proposed treatment strategies to enable MG patients to achieve the target early and live a normal lifestyle. 22 Herein, we introduce our findings and current thinking about MG treatment. ...
Our multicenter studies have repeatedly demonstrated that disease severity and oral steroid dose are major independent factors negatively impacting health‐related quality of life (QOL) in patients with myasthenia gravis. Even if pharmacologic remission is achieved, QOL is low in patients taking oral prednisolone >10 mg/day. Disease severity tends to affect QOL by decreasing personal activities, whereas insufficiently reduced steroids affects QOL by decreasing social activities. MG patients often experience unemployment and decreased income, and many patients report reduced social positivity. More effort is required to reduce both the severity and dose of oral steroids. QOL in patients with minimal manifestations (MM) or better status who are treated with prednisolone at ≤5 mg/day (MM‐or‐better‐5 mg) is almost identical to that in patients achieving complete stable remission. Early achievement of MM‐or‐better‐5 mg is now recommended as a target for MG treatment in Japan. However, our studies suggest the percentage of patients achieving MM‐or‐better‐5 mg was not high in 2010 and 2012 (<40% of generalized MG patients) and was not considered to be increased by physician skill in steroid dosing. In Japan, treatment strategies are now being reconsidered to further increase treatment success, placing a focus on helping MG patients resume a normal lifestyle by achieving the target as soon as possible. An initial attempt to achieve early MM‐or‐better‐5 mg for some period through aggressive use of non‐oral fast‐acting therapies can be more important for patient QOL, even if long‐term stability cannot be provided.
(241 words)
... The revised version of the guidelines, including both MG and Lambert Eaton myasthenic syndrome (Japanese MG/LEMS guidelines 2022), were published in May 2022. The new guidelines include the concept that treatment for MG is often lifelong and should aim to maintain a sufficient quality of life and mental health [5,6]. The goal of MG treatment is minimal manifestations (MM) or a better status with an oral prednisolone dose of 5 mg/day or less (MM-5 mg) [7]. ...
... The prednisolone dose cutoff for a good quality of life for MG patients was calculated: 6 mg/day [7]. Since the prednisolone dose is usually given in 5-mg increments in Japan, 6 mg is unusual, and thus an oral prednisolone dose of 5 mg/ day or less is accepted as the treatment goal by the Japanese MG/LEMS guidelines 2022 [5,6]. ...
Introduction:
The management of myasthenia gravis (MG) has been improved due to immunotherapy advances, but 20% of individuals with MG are refractory to the conventional therapy, and the need for novel biological drugs remains.
Area covered:
The Japanese clinical guidelines for MG published in May 2022 include the concept that treatment is often lifelong and should aim to maintain a sufficient quality of life and mental health. We provide an overview of the therapeutic strategy for generalized MG in Japan, in comparison with the international consensus. We summarize the clinical efficacy, safety, and tolerability of efgartigimod, the first approved anti-neonatal Fc receptor inhibitor for MG. A phase III study showed that efgartigimod was well-tolerated and efficacious in patients with generalized MG.
Expert opinion:
Efgartigimod is a promising biological drug for patients with moderate to severe generalized MG with or without anti-acetylcholine receptor antibodies in Japan.
... Symptoms of depression frequently affect the HRQoL negatively [23,44,51]. Patient characteristics, such as gender, age, education, course of disease, the use of immunosuppressive drugs, the occurrence of side effects, acceptance of disease as well as anxiety and perceived social support, have been demonstrated to be additionally associated with a poor quality of life in MG patients [2,5,45]. However, none of these studies determined whether the factors influencing HRQoL are myasthenia-specific or also apply to the normal population. ...
... Therefore, low social support might increase the burden of disease. Clinical aspects, such as muscle weakness, double vision, myasthenic crisis, pain, sleep disturbances, the use of immunosuppressive drugs, and medication side effects, as well as demographic aspects, like gender, age, place of residence and medical infrastructure have been demonstrated to be additionally associated with a poor quality of life in MG patients [2,5,45] and thus influencing the burden of disease. ...
Background
Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL.
Methods
This case–control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group.
Results
In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22–29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2–8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients.
Discussion
HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas.
Trial registration information
Clinicaltrials.gov, NCT03979521, submitted: June 7, 2019, first patient enrolled: May 1, 2019, https://clinicaltrials.gov/ct2/show/NCT03979521
... 10% of patients achieve Myasthenia Gravis Foundation of America post-intervention status of complete stable remission [1]. The international consensus-based guidance for the management of MG proposes minimal manifestation status or better as a treatment goal and recommends that corticosteroids or immunosuppressive therapy be used in all who have not met that goal with an adequate dose of pyridostigmine [2]. ...
... For instance, we were not able to obtain serum trough tacrolimus concentrations, anti-AChRAb titers or quantitative MG score. Moreover, the ratio of men to women and the distribution of patients in the E-L-T classification in this study were not exactly same as those of all patients with MG in Japan [1]. Although prospective studies are difficult to perform, they could more effectively establish a protocol for tapering calcineurin inhibitor dosage. ...
Background:
Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation has not been known.
Objective:
To clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody (anti-AChRAb)-positive MG, and to determine the factors that predict exacerbations.
Methods:
We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms less than 3 months after the reduction.
Results:
Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No one developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, p = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, p = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cutoff values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction.
Conclusion:
Tapering of tacrolimus is possible in most patients with well-controlled anti-AChRAb-positive MG. Early age at onset and a large reduction from maintenance dosage are associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease. This article is protected by copyright. All rights reserved.
... 13 Approximately 10%-15% of patients with MG do not respond adequately to traditional therapies for MG, or cannot tolerate these therapies, and are considered to have refractory MG. 1,11,[14][15][16] The health-related quality of life (QOL) of these patients with MG remains diminished compared with healthy controls, 17-20 particularly among the subset who do not achieve adequate symptom control and those who endure burdensome side effects of therapy. 21,22 However, no studies to date have evaluated the impact of refractory MG on QOL. ...
... 30 In addition, the sensitivity analysis that included the 26 participants with refractory MG, defined only according to treatment criteria, confirmed that the significantly worse QOL was also found in this larger refractory MG population compared with those with nonrefractory MG. The results are not unexpected because previous research has also shown that poor QOL is correlated with higher levels of disease activity, functional impairments, fatigue, and depression in patients with refractory MG. [17][18][19][20][21][22] To the best of our knowledge, this is among the first reported total and item-specific MG-QOL15 scoring for individuals with refractory disease. A closer look at the clinical characteristics of the study population (shown by MG-ADL total scores) provides greater insight into the study findings. ...
Objectives:
Myasthenia gravis (MG) may be refractory to traditional therapies. Quality of life (QOL) and disease burden in patients with refractory and nonrefractory MG were compared using Myasthenia Gravis Foundation of America MG Patient Registry data.
Methods:
Adults aged 18 years or older with MG diagnosed ≥2 years before enrollment were included. Participants with refractory MG had received ≥2 previous and 1 current MG treatment and had MG Activities of Daily Living Scale total score ≥6 at enrollment; other participants had nonrefractory MG. MG QOL 15-item scale (MG-QOL15) scores were compared.
Results:
In total, 56 participants with refractory and 717 participants with nonrefractory MG enrolled. Participants with refractory MG had significantly higher mean (SD) MG-QOL15 total scores [31.4 (11.1) vs. 20.8 (15.0), P < 0.0001] and were more likely to have had exacerbations, emergency department visits, and recent hospitalizations.
Conclusions:
Participants with refractory MG experience worse QOL and greater clinical burden than those with nonrefractory disease.
... The cumulative corticosteroid dose until the initial improvement and the achievement of MM was, respectively, approximately 10 times and four times higher in the IH group. High-dose corticosteroid can negatively impact health-related quality of life in patients with MG [26] and elevate the risk of various complications such as osteoporosis, cardiovascular disease, and adrenal insufficiency [27,28]. Thus, the difference in cumulative dose required to achieve treatment outcomes should be considered when selecting the initial steroid regimen. ...
Background: Corticosteroids remain the cornerstone in the management of myasthenia gravis (MG). Initiation of corticosteroid treatment at a high dose and subsequently decreasing the dose or gradual escalation from a low dose is recommended. We aimed to investigate the association between the initial corticosteroid regimen and treatment response.
Methods: A retrospective study was conducted on 234 acetylcholine receptor (AChR) antibody (Ab)–positive MG patients who visited our institution between January 2010 and February 2023. Patients were grouped based on prednisolone dosages received: initial high (IH, ≥50 mg/day) or initial low (IL, ≤20 mg/day). Time to initial improvement and the achievement of minimal manifestation (MM) status were the main outcomes.
Results: Of the 234 patients, 135 were classified as IH and 99 as IL group. The IH group demonstrated a faster onset of improvement compared with the IL group (20.0 [16.0–29.0] vs. 40.0 [27.0–84.0] days), with the IH group being a significant prognostic factor for initial improvement (HR, 2.44; 95% CI, 1.76–3.39). However, the IH group had a higher incidence of steroid-induced exacerbation (51.9% vs. 2.0%, p<0.001). No significant difference between the IH and IL groups was found in terms of the proportion of patients achieving MM or the time to achieve MM within the first year after treatment initiation.
Conclusion: While an initial high dose of corticosteroid treatment accelerated the onset of therapeutic responses in patients with AChR Ab–positive MG, it was associated with a higher cumulative steroid dose and an increased risk of steroid-induced exacerbations.
... As in all neuromuscular junction diseases, progressive loss of muscle strength, fatigue, decrease in exercise capacity, difficulty in transfer activities, pain and weight problems are observed in MG 11 There is no definitive treatment for MG, but in many cases, symptoms can be controlled with current treatments 13 . The main aim of treatment is to achieve remission with few or no myasthenic symptoms or to obtain a stable clinical picture with subjective and objective minimal symptoms that do not affect daily life 5 . ...
Myasthenia Gravis (MG) is an autoimmune disease in which neuromuscular transmission is blocked and neuromuscular junction physiology is affected. The main feature in MG is altered muscle weakness and fatigue of muscle groups that worsens with exercise and improves with rest. With the emergence of muscle weakness in the following periods, walking is affected in MG. This causes balance and walking problems. Most of the patients have complaints of falling and fear of falling. While applying MG treatment, myasthenic symptoms should be reduced and a stable clinical picture should be obtained in which the daily activities of the person are relieved. The aim of this study is to understand the effect of rehabilitation practices on gait in MG and to determine which exercises are effective. As a result, physiotherapy and rehabilitation approaches can provide solutions to patients' complaints, albeit symptomatically. Active resistance exercises, aerobic exercises, balance strategy training, endurance exercises, posture exercises, stretching exercises and active–passive range of motion exercises should be performed in an exercise program. In addition, rhythmic auditory stimulation and pre-surgical respiratory physiotherapy also have positive effects on walking.
... We have previously shown that 90% of patients in this cohort were treated, 68% with CSs and 33% with NSISTs. 17 Chronic use of high-dose steroids, which is often part of the treatment paradigm for patients with MG, is associated with increased risk for long-term adverse events 18,19 and a significant impact on quality of life in patients with MG. 20 Similarly, in addition to steroids, NSIST therapy leads to general immunosuppression with increased susceptibility to infections, and in this study, the risk of infection-related hospitalization was 3.5 times higher among patients with MG compared with controls. NSIST use is also associated with an increased risk of malignancy. ...
Background
There are limited data on the impact of myasthenia gravis (MG) on real-world healthcare resource use (HCRU) and patient burden in the United States.
Objectives
This study aims to assess HCRU in patients with MG using data from a US health claims database.
Design
A retrospective, database study of adult patients newly diagnosed with MG, using the IBM ® MarketScan ® Commercial Claims and Encounters and Medicare supplemental health insurance claims database.
Methods
Patients with ⩾2 MG International Classification of Disease diagnosis codes ⩾3 months apart were followed from the date of their first MG diagnosis record or start of treatment. HCRU and use of immunoglobulins and plasma exchange during follow-up was assessed, as well as comorbidities, hospitalizations, emergency room (ER) visits, intensive care unit (ICU) admissions, and specialist visits per year after diagnosis, and compared with age- and sex-matched non-MG controls.
Results
During 2010–2019, 7194 patients were followed for up to 10 years (median = 2.3 years). During follow-up, patients with MG were 2.6-fold more likely than controls to be hospitalized, and 4.5-fold more likely to be admitted to an ICU. Risk and numbers of ER admission, hospitalization, and ICU visits were the highest in the 12 months post-diagnosis of MG and were consistently higher than controls during follow-up. MG was the main cause for most hospitalizations.
Conclusion
Patients with MG have higher HCRU, compared with the age- and sex-matched non-MG controls. The early years after MG diagnosis are a period of particularly high healthcare burden, with many patients requiring hospitalization and ICU care to manage serious exacerbations.
... La puntuación de cada ítem va de 0 a 3 con un rango total del instrumento de 0 a 24, las puntuaciones más altas indican una mayor gravedad de los síntomas de la MG 12 . 15-item Myasthenia Gravis Quality of Life scale revised (MG-QOL15R-S) es un instrumento formado por 15 ítems que evalúa la CV relacionada con la salud específico para pacientes con MG, valorando la movilidad, los síntomas, el bienestar emocional y la satisfacción general. El instrumento tiene un rango de puntuación de 0 a 30, las puntuaciones más altas indican una mayor insatisfacción con la CVRS relacionada con la MG 13 . ...
Resumen
Objetivo
Determinar la relación del soporte social percibido con las variables clínicas, el perfil de las actividades de la vida diaria y la calidad de vida en los pacientes diagnosticados de miastenia gravis (MG) residentes en España y Latinoamérica.
Método
Estudio observacional y transversal. Los sujetos diagnosticados de MG fueron reclutados a partir de asociaciones, fundaciones y medios sociales en el primer trimestre del 2022. Se incluyeron los instrumentos Medical Outcomes Study (MOS-SSS), Myasthenia gravis activities of daily living profile (MG-ADL) y 15-item Myasthenia Gravis Quality of Life scale revised (MG-QOL15R-S).
Resultados
El tiempo medio del diagnóstico (t = 2,38; p < 0,05), los antecedentes de timoma (χ² = 5,18; p < 0,05), la puntuación global de MG-ADL (t = 4,29; p < 0,001) y la puntuación global de MG-QOL15R-S (t = 7,67; p < 0,001) se relacionaron con la percepción del soporte social en los sujetos con MG. También encontramos que la puntuación de MOS-SSS se correlacionó significativamente con las puntuaciones de MG-ADL (r = −0,15; p < 0,001) y MG-QOL15R-S (r = −0,27; p < 0,001).
Conclusiones
Los antecedentes de timoma reducen la probabilidad de presentar alta percepción del soporte social, y diagnosticar la enfermedad en menos de 2 años se ha asociado a una mayor frecuencia de presentar una alta percepción del soporte social. Además, es esperado que la alta percepción del soporte social se correlacione con la alta calidad de vida y con una menor gravedad de los síntomas de la MG.
... Both disease symptoms and side effects/burdens from treatment negatively affect patients' mental status (emotion, mood, anxiety/depression and cognitive function) and social activities; ideally, disease severity and treatment type and intensity should therefore be taken into account in assessing a treatment goal of gMG [39]. This is particularly important as participants sometimes had difficulty disentangling gMG symptoms from those of other conditions (e.g., depression) and medication side effects (e.g., cramps, spasms). ...
Introduction:
Patients with generalized myasthenia gravis (gMG) experience functional impairment due to MG symptoms. This study aimed to assess, from the patient perspective, the symptoms, impacts, and treatment goals of individuals diagnosed with gMG.
Methods:
Semi-structured, in-depth concept-elicitation interviews were conducted with 28 individuals diagnosed with gMG in the United States.
Results:
Participants reported gMG symptoms that affected many body regions and functions, with an average of 16 symptoms per participant. The most frequently reported symptoms were eyelid drooping (93%), physical fatigue (89%), symptoms affecting the legs (82%), difficulty breathing (82%), and difficulty holding head up (82%). Nearly all participants (96%) reported fluctuations in symptoms and severity. Participants' most bothersome symptoms were blurry/double vision (43%), breathing difficulties (36%), all-over fatigue (36%), and swallowing problems (29%). Impacts on physical functioning included an inability to participate in hobbies/sports, need for increased planning, and difficulties performing activities of daily living. All participants reported emotional impacts and impacts on their work and finances. Their treatment goals included reduced fatigue and weakness, improved symptom stability, and minimization of the impact of symptoms, in particular the emotional impact.
Conclusions:
The fluctuating and unpredictable nature of gMG symptoms was found to have a substantial impact on patients' emotional, social, and economic well-being. Participants' goals for symptom management suggest that greater focus is needed to help them quickly resume a normal lifestyle by achieving symptom stability. Impacts of fluctuating and unpredictable symptoms are difficult to measure, but it is important to consider symptom fluctuation as well as ongoing symptomatology when making treatment decisions, and to recognize the impact of uncontrolled symptoms on patients, their partners/caregivers, and family/friends. These factors are often not reflected in burden/cost-of-illness studies.
... Според други проучвания съществува обратна зависимост между тежестта на МГ и КЖСЗ [29][30][31][32][33][34]. Лошата самооценка на здравето е свързана с честотата и тежестта на симптомите, субективната умора, качеството на съня, нивото на увреждане, регионалното мускулно засягане и слабостта на дихателната мускулатура, както и с нарушеното нервно-мускулно предаване в делтоидния мускул, измерено чрез ЕМГ изследване на единично влакно [19,32,[35][36][37]. ...
Миастения гравис (МГ) е сравнително рядко, но недостатъчно проучено заболяване със социална значимост, за което особено дефицитни в световен мащаб са данните за качеството на живот, свързано със здравето, (КЖСЗ) и социално-икономическата тежест. Целта на настоящия обзор е да представи обобщение на резултатите за КЖСЗ при МГ, докладвани в достъпните съвременни литературни източници, както и да очертае стратегии за неговото подобряване. Публикуваните данни за КЖСЗ варират по страни, като роля за това оказват и различията в използваната методология. Установена е сигнификантна връзка между клиничните фактори и КЖСЗ. По-лошо КЖСЗ се отчита при по-висока честота на симптомите и тежестта на изява, при по-високо ниво на инвалидност, както и при булбарна или генерализирана манифестация. Загубата на трудовата заетост и наличието на депресия са по-достоверни предиктори за влошено КЖСЗ при пациентите с MГ, отколкото тежестта на физическите симптоми. Наличието на коморбидност се отразява неблагоприятно върху КЖСЗ, особено в психоемоционален и ментален аспект. Навременната и адекватна терапия при МГ, водеща до редукция на инвалидността, се свързва с по-добро КЖСЗ. Правилният медицински подход оптимизира най-вече физическите аспекти на КЖСЗ, докато за намаляване на психоемоционалните симптоми се препоръчва психосоциална рехабилитация, каквато все още не е въведена в много страни, включително и в България.
... QMG scores were assessed at baseline and follow up to evaluate disease severity. Moreover, patient reported outcome regarding impact on daily living was assessed at both corresponding time points using the MG-ADL [27,28]. ...
Myasthenia gravis (MG) is the most common autoimmune disease affecting the neuromuscular junction by specific autoantibodies. The etiology of MG and its heterogeneity in clinical courses are poorly understood, although it was recently shown that gut microbial dysbiosis plays a critical role. Since levels of Calprotectin (CLP) seem to correlate with level of dysbiosis, we hypothesize that CLP may serve as potential disease activity biomarker in MG. Sera from 251 patients with MG and 90 controls were analyzed in an explorative, cross-sectional design. Prospectively, we tested CLP levels in MG patients up to 3 years. Association of CLP levels with socio-demographics, disease activity (quantitative myasthenia gravis (QMG) score, myasthenia gravis-specific Activities of Daily Living scale (MG-ADL)), antibody (Abs) status, history of myasthenic crisis, treatment regime, and history of thymectomy were investigated using univariate analysis. Mean baseline serum levels of CLP were significantly higher in MG patients compared to controls (4.3 μg/ml vs. 2.1 μg/ml; p < 0.0001). Higher levels of CLP were associated with a higher clinical disease severity measured by MGFA classification and QMG score. Nevertheless, the only weak correlation of CLP with clinical outcome parameters needs confirmation in future studies. Currently, there are no validated blood biomarkers for MG. The significantly elevated CLP and mild correlation with parameters of disease activity suggests that CLP holds promise as a biomarker for measurement of individual disease severity.
... Treatment should be as much as possible patienttailored, balancing therapeutic needs and potential AEs. Lowdose maintenance regimens are well tolerated and associated with a good self-perceived quality-of life (QoL) [109]. ...
Introduction
Myasthenia gravis is a rare disease of the neuromuscular junction and a prototype of B cell driven immunopathology. Pathogenic antibodies target post-synaptic transmembrane proteins, most commonly the nicotinic acetylcholine receptor and the muscle-specific tyrosine kinase, inducing end-plate alterations and neuromuscular transmission impairment. Several clinical subtypes are distinct on the basis of associated antibodies, age at symptom onset, thymus pathology, genetic factors and weakness distribution. These subtypes have distinct pathogenesis that can account for different responses to treatment. Conventional therapy is based on the use of symptomatic agents, steroids, immunosuppressants and thymectomy. Of late, biologics have emerged as effective therapeutic options.
Areas covered
In this review we will discuss the management of myasthenia gravis in relation to its phenotypic and biological heterogeneity, in the light of recent advances in the disease immunopathology, new diagnostic tools and results of clinical trials
Expert opinion
Clinical management is shaped on serological subtype, and patient age at onset, lifestyle and comorbidities, balancing therapeutic needs and safety. Although reliable biomarkers predictive of clinical and biologic outcome are still lacking, recent developments promise a more effective and safe treatment. Disease subtyping according to serological testing and immunopathology is crucial to the appropriateness of clinical management.
... 13,14 Furthermore, some patients are unable to tolerate corticosteroids and conventional immunosuppressants. 15,16 Refractory disease is associated with significantly higher risk of exacerbation, myasthenic crisis, inpatient hospitalization, and emergency room visits, and significantly longer duration of hospital stay. 15,17 Guidelines recommend repeated treatment with high-dose intravenous immunoglobulin (IVIg) and/or plasmapheresis to achieve the target of minimal manifestations status in patients with refractory gMG who are experiencing symptoms despite immunosuppressive therapies. ...
Background
Eculizumab, a humanized monoclonal antibody targeted to terminal complement protein C5, is approved in Japan for treatment of patients with anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (gMG) whose symptoms are difficult to control with high-dose intravenous immunoglobulin (IVIg) therapy or plasmapheresis.
Methods
This interim analysis of mandatory post-marketing surveillance in Japan assessed the safety and effectiveness of eculizumab at 26 weeks after treatment initiation in patients with AChR+ gMG.
Results
Data were available for 40 adult patients in Japan [62.5% (25/40) female; mean age at eculizumab initiation, 51.0 years]. Fifteen patients had a history of thymoma. Six patients were excluded from the effectiveness analysis set due to participation in the open-label extension part of the phase III, randomized, double-blind, placebo-controlled REGAIN study [ClinicalTrials.gov identifier: NCT02301624]. After 26 weeks’ follow up, 32 patients (80%) were continuing eculizumab treatment. Adverse drug reactions were reported by seven patients [most frequently headache ( n = 3)]. One death was reported during eculizumab treatment (relationship unclear as determined by the treating physician) and there was one death 45 days after the last dose (considered unrelated). No meningococcal infections were reported. Mean (standard deviation) changes from baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores were −3.7 (2.61) ( n = 27) and −5.6 (3.50) ( n = 26), respectively, at 12 weeks, and −4.3 (2.72) ( n = 26) and −5.6 (4.02) ( n = 24), respectively, at 26 weeks. Improvements in MG-ADL and QMG scores were generally similar in patients with/without a history of thymoma. Frequency of IVIg use decreased following eculizumab initiation.
Conclusion
In a real-world setting, eculizumab was effective and well tolerated for the treatment of AChR+ gMG in adult Japanese patients whose disease was refractory to IVIg or plasmapheresis. These findings are consistent with the efficacy and safety results from the global phase III REGAIN study of eculizumab.
... Once symptom control has been achieved, prednisone is slowly tapered to the lowest effective dose or withdrawal. Maintenance doses ≤5 mg/day are well-tolerated with a favorable impact on QoL (91). Prednisone is largely available and has a rapid effect, and, in OMG, the risk of "early deterioration" is not a concern. ...
Myasthenia gravis (MG) with symptoms limited to eye muscles [ocular MG (OMG)] is a rare disease. OMG incidence varies according to ethnicity and age of onset. In recent years, both an increase in incidence rate, particularly in the elderly, and a lower risk for secondary generalization may have contributed to the growing disease prevalence in Western countries. OMG should be considered in patients with painless ptosis and extrinsic ophthalmoparesis. Though asymmetric muscle involvement and symptom fluctuations are typical, in some cases, OMG can mimic isolated cranial nerve paresis, internuclear ophthalmoplegia, and conjugate gaze palsy. Diagnostic confirmation can be challenging in patients negative for anti-acetylcholine receptor and anti-muscle-specific tyrosine kinase antibodies on standard radioimmunoassay. Early treatment is aimed at relieving symptoms and at preventing disease progression to generalized MG. Despite the absence of high-level evidence, there is general agreement on the efficacy of steroids at low to moderate dosage; immunosuppressants are considered when steroid high maintenance doses are required. The role of thymectomy in non-thymoma patients is controversial. Prolonged exposure to immunosuppressive therapy has a negative impact on the health-related quality of life in a proportion of these patients. OMG is currently excluded from most of the treatments recently developed in generalized MG.
... Our results showed that excessive weight and obesity have a significant negative impact on QoL in women with MG. BMI as predictor of low quality of life in MG was demonstrated by Winter et al. using EuroQol and in SF 36 in a physical composite score (27) but a large study using MG-QOL15-J on 640 MG patients from Japan showed that BMI was not a predictor of lower QoL (28). Authors are convinced that patients with MG should be carefully monitored for signs of obesity and should be advocated to lose weight not only for clear health-related issues but also for better QoL. ...
Background: Although approximately half of myasthenia gravis (MG) patents achieve remission, for the remaining group MG is often a life-long disease. Better understanding of the determinants of Quality of Life (QoL) in MG is needed to optimize treatment goals in chronic cases.
Materials and Methods: We performed a single center cross-sectional study in 339 MG adult patients (64.9% women), with ocular or generalized disease. SF-36 and a structured questionnaire was administered, including information on previous and current MG severity, medications, comorbidities, education, occupation and BMI of the patient. Mean disease duration was 7.5 + 9.3 years. Current age was 51.6 + 18.3 years, 55% had Early-Onset (<50 years) MG.
Results: There were no statistically significant differences in mean SF-36 subscores between women and men. Worse MGFA class was related to lower QoL in physical (PCS) and mental (MCS) subscore (p = 0.000 for both). Patients with MGFA I-II class had significantly better QoL in physical and mental subscores than patients with more severe MG (p < 0.005). Late-onset MG patients had worse QoL than EOMG in physical score domain PCS (p = 0.049). Overweight and obese patients had lower PCS (p = 0.002) and MCS (p = 0.038) than patients with normal BMI. University education was related to statistically higher PCS (p = 0.015) and MCS (p = 0.006). QoL in currently employed was better in PCS and MCS (p = 0.000), with white collar workers reporting higher PCS (p = 0.049) than the remaining group. Patients living with family evaluated their MCS (p = 0.015) better than living alone. Moderate physical activity (twice a week) improved PCS (p = 0.045).
Conclusion: Our study confirmed that greater severity of symptoms, age, age of onset but also BMI, type of work, education status and physical activity affect QoL in MG.
... MG tedavi edilebilir nörolojik bozukluklardan biridir. Çoğu MG hastasının semptomları mevcut tedaviler ile kontrol altına alınabilir ki bu hastalar normal bir yaşam beklentisine ve yaşam kalitesine sahiptirler (75) . Tedavide ana amaç miyastenik belirtilerin az veya hiç olmadığı remisyonun sağlanması ya da subjektif veya günlük yaşantıyı etkilemeyen objektif minimal belirtilerin izlendiği stabil klinik tablonun elde edilmesi olmalıdır. ...
... 26 In this study, we extended this treatment objective to A C C E P T E D be MMS or better with complete withdrawal of prednisone as a mean to minimize treatment-related side effects. Although the quality of life study by a large Japanese group has shown that small dose of corticosteroids (prednisolone ≤5 mg a day) does not affect quality of life, 37 we found that the TAS distress level does increase even at very low dosing levels. Literature on the safety of chronic low-dose steroid treatment is scarce and inconclusive. ...
Objective
To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized myasthenia gravis (MG) patients.
Methods
This study is a post hoc analysis of data from the randomized trial of thymectomy in myasthenia gravis (MGTX). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone versus prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100mg on alternate-days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone, was compared between the thymectomy plus prednisone and prednisone alone groups.
Results
MG patients in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, P<0.001) over the 5-year study period. Prednisone associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.
Conclusions
Thymectomy benefits MG patients by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.
Trial Registration
The trial was registered on clinicaltrials.gov, number NCT00294658
Classification of Evidence: This study provides Class II evidence that for generalized MG patients with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
... Population-based assessments indicate that prednisone daily doses of < 5 to 7.5 mg can help avoid most side effects [80,81]. A study on the quality of life in MG patients suggested that prednisolone < 5 mg per day should be targeted [82]. In patients with poor corticosteroid tolerance or contraindication such as poorly controlled diabetes mellitus, or those at high risk for osteoporosis, early use of immunosuppressive agents to be given concurrently or in place of corticosteroids is preferred. ...
Therapies for myasthenia gravis (MG) include symptomatic and immunosuppressive/immunomodulatory treatment. Options for immunosuppression include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, rituximab, cyclophosphamide, eculizumab, intravenous immunoglobulin, subcutaneous immunoglobulin, plasmapheresis, and thymectomy. The practical aspects of long-term immunosuppressive therapy in MG are critically reviewed in this article. Application of one or more of these specific therapies is guided based on known efficacy, adverse effect profile, particular disease subtype and severity, and patient co-morbidities.
... Neither the current use of prednisolone nor the average daily dose of prednisolone during the past 3 months showed a significant association with the MGQoL15R-A in this study. This could be partially explained, as reported by Utsugisawa et al., by the fact that the negative effect of prednisolone on HRQoL is probably due to the cumulative adverse effects of long-term use of prednisolone.2 Thus, we hypothesize that the relationship between the MGQoL15R and prednisolone is J-shaped; the MGQoL15R score decreases (improves) with prednisolone initiation as a reflection of improvement in MG status, and subsequently increases (worsens) as a reflection of the cumulative side effects of steroids. ...
Introduction:
The revised 15-item myasthenia gravis (MG) quality-of-life questionnaire (MGQoL15R) is a validated scale of quality-of-life in patients with MG. We aimed to study the factors causing the variability within the Arabic version of the MGQoL15R (MGQoL15R-A).
Methods:
A standardized questionnaire was completed by 118 patients. Correlations and hierarchical regression analyses were used to assess the contribution of sociodemographic variables, clinical factors, Patient Health Questionnaire-9 (PHQ9-A), and Generalized Anxiety Disorder-7 (GAD7-A) to the variability in the MGQoL15R-A.
Results:
The MGQoL15R-A was highly correlated with PHQ9-A (r=0.76), and moderately correlated with GAD7-A (r=0.52). Clinical factors and PHQ9-A independently explained 30.4% and 34.5% of the variability, respectively. Among the clinical factors, uncontrolled MG status, relapse within the last year, and a higher number of current MG therapies were significantly associated with a higher MGQoL15R-A score.
Discussion:
MG severity and depressive symptoms (measured by PHQ9-A) can affect the MGQoL15R-A score. This article is protected by copyright. All rights reserved.
... The primary endpoint was to achieve the MGFA-PIS minimal manifestation or better status with low-dose prednisolone (⩽5 mg per day). 33 Patients were monitored for abnormal infusion reactions and adverse effects of rituximab. Oral prednisolone was gradually tapered in steps with clinical improvement. ...
Background
The objective of this study was to evaluate the efficacy and safety of repeated low-dose rituximab treatment guided by monitoring circulating CD19+ B cells in patients with refractory myasthenia gravis (MG).
Methods
Patients with refractory MG who had received rituximab treatment at two teaching hospitals between September 2013 and January 2017 were reviewed retrospectively. The treatment protocol consisted of an induction treatment with low-dose rituximab (375 mg/m ² twice with a 2-week interval), followed by retreatment (375 mg/m ² once). Retreatment was based on either circulating CD19+ B-cell repopulation or clinical relapse. Outcome measures included the MG Foundation of America (MGFA) clinical classification and postintervention status, prednisolone dose, CD19+ B-cell counts, clinical relapse, and adverse effects.
Results
Of 17 patients, 11 (65%) achieved the primary endpoint, defined as the minimal manifestation or better status with prednisolone ⩽5 mg/day, after median 7.6 months (range, 2–17 months) following rituximab treatment. Over a median follow up of 24 months (range, 7–49 months), a total of 30 retreatments were undertaken due to clinical relapse without B-cell repopulation ( n = 6), on the basis of B-cell repopulation alone ( n = 16) and both ( n = 8). B-cell recovery appeared to be in parallel with clinical relapse on the group level, although the individual-level association appeared to be modest, with B-cell repopulation observed only at 57% (8/14) of clinical relapses.
Conclusions
The repeated low-dose rituximab treatment based on the assessment of circulating B-cell depletion could be a cost-effective therapeutic option for refractory MG. Further studies are needed to verify the potentially better cost-effectiveness of low-dose rituximab, and to identify biomarkers that help optimize treatment in MG patients.
... Another survey (1999)(2000) showed that up to 70% of Japanese patients with MG who had received standard treatment had persistent ocular or generalized weakness that may result in moderate or severe disability [23]. The Japanese guidelines for MG treatment were updated in 2014 to emphasize the importance of patients' quality of life [24][25][26]. These changes were informed by a large retrospective analysis of Japanese patients with MG that evaluated factors impacting on quality of life, and recommended using early, fast-acting treatment strategies [27]. ...
The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.
... 16 The health-related quality of life of patients with MG is negatively impacted when adequate symptom control cannot be achieved and by the possible burden of MG-treatment side effects. 19,20 In light of the persistent clinical burden experienced by patients with refractory MG as a result of poor symptom control and increased risk of MG exacerbations, it is reasonable to assume that patients with refractory MG use more healthcare resources than those with nonrefractory disease. Data from a United States (US) claims database have shown that compared with those with nonrefractory MG, patients with refractory MG who experience more myasthenic exacerbations (including crises) visit the emergency room (ER) more often and have more inpatient hospitalizations. ...
Background and purpose:
Patients with refractory myasthenia gravis (MG) experience ongoing disease burden that might be reflected in their healthcare utilization. Here we examine the impact of refractory MG on healthcare utilization.
Methods:
The 825 included participants were aged 18-64 years, enrolled in the Myasthenia Gravis Foundation of America Patient Registry between July 2013 and February 2018, and had been diagnosed with MG ≥2 years previously.
Results:
Participants comprised 76 (9.2%) with refractory MG and 749 (90.8%) with nonrefractory MG. During the 6 months before enrollment, participants with refractory MG were significantly more likely than those with nonrefractory MG to have experienced at least one exacerbation [67.1% vs. 52.0%, respectively, p=0.01; odds ratio (OR)=1.882, 95% confidence interval (CI)=1.141-3.104], visited an emergency room at least once [43.4% vs. 27.1%, p<0.01; OR=2.065, 95% CI=1.276-3.343], been hospitalized overnight at least once (32.9% vs. 20.5%, p=0.01; OR=1.900, 95% CI=1.140-3.165), ever been admitted to an intensive care unit (ICU) (61.8% vs. 33.4%, p<0.01; OR=3.233, 95% CI=1.985-5.266), or ever required a feeding tube (21.1% vs. 9.1%, p<0.01; OR=2.671, 95% CI=1.457-4.896). A total of 75.8% younger females with refractory disease (<51 years, n=33) experienced at least one exacerbation, 69.7% had been admitted to an ICU, and 30.3% had required a feeding tube. For older females with refractory disease (≥51 years, n=33), 60.6%, 54.6%, and 6.1% experienced these outcomes, respectively (between-group differences were not significant).
Conclusions:
Refractory MG is associated with higher disease burden and healthcare utilization than nonrefractory MG.
... Although the mortality of MG has reduced remarkably by the use of high-dose oral corticosteroids with escalation and de-escalation, 2 long-term full remission without treatment is uncommon in MG. [3][4][5][6] In fact, only <10% of MG patients achieve Myasthenia Gravis Foundation of America (MGFA) postintervention status of complete stable remission (CSR). [5][6][7][8] Therefore, treatment strategies should consider the probability of prolonged treatment and aim at with IgG isotypes, resulting in reduction in muscle-specific kinase (MuSK) antibody as well as AChR antibody. Rituximab, a CD20 + B-cell depleting monoclonal antibody, also results in a significant decrease in autoantibody titers in serum. ...
Despite the availability of an increasing variety of disease‐modifying therapies, the proportion of patients with generalized myasthenia gravis (MG) who achieved the practical treatment goal remained low at approximately 50‐60% in our latest survey. Therefore, there is a need for further development of new treatment options based on novel mechanisms of action for MG treatment. Eculizumab and ravulizumab are monoclonal antibodies used to prevent complement‐mediated damage at the endplate of neuromuscular junction in MG with acetylcholine receptor (AChR) antibody. Neonatal Fc receptor (FcRn) antibodies including efgartigimod and rozanolixizumab are currently in different stages of clinical trial. The FcRn antibodies would be rational therapeutic agents for decreasing the levels of pathogenic autoantibodies with IgG isotypes, resulting in reduction of muscle‐specific kinase (MuSK) antibody as well as AChR antibody. Rituximab, a CD20⁺ B‐cell depleting monoclonal antibody, also results in a significant decrease in autoantibody titers in serum. Several studies indicate that rituximab may have the potential to treat MuSK‐MG. Monarsen, an antisense oligonucleotide, may reduce the production of acetylcholinesterase. A phase 2 study showed improvement in quantitative MG scores while on the drug. Several case reports showed the efficacy of autologous hemopoietic stem cell transplantation in patients with severe MG refractory to conventional therapies. This article introduces the new drugs and their latest development, and discusses the evidence for thymectomy in relation to the Japanese clinical guidelines for MG.
This article is protected by copyright. All rights reserved.
... Unlike previous studies, the treatment target was, rather than remission, the status of MM, i.e. 'the patient had no functional limitation from MG, even though there could be some weakness on examination of some muscles' [59]. MM status is a pragmatic outcome measure, associated with a highly satisfactory patient perception, particularly when combined with reduced steroid doses [60]. The MGTX study provided Class I evidence that patients with generalized AChR-MG, undergoing extended transsternal thymectomy have a 67% probability to achieve optimal control of their disease within 12 months, with a significantly reduced exposure to steroids and immunosuppressants, and a much lower rate of treatment associated symptoms. ...
Introduction: Myasthenia gravis (MG) is one of the best treatable autoimmune diseases. However, in most patients, treatment is necessarily long-term and related side effects are a serious burden. Thymectomy has a special place in the disease management as a non-pharmacological disease-modifying therapy. For several decades, its role has only been supported by observational studies. Despite the recently achieved class I evidence, many questions remain unaddressed.
Areas covered: This review discusses the pathogenic role of the thymus and evidence and controversies concerning therapeutic thymectomy. It also describes minimally invasive techniques that have largely replaced open surgery and the available evidence in MG patients.
Expert opinion: Thymectomy plays a primary role in MG management, though its use is still controversial in some disease subtypes. Patient selection for surgery and adequate pre-operative MG control are critical. Thymectomy must ensure the exeresis of the whole thymus together with peri-thymic fat tissue. Minimally invasive techniques have many advantages over open approaches, provided they are as extensive as trans-sternal thymectomy. The investigation of thymectomy-related biomarkers will contribute to enhance the knowledge of its impact on the specific immune response.
... Japanese experts as a goal of therapy in their national guideline for myasthenia gravis. 17,18 Several studies [19][20][21] have focused on longterm outcomes of treatments for patients with myasthenia gravis and on which management strategies might better control disease over time if used early in the disease course. Although full remission after treatment is uncommon, 19 two largescale retrospective studies have shown that outcomes in patients with myasthenia gravis have improved substantially during the past 50 years, 20 and that 95% of patients have either no weakness, purely ocular weakness, or only mild generalised weakness after several years of treatment. ...
Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.
Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years’ duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had
Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with Clinical Trials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.
Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.
Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised nonthymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.
... In many cases with chronic illness, depression has been reported to be prevalent, even longitudinally [3]. Considering the interferences of daily functioning due to the symptoms of MG, heightened depression and lowered quality of life (QOL) are not unanticipated [4][5][6][7][8][9][10][11][12]. Disease's severity [4], lower education [5], older age [5][6], being woman [7], as well as lower social support [5] were positively correlated with patient's physical health [4][5][6][7], while being optimistic, positive thinking, and sense of humor functioned as protective factors [8] for a better QOL. ...
Purpose
As most of patients with Myasthenia Gravis have limitations in their physical functioning, many experience changes in psychological states and often have depression. The objective of the current study was to examine the roles of communication with medical professionals, patients’ loneliness, and patients’ depression, in relation to their effects on the patients’ quality of life.
Methods
For 120 patients with MG of 18 years and older, demographic variables, along with communication with medical professionals, loneliness, depression, and quality of life were measured.
Results
As a result, people suffering from MG experienced lower quality of life when their career has changed due to the illness. At the same time, depression was a significant predictor of their quality of life, both in physical and mental domains.
Conclusions
The implications for clinical settings and the suggestions for future research are discussed.
Background
Disturbed sleep and its impact on quality of life (QoL) are underrecognized in myasthenia gravis (MG).
Aims
To evaluate the quality of sleep in MG using standard sleep questionnaires and assess factors that determine sleep.
Settings and Design
Prospective, cross-sectional, hospital-based study.
Patients and Methods
Fifty patients on stable drug therapy for at least 1 month and age- and gender-matched controls were assessed using standard sleep questionnaires [Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and NIMHANS Comprehensive Sleep Disorders Questionnaire (NCSDQ)].
Results
Myasthenia Gravis Foundation of America (MGFA) grade was I, IIA, IIB, IIIA, IIIB, and IVA in 11, 19, 3, 10, 6, and 1 respectively. The mean PSQI and ESS scores were similar in patients and controls. Patients with abnormal ESS (>10) were older and had greater neck circumference ( P = 0.018 and <0.001). Body mass index was greater in patients with PSQI > 5 ( P < 0.05). Age, gender, and clinical severity did not affect PSQI. Compared with ESS and PSQI, NCSDQ showed higher frequency of disturbed sleep, snoring, early morning headache, difficulty in initiation, and maintenance of sleep in MG, although the differences between patients and controls were not significant. No correlation was found between QoL and ESS or PSQI.
Conclusion
Patients of MG with stable clinical course with adequate treatment have sleep quality comparable with healthy controls. Longitudinal assessment of sleep quality at multiple time points throughout the disease course and correlating with cross-sectional disease severity may further delineate the impact of disease on sleep and QoL.
Introduction/Aims
The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody‐positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis.
Methods
Changes from baseline to week 26 in MG‐ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least‐squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures.
Results
In ravulizumab‐treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2‐years subgroup versus the >2‐years subgroup for MG‐ADL (−4.3 [0.70] vs. −2.9 [0.37]; p = .0511) or QMG (−4.3 [0.94] vs. −2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG‐ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2‐years and >2‐years subgroups was not statistically significant. No clinically meaningful between‐subgroup differences in treatment‐emergent adverse events were observed in ravulizumab‐treated patients.
Discussion
Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.
A 41-year-old woman diagnosed with seronegative myasthenia gravis struggled to maintain remission for a decade, facing crises every 3 months for several years. After repeated apheresis using a non-tunneled non-cuffed central venous dialysis catheter (NTNCC), complications such as catheter-related thrombus in the internal jugular veins and morbid obesity from steroids made the insertion of NTNCC increasingly difficult, leading to consideration of an alternative permanent vascular access (VA) approach. Thus, we created a subcutaneously superficialized brachial artery as the VA, which allowed the patient to undergo safe and uninterrupted apheresis therapy.
Background
A realistic treatment goal for myasthenia gravis (MG) is achieving minimal manifestations or better status with prednisolone at ≤5 mg/day (MM‐or‐better‐5 mg), considering a patient's health‐related quality of life. Prognosis prediction during the early phases of immunotherapies might be critical for determining subsequent treatment strategies; however, the appropriate biomarkers remain unknown.
Aim
This study aimed to clarify whether the reduction rate of anti‐acetylcholine receptor antibody (RR‐AChR Ab) titer levels is a useful biomarker for predicting MM‐or‐better‐5 mg achievement.
Methods
We retrospectively investigated patients with MG and AChR Abs who received immunotherapy for the first time. The RR‐AChR Ab titer levels were calculated in the early (within 30 days), middle (31–60 days), and late (61–100 days) periods after starting immunotherapies. A receiver operating characteristic (ROC) curve was generated to determine an appropriate cutoff value for RR‐AChR Abs to achieve an MM‐or‐better‐5 mg.
Results
Of 53 patients, 24 (45%) achieved MM‐or‐better‐5 mg after 1 year. For the early period, the RR‐AChR Ab cutoff value to predict MM‐or‐better‐5 mg was 1.68%/day with an area under the curve (AUC) of 0.75 (sensitivity, 85%; specificity, 70%). However, the middle and late posttreatment AUC values did not predict MM‐or‐better‐5 mg achievement.
Conclusion
The RR‐AChR Ab might be an appropriate prognostic biomarker during the early period of MM‐or‐better‐5 mg achievement. In the era of early fast‐acting treatment strategies, the RR‐AChR Ab trend after starting immunotherapies may guide the subsequent treatment choices.
Objectives
This study aims to explore the impact of myasthenia gravis (MG) — in terms of treatments, side effects, comorbidities, psychological health and work or study— in the real world from a patient perspective.
Design and participants
This is a prospective, observational, digital, longitudinal study. Adults diagnosed with MG residing in the USA, Japan, Germany, the UK, Italy, Spain or Canada were eligible to participate in the study. There were no other exclusion criteria. Participants used a bespoke smartphone application to confirm eligibility, provide consent and enter data about their MG into a profile, a tracker to record MG-related events and a series of patient-reported outcome instruments. 1693 participants completed at least 1 survey and were included in this analysis.
Results
Results are presented as a percentage of respondents to each survey question. The study population was largely female (69% of 1586 respondents), with an average age of 49.9 years (SD 14.8). In the previous 12 months, 83.7% of 1412 respondents confirmed that they had received one or more routine treatments for MG, and 67.1% of 255 respondents confirmed that they had experienced a side effect in the previous month. Commonly experienced comorbidities reported by 966 respondents were thyroid problems, hypertension and anxiety, experienced by 37.5%, 31.4% and 28.0% of respondents, respectively.
According to 889 respondents to the Hospital Anxiety and Depression Scale survey, 52.7% and 43.2% had a score indicative of at least mild anxiety and mild depression, respectively. Of 257 respondents, 33.0% reported experiencing a work or study impact in the past month.
Conclusions
This analysis of baseline characteristics of the MyRealWorld MG study population indicates that, despite current treatments, patients experience notable burden. Further scheduled analyses will develop a longitudinal picture of MG burden.
Trial registration number
NCT04176211 .
Introduction:
Myasthenia gravis (MG) is caused by IgG antibodies forming against different proteins at the neuromuscular junction. Anti-acetylcholine receptor (AChR) Abs are detected in the great majority of patients. MG management consists of long-term immunotherapy, based on steroids and immunosuppressants, short-term treatments and therapeutic thymectomy. Targeted immunotherapies that reduce B cell survival, inhibit complement activation, and decrease serum IgG concentration have been evaluated in trials and have entered clinical practice.
Areas covered:
Herein, the efficacy and safety data of conventional and novel therapeutic options is reviewed and their indications in the disease subtypes are discussed.
Expert opinion:
Even though conventional treatment is generally effective, 10-15% of patients have refractory disease and there are safety concerns related to long-term immunosuppression. Novel therapeutic options offer several advantages but also have limitations. Safety data based on long-term treatment are not yet available for some of these agents. The mechanisms of action of new drugs and the immunopathogenesis of different MG subtypes must be considered in therapy decision making. Integrating new agents in the treatment scenario of MG can significantly improve disease management.
Myasthenia gravis is a disorder of neuromuscular junction transmission, the result of antibodies against the post-synaptic aspect of the neuromuscular junction. Its clinical hallmark is fatigable weakness of skeletal muscles, which tends to vary in location and severity among patients. It is treated with pyridostigmine, immunotherapy, and thymectomy. Treatment is often individualized according to disease severity, antibody status, comorbidities, and other factors. This review uses a question-and-answer format to provide up-to-date, high-yield, clinically relevant information on myasthenia gravis.
The revised Japanese clinical guidelines for myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome (LEMS) were published in 2022. The notable points in these guidelines (GLs) are as follows. 1) These are the first Japanese GLs to include a description of LEMS. 2) Diagnostic criteria of MG are revised to lessen the incidence of false‐negative patients. 3) MG is divided into six clinical subtypes. 4) A high‐dose oral steroid regimen with escalation and de‐escalation schedule is not recommended by the GLs. 5) The GLs promote the early fast‐acting treatment strategy initially proposed in the previous GLs. 6) Refractory MG is defined. 7) The use of molecular‐targeted drugs is included. 8) Diagnostic criteria of LEMS are proposed. 9) Treatment algorithms for both MG and LEMS are presented. These new GLs are expected to improve the patients’ quality of life and will serve to bridge the present with the molecular‐targeted treatment eras.
Neurological autoimmune diseases (NADs) are characterized by an aberrant immune response against antigens in the central nervous system or peripheral nervous system (PNS). The wide spectrum of these diseases depends on an individual’s ancestry, immunopathology, and mechanism of injury. Some of the most important autoimmune neurological syndromes include multiple sclerosis, neuromyelitis optica (NMO), Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis (MG), autoimmune encephalitis, and paraneoplastic neurological disorders (PNDs). Patients experience different neurological manifestations based on the localization of the disease process. The importance of NADs is related to an increase in physician awareness of these diseases. Given the large number of diseases described and the plentiful number of factors that are associated with an autoimmune response, the identification of a common immunopathological mechanism that can explain NADs is a challenge. Among the factors studied, previous infections, genetic predisposition, cancer, vitamin D metabolism, and microbiota have been identified. Autoantibodies to various self-antigens have been shown to occur in many of these diseases, including antimyelin oligodendrocyte glycoprotein and antiaquaporin 4 in NMO, anti-N-methyl-d-aspartate receptor in AIE, antiacetylcholine receptor in MG, and others. A genetic component to the pathogenesis is supported by the identification of human leukocyte antigen associations in patients with NADs. Other possible pathogenic mechanisms include molecular mimicry, CD4+ activation, and CD8+ cytotoxicity. Treatment of NADs on reversing the inflammatory pathway activation present in many of these diseases; however, not all forms of immunosuppressive are equally effective. Future research focusing on identifying the roles of genetics and epigenetics in the pathogenesis will help to develop targeted therapies and a more personalized approach to management.
Objectives
Evidence on factors contributing to the development of infections in myasthenia gravis (MG) patients on immunotherapy is scarce.
Methods
We studied 192 MG patients attending our hospital between April 2000 and May 2021. We examined the data of patients who had undergone immunotherapy and developed an infection and analyzed factors influencing infectious events including MG severity, antibody type, thymoma, thymectomy, treatment regimens and duration, and status of MG.
Results
A total of 148/192 (77%) patients (52 men, mean onset 43 y) underwent immunotherapy. Of these, 22/148 (14.8%) patients developed an infection‐related hospitalization within 10 y of starting immunotherapy. Respiratory infections occurred in 14/22 (63.6%) of patients. The infections were fatal in 6/22 (27.2%) of patients. Infection‐associated myasthenic crisis developed in 4/22 (18.1%) patients. Age at MG onset was the only variable associated with the development of infection (hazard ratio [HR]; 1.056, 95% confidence interval (95% CI): 1.0291.085, P < .001). The infection‐free rate within 10 y of starting immunotherapy by MG subtype was 83.5% (95% CI: 61.4–93.5%) in ocular‐MG ( n = 29), and 87.5% (95% CI: 72.3–94.7%) in generalized early‐onset MG ( n = 55), 46.1% (95% CI: 21.7–67.6%) in generalized late‐onset MG ( n = 22), 87.7% (95% CI; 66.3–95.9%) in thymoma‐associated MG ( n = 29). Patients with muscle‐specific tyrosine kinase antibody‐positive MG ( n = 2) and antibodies‐negative MG ( n = 11) did not experience infections.
Conclusion
Age at onset of MG was a significant contributor to the development of infection. Generalized late‐onset MG is the most susceptible to infection and should be carefully monitored during immunotherapy.
Objective
We investigated the efficacy of low-dose prednisolone (PSL) regimen in patients with generalized myasthenia gravis (MG) post-thymectomy and its correlation with long-term outcome.Methods
This is a 2-year observational study. The subjects were aged 16–75 years, a Myasthenia Gravis Foundation of America (MGFA) clinical classification of II to IV, generalized MG after thymectomy. We selected a low-dose (5 mg/day) initiation and slowly incrementing (10 mg every 4 weeks) PSL therapy regimen. We collected the clinical characteristics, treatment-related data, and 2-year clinical outcomes of MG patients, and analyzed the effect of various factors on the achievement of the treatment target.ResultsSixty-three generalized MG were recruited in our study. After 2 years of observation, 52 patients (82.5%) of generalized MG achieved treatment goal. Based on the maximum daily dose of PSL received, the MG patients were divided into 20 mg, 30 mg, and ≥ 40 mg groups. Subgroup analysis showed that the 20 mg group had the highest rate of achieving the treatment target (94.9%), followed by the 30 mg group (73.3%) and the lowest rate was among the ≥ 40 mg group (44.4%). Using a multivariate logistic regression analysis, we identified that the maximum daily dose of PSL 20 mg was the only positive, independent predictor of treatment goal achievement after 2 years.Conclusion
Low-dose initiation, slowly incrementing PSL therapy is feasible for generalized MG patients after thymectomy. Early response to low-dose PSL therapy may predict better long-term outcomes.
Background
An aggressive therapeutic strategy used in the early stages of generalized myasthenia gravis (MG), called early fast-acting treatment (EFT), involves the use of plasmapheresis, intravenous immunoglobulin (IVIg), and/or intravenous high-dose methylprednisolone (IVMP). The EFT strategy has been proven to have advantages in achieving a treatment goal of MG, minimal manifestations or better with oral prednisolone (PSL) at a dose of 5 mg/day or lower.
Case presentation
A 72-year-old woman with anti-acetylcholine receptor antibody-positive MG underwent EFT. Even a modified IVMP regimen with a reduced dose of only 250 mg/day for 2 days, given after 6 cycles of plasmapheresis and 10 mg/day of oral PSL for 5 days, triggered a severe myasthenic exacerbation. Subsequent IVIg therapy successfully averted a crisis.
Conclusions
Such acute exacerbation after only 250 mg/day of IVMP for 2 days is rare. However, caution is needed when using IVMP for EFT of MG because the risk factors for exacerbation after IVMP use, and the best approach for treating the exacerbation, are not yet known.
A new version of the Japanese clinical guidelines for myasthenia gravis is under development. The current version was published in 2014, in which the top priority in treatment was to maintain patients’ health‐related quality of life. The treatment goal was to achieve a post‐intervention status of minimal manifestations or better (according to the Myasthenia Gravis Foundation of America classification), with an oral prednisolone dose of 5 mg/day or less. The guidelines recommend minimizing the oral prednisolone dose, starting calcineurin inhibitors early in the course of treatment, and effectively treating patients with an early fast‐acting treatment regimen.
Since the release of the 2014 version, the therapeutic tendencies in myasthenia gravis have been gradually changing in Japan, with an observed increase in the number of patients that achieved the treatment goal. Therefore, it is conceivable that the rationale of the 2014 guidelines was appropriate to treat patients with myasthenia gravis and that it should be taken over by the new guidelines. Meanwhile, the anti‐complement antibody (eculizumab) has been approved, and although off‐label in Japan, the effect of the anti‐CD20 antibody rituximab has been reported repeatedly. Many other agents are currently undergoing clinical trials. In the new guidelines, the treatment strategy should be demonstrated clearly, including these most recent developments.
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.
Objectives The objective of this study was to examine clinical factors associated with depressive state in patients with myasthenia gravis (MG).
Design Cross-sectional study.
Setting and participants We evaluated 287 consecutive cases of MG seen at six neurological centres located in Eastern Japan.
Outcome measures All MG patients completed the Japanese version of the Beck Depression Inventory–Second Edition (BDI-II). Disease severity was determined according to the MG Foundation of America (MGFA) quantitative MG score, MG activities of daily living scale and MG composite scale (MG composite). Clinical state following treatment was categorised according to MGFA postintervention status. Associations between detailed clinical parameters of MG and BDI-II score were then examined statistically.
Results Mean BDI-II score for patients with MG (11.0±8.1) did not differ substantially from and overlapped with that reported as the Japanese standard (8.7±6.4). The mean +2 SDs for the Japanese standard is 21.5, approximately equal to the cut-off level indicative of moderate or worse depression (>20 points) in the original English version. We thus defined BDI-II >21.5 as depressive state, with a frequency of 13.6% in patients with MG. Multivariate logistic regression analysis revealed current dose of oral prednisolone (OR 1.09, 95% CI 1.02 to 1.17; p=0.01), unchanged MGFA postintervention status (OR 3.55, 95% CI 1.18 to 10.71; p=0.02), time since onset (OR 0.93, 95% CI 0.87 to 0.99; p=0.03) and MG composite (OR 1.16, 95% CI 1.00 to 1.34; p=0.046) as factors independently associated with depressive state in MG.
Conclusions Dose of oral corticosteroids appears to represent the major factor associated with depressive state in MG. Unchanged status despite treatment and early disease stage are also significant background factors for depressive state, along with disease severity.
Inclusion body myositis (IBM) is a poorly understood and refractory autoimmune muscle disease. Though widely believed to have no significant humoral autoimmunity, we sought to identify novel autoantibodies with high specificity for this disease.
Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein.
Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.
In treating myasthenia gravis (MG), our aims were to achieve early minimal manifestations (MM) by performing early aggressive therapy (EAT) using plasmapheresis and high-dose intravenous methylprednisolone, and then to maintain the status with low-dose oral corticosteroids (EAT strategy). We examined the merits of the EAT strategy.
We retrospectively analyzed long-term effects of the EAT strategy (duration of therapy: 4.1 years) for 49 de novo MG patients and compared the effects to those of high-dose oral prednisolone therapy for 22 patients.
The EAT group achieved marked early improvement with much lower doses of oral prednisolone compared to the high-dose prednisolone group. The patients who achieved MM with prednisolone ≤5 mg/day were more frequent in the EAT group at both 1 year (57.1 vs. 4.5%) and final observation (77.6 vs. 27.3%). Both new-onset diabetes and patients who had complained of moon face were less frequent in the EAT group. However, in the EAT group, due to a temporary inability to maintain MM, additional short-term hospitalizations to return to MM by EAT were required.
The EAT strategy has advantages of early improvement with less frequent steroid-related complications. The labor and cost required are evident disadvantages.
Nucleoside analogs are important in the treatment of hematologic malignancies, solid tumors, and viral infections. Their metabolism
to the triphosphate form is central to their chemotherapeutic efficacy. Although the nucleoside kinases responsible for the
phosphorylation of these compounds have been well described, the nucleotidases that may mediate drug resistance through dephosphorylation
remain obscure. We have cloned and characterized a novel human cytosolic 5′-nucleotidase (cN-I) that potentially may have
an important role in nucleoside analog metabolism. It is expressed at a high level in skeletal and heart muscle, at an intermediate
level in pancreas and brain, and at a low level in kidney, testis, and uterus. The recombinant cN-I showed high affinity toward
dCMP and lower affinity toward AMP and IMP. ADP was necessary for maximal catalytic activity. Expression of cN-I in Jurkat
and HEK 293 cells conferred resistance to 2-chloro-2′-deoxyadenosine, with a 49-fold increase in the IC50 in HEK 293 and a greater than 400-fold increase in the IC50 in Jurkat cells. Expression of cN-I also conferred a 22-fold increase in the IC50 to 2′,3′-difluorodeoxycytidine in HEK 293 cells and an 82-fold increase in the IC50 to 2′,3′-dideoxycytidine in Jurkat cells. These data indicate that cN-I may play an important role in the regulation of physiological
pyrimidine nucleotide pools and may also alter the therapeutic efficacy of certain nucleoside analogs.
Myasthenia gravis is a potentially serious but treatable muscle disease caused by autoantibodies directed at the acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction. There is anecdotal evidence that the diagnosis is sometimes missed in older patients.
To examine the incidence and age distribution of positive AChR antibodies in samples referred to diagnostic laboratories in the UK, and the prevalence of positive AChR antibodies in samples from a cohort of older individuals.
Positive AChR antibody tests were identified from all UK centres registered for the assay with the European quality assurance scheme (EQAS) during 1997-99, and the age and sex specific incidence was calculated, based on the UK population. The prevalence of AChR antibodies in sera from a sample of 2000 individuals aged > or =60 years was determined.
3183 individuals had positive AChR antibody tests on routine screening during the years 1997 to 1999 in the UK, giving an annual incidence of 1.8/100 000. In both sexes, the age specific incidence rose steeply between the ages of 45 and 74, reaching 9.9/100 000 in men, and then fell, with a sharp decline above the age of 80. In the prevalence study, whereas only one serum from individuals aged 60-74 years was positive for AChR antibodies (0.12%), sera from eight individuals aged > or =75 years were positive (0.7%). Only one had a previous clinical diagnosis of myasthenia gravis but four others had histories of stroke or transient ischaemic attacks.
The sharp fall in the incidence of clinically recognised myasthenia gravis in people over 80 years of age in our national AChR antibody incidence study, and the high prevalence of previously unrecognised positive AChR antibodies in those > or =75 years old, suggest that myasthenia gravis may be substantially underdiagnosed in older people.
We previously identified a circulating autoantibody against a 43 kDa muscle autoantigen in sporadic inclusion body myositis (IBM) and demonstrated the feasibility of an IBM diagnostic blood test. Here, we sought to identify the molecular target of this IBM autoantibody, understand the relationship between IBM autoimmunity and muscle degeneration, and develop an IBM blood test with high diagnostic accuracy.
IBM blood samples were screened using mass spectrometry and a synthetic human peptidome. Plasma and serum samples (N=200 patients) underwent immunoblotting assays, and results were correlated to clinical features. Muscle biopsy samples (n=30) were examined by immunohistochemistry and immunoblotting. Exome or whole genome sequencing was performed on DNA from 19 patients.
Both mass spectrometry and screening of a 413,611 human peptide library spanning the entire human proteome identified cytosolic 5'-nucleotidase 1A (cN1A; NT5C1A) as the likely 43 kDa IBM autoantigen, which was then confirmed in dot blot and Western blot assays using recombinant cN1A protein. Moderate reactivity of anti-cN1A autoantibodies was 70% sensitive and 92% specific, and high reactivity was 34% sensitive and 98% specific for the diagnosis of IBM. One to 3 major cN1A immunodominant epitopes were identified. cN1A reactivity by immunohistochemistry accumulated in perinuclear regions and rimmed vacuoles in IBM muscle, localizing to areas of myonuclear degeneration.
Autoantibodies against cN1A are common in and highly specific to IBM among muscle diseases, and may provide a link between IBM's dual processes of autoimmunity and myodegeneration. Blood diagnostic testing is feasible and should improve early and reliable diagnosis of IBM. Ann Neurol 2013;73:408-418.
Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, myositis-specific autoantibodies had not been found in sIBM patients until recently. We used human skeletal muscle extracts as a source of antigens to detect autoantibodies in sIBM and to characterize the corresponding antigen.
Autoantibodies to skeletal muscle antigens were detected by immunoblotting. The target antigen was immunoaffinity-purified from skeletal muscle extracts and characterized by mass spectrometry. A cDNA encoding this protein was cloned and expressed in vitro, and its recognition by patient sera was analyzed in an immunoprecipitation assay. Epitopes were mapped using microarrays of overlapping peptides.
An Mr 44,000 polypeptide (Mup44) was frequently targeted by sIBM autoantibodies. The target protein was purified, and subsequent mass spectrometry analysis revealed that Mup44 is the cytosolic 5′-nucleotidase 1A (cN1A). By immunoprecipitation of recombinant cN1A, high concentrations of anti-Mup44 autoantibodies were detected in 33% of sIBM patient sera, whereas their prevalence in dermatomyositis, polymyositis, and other neuromuscular disorders appeared to be rare (4.2%, 4.5%, and 3.2%, respectively). Low concentrations of anti-Mup44 antibodies were found in myositis as well as other neuromuscular disorders, but not in healthy controls. Three major autoepitope regions of cN1A were mapped by using microarrays containing a set of overlapping peptides covering the complete cN1A amino acid sequence.
Anti-Mup44 autoantibodies, which are targeted to cN1A, represent the first serological biomarker for sIBM and may facilitate the diagnosis of this type of myositis. ANN NEUROL 2013;73:397–407
Patients with myasthenia gravis (MG) may have various non-motor symptoms in addition to fatigability and weakness of skeletal muscles. Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells. Thymomas are found in 15-25% of patients with MG and are associated with severe symptoms. We suggest that non-motor symptoms are based on the autoimmune disorders probably owing to an abnormal T cell repertoire from thymomas. Using previously reported cases and cases from our multicentre cooperative study, we review the clinical characteristics of patients with thymoma-associated MG who have non-motor symptoms. CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles lead to the development of pure red cell aplasia, immunodeficiency and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and the related molecules can evoke various neurological and cardiac disorders. About 25% of patients with thymoma-associated MG have at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad spectrum of disease, ranging from the impairment of quality of life to lethal conditions. Since relatively little attention is paid to non-motor symptoms in patients with thymoma-associated MG, the symptoms may be overlooked by many physicians. Early diagnosis is important, since non-motor symptoms can be treatable. A complete understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.
Background Intravenous immunoglobulin (IVIG) and plasmapheresis (plasma exchange (PLEX)) have comparable efficacy in reducing the Quantitative Myasthenia Gravis Score for disease severity (QMGS) in patients with moderate to severe myasthenia gravis (MG).
Objective To determine if the improvement in the quality of life (QOL) after immunomodulation is comparable with either IVIG or PLEX.
Methods 62 patients participated in the MG-QOL-60 study, completing the questionnaire at baseline and at day 14 after treatment. The MG-QOL-15 scores were computed from the MG-QOL-60 questionnaire responses. We analysed the change in the QOL scores from baseline to day 14 in both treatment groups.
Results The scores in both QOL scales decreased at day 14 in the IVIG and PLEX groups, without significant difference between groups (QOL-15: IVIG −5.7±8.5, PLEX: −7.0±7.6, p=0.52; QOL-60: IVIG −13.3±16.9, PLEX −18.5±22.0, p=0.41). The improvement in QOL showed a good correlation with the decrease in QMGS. There was an excellent correlation between the MG-QOL-15 and MG-QOL-60 scores at baseline and at day 14.
Conclusions This study of MG-QOL changes supports recent findings that IVIG and PLEX are comparable in the treatment of patients with moderate to severe MG and worsening symptoms. Furthermore, our study supports the use of the MG-QOL-15 as a secondary outcome measure in future clinical trials in MG.
The cardinal symptom of myasthenia gravis (MG) is weakness of voluntary muscles, a feature that may restrict full participation in life activities. In turn, such limitations may negatively affect quality of life (QOL) and well-being among individuals with the disease. In the present study, we administered a measure of QOL to 27 patients with generalized MG. Results revealed that functional status was negatively impacted in the domains of physical functioning, energy, and general health. However, a clinically meaningful difference was evident only on perceived ability to accomplish physical tasks. The results suggest that although MG requires accommodations in physical activities, general QOL and well-being does not differ markedly from the general population. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 512–516, 2001
Our study aim was to produce a Japanese translation of the 15-item Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), assess its reliability and validity, and examine clinical factors affecting self-perceived QOL in MG.
We evaluated 327 consecutive patients with MG seen at six neurological centers. All patients completed the Japanese version of the MG-QOL15 (MG-QOL15-J), the Beck Depression Inventory-second edition (BDI-II), and a generic health-related QOL questionnaire, the SF-36. Disease severity was determined according to the Myasthenia Gravis Foundation of America (MGFA) quantitative MG score and the MG composite.
The MG-QOL15-J exhibited adequate internal reliability, test-retest repeatability, and concurrent validity with SF-36, disease severity, and known-patient groups categorized by MGFA post-intervention status. Multivariate analysis revealed severity, dose of oral corticosteroids, and BDI-II as independent factors negatively affecting QOL.
The MG-QOL15-J is anticipated to be a valuable clinical measure of QOL in Japanese patients with MG.
The MG Composite (MGC) is a validated outcome measure of the clinical manifestations of myasthenia gravis.
We performed Rasch analyses of the MGC to investigate additional properties, including its unidimensionality and the appropriateness of the weights assigned to the response categories for the MGC items.
The fit statistics indicated that the 10 items belong together and can be summated for a total score. There was an overall absence of item order distortion between response categories. The Rasch model's expected category response values were compatible with item weights previously assigned.
Our analysis suggests that: (1) the score can be summated to estimate an overall disease severity score; (2) the response options of the 10 items are not significantly distorted; and (3) the assigned weights of the response options are appropriate.
We describe the process whereby a recently developed myasthenia gravis (MG)-specific quality-of-life (QOL) instrument was reduced from 60 items to 15 items while maintaining potential usefulness in the clinic and in prospective treatment trials. In data from a recently completed prospective trial of mycophenolate mofetil (MMF) in MG, the MG-QOL15 correlated as highly as the 60-item MG-QOL for physical and social domains of the 36-item health survey of the Medical Outcomes Study Short Form (SF-36). Correlation coefficients for the MG-QOL15 were similar to the 60-item MG-QOL for the Quantitative Myasthenia Gravis (QMG), MG-specific Manual Muscle Testing (MG-MMT), and the MG-specific Activities of Daily Living (MG-ADL) scores at week 0 and for change in scores from week 0 to week 12 in the MMF trial. Using the physician global impression at week 12 of the trial as the "gold standard," the MG-QOL15 demonstrated high sensitivity. Because the MG-QOL15 instrument can be quickly and easily administered and interpreted, it is a potential QOL measure for treatment trials and the clinical evaluation of patients with MG.
One hundred sixteen patients, aged 8 to 82 years, with myasthenia gravis were treated with prednisone, 60 to 80 mg daily, until the onset of improvement, followed by lower-dose alternate-day therapy of several years' duration. Of all patients, 80.2% achieved either remission (27.6%) or marked improvement (52.6%). Moderate improvement occurred in 14.7%, and 5.2% showed no improvement. Increasing age correlated with a favorable outcome, but sex, duration of illness prior to treatment, severity and distribution of weakness at the time of onset of treatment, and presence of thymoma were not factors in the response to therapy.
To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan.
We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships.
A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively.
Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.
The MG-QOL15 is helpful in informing the clinician about the patient's perception of the extent of and dissatisfaction with myasthenia gravis (MG)-related dysfunction. The aims of this study were to determine the usefulness of the MG-QOL15 for following individuals with MG and to guide clinical researchers who plan to use the MG-QOL15. We assessed sensitivity and specificity for detecting clinical change and evaluated test-retest reliability. Sensitivities and specificities of various cut-points of change in scores are presented. Also presented are means and standard deviations of MG-QOL15 scores for all patients and for subgroups of patients. The test-retest reliability coefficient was 98.6%. The MG-QOL15 has an acceptable longitudinal construct validity. We consider this instrument to be most useful for informing the clinician about the patient's perception and tolerance of MG-related dysfunction. More objective measures, such as the MG Composite, should also be used to follow disease severity.
Myositis muscle contains antigen-matured B-cells and plasma cells. Myositis muscle biopsy specimens were examined for nodular collections of T-cells, B-cells, myeloid dendritic cells, plasma cells, and follicular dendritic cells. Immunoglobulin and B-cell-activating factor (BAFF) transcripts were quantitated. Laser-capture microdissection was used to isolate single plasma cells, and their immunoglobulin transcripts were sequenced. Dense inflammatory infiltrates contained histological elements of ectopic lymphoid tissue but not B-cell follicles. Immunoglobulin transcript sequence analysis demonstrated spatially distributed, clonally related B-cells and plasma cells, suggesting local maturation of B-cells into plasma cells in myositis muscle. Regions of dense cellular infiltrates in myositis muscle are sometimes areas of B-cell maturation into antibody-producing plasma cells. An atypical lymphoid histology, lacking concentrated collections of germinal-center-like B-cell follicles, is capable of antigen-stimulated clonal maturation of antibody-producing plasma cells.
Cyclosporine (CsA) microemulsion pre-concentrate (MEPC) is a potential steroid-sparing agent for myasthenia gravis (MG) patients; however, there is a paucity of information on the long-term use of CsA MEPC in these patients.
We examined the efficacy and safety of CsA MEPC therapy administered to MG patients in a 2-year prospective open trial.
From Hanamaki General Hospital and Keio University Hospital, 28 patients provided informed consent. They were enrolled in a prospective open study of CsA MEPC for the initial 6-month observation period; after this 9 were defined as poor responders and excluded from the long-term analysis.
The proportion of patients with minimal manifestations or pharmacologic remission status increased significantly. Among 18 patients taking oral prednisolone, 16 (88.9%) achieved a >or=50% reduction in prednisolone dose. Time to attain the minimal quantitative MG (QMG) score (4.2 +/- 2.6) was 4.2 +/- 4.2 months. Time to attain the minimal dose of prednisolone (2.9 +/- 3.1 mg/day) was 9.3 +/- 6.9 months. The dose of CsA MEPC was reduced to 2.6 mg/kg/day 2 years after starting the drug. Both total and ocular QMG scores were significantly decreased at 6 months and were generally maintained thereafter. The dose of prednisolone was significantly reduced at 1 year, and further reduced at 2 years. BMI decreased significantly, and 9 of 12 (75%) patients complaining of moon face reported that this had resolved on exit. All patients tolerated CsA MEPC without significant side effects.
CsA MEPC therapy in responder MG patients suppressed disease severity, reduced steroid requirements, and alleviated steroid-related side effects. These findings should be confirmed by prospective controlled double-blind trials.
This review illustrates how measurements of clinical status in patients with myasthenia gravis have evolved from clinical descriptions and estimates of mortality rates to more sophisticated evaluative instruments, including numerical rating scales that measure strength, endurance, quality of life, and activities of daily living. The rationale and use of weighting and the importance of patient-reported outcomes are also discussed. The measurement of the steroid-sparing effect of an immunosuppressant is also reviewed.
To study the concurrent and construct validity and test-retest reliability in the practice setting of an outcome measure for myasthenia gravis (MG).
Eleven centers participated in the validation study of the Myasthenia Gravis Composite (MGC) scale. Patients with MG were evaluated at 2 consecutive visits. Concurrent and construct validities of the MGC were assessed by evaluating MGC scores in the context of other MG-specific outcome measures. We used numerous potential indicators of clinical improvement to assess the sensitivity and specificity of the MGC for detecting clinical improvement. Test-retest reliability was performed on patients at the University of Virginia.
A total of 175 patients with MG were enrolled at 11 sites from July 1, 2008, to January 31, 2009. A total of 151 patients were seen in follow-up. Total MGC scores showed excellent concurrent validity with other MG-specific scales. Analyses of sensitivities and specificities of the MGC revealed that a 3-point improvement in total MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC also appears to represent a meaningful improvement to most patients, as indicated by improved 15-item myasthenia gravis quality of life scale (MG-QOL15) scores. The psychometric properties were no better for an individualized subscore made up of the 2 functional domains that the patient identified as most important to treat. The test-retest reliability coefficient of the MGC was 98%, with a lower 95% confidence interval of 97%, indicating excellent test-retest reliability.
The Myasthenia Gravis Composite is a reliable and valid instrument for measuring clinical status of patients with myasthenia gravis in the practice setting and in clinical trials.
Immunosuppression is the mainstay of treatment for myasthenia gravis (MG). In this paper, we review the mechanisms of action and clinical application of corticosteroids and different classes of immunosuppressive drugs that are currently used in MG patients, and present the results of their use in more than 1000 patients with MG seen at our two centers. Immunosuppressive treatment was considered along with, or as an alternative to thymectomy in MG patients with disabling weakness, not adequately controlled with anticholinesterase drugs. Overall, 82% of our patients received immunosuppressants for at least 1 year, with frequencies varying according to disease severity, from 93-95% of those with thymoma or MuSK antibodies to 72% in ocular myasthenia. Prednisone was used in the great majority of patients, azathioprine was the first-choice immunosuppressant; mycophenolate mofetil and cyclosporine were used as second-choice agents. All clinical forms of MG benefited from immunosuppression: the rate of remission or minimal manifestations ranged from 85% in ocular myasthenia to 47% in thymoma-associated disease. Treatment was ultimately withdrawn in nearly 20% of anti-AChR positive early-onset patients, but in only 7% of thymoma cases. The risk of complications appears to depend on drug dosage, treatment duration, and patient characteristics, the highest rate of serious side effects (20%) having been found in late-onset MG and the lowest (4%) in early-onset disease. Although nonspecific, current immunosuppressive treatment is highly effective in most MG patients. Lack of randomized evidence, the need for prolonged administration, and unwanted effects are still relevant limitations to its use.
Health-related quality of life (HRQOL) estimates can play an important role in patient care by providing information about the patient's perception of impairment and disability and the degree to which the patient tolerates disease manifestations. The 15-item myasthenia gravis quality of life scale (MG-QOL15) is an HRQOL evaluative instrument specific to patients with myasthenia gravis (MG) that was designed to be easy to administer and interpret. In this multicenter study we demonstrate the construct validity of the MG-QOL15 in the practice setting. To assess the construct validity, score distributions were examined for test items in different MG patient groups that represent the clinical spectrum of the disease. For example, patients in remission more frequently scored test items as normal than did patients in other groups. Patients with lower (better) MG composite scores also more frequently scored items as normal than did patients with higher (worse) scores. There was also appropriate correlation between the MG-QOL15 and the other MG-specific scales studied. The study findings shed light on what troubles MG patients. The MG-QOL15 has construct validity in the clinical practice setting and represents an efficient and valuable tool for assessing HRQOL for patients with MG.
Myasthenia gravis (MG) is an autoimmune neuromuscular transmission disorder where well-defined autoantibodies against muscle and muscle cell membrane molecules are directly pathogenetic. All MG patients should be defined for subtype, as such a subclassification has treatment consequences. Ocular MG, early-onset MG, late-onset MG, MG with thymoma, MG with anti-muscle-specific tyrosine kinase antibodies and MG with no defined antibodies constitute the six MG categories. The MG diagnostic process includes neurophysiology, neuroimmunology, neuropharmacology and imaging. In addition to symptomatic therapy with acetylcholine esterase inhibitors, most patients need thymectomy and/or immunosuppressive drugs. Today's treatment is not immunospecific and far from antigen-specific, even if the pathogenesis is known in detail. Strategies for acetylcholine receptor tolerance induction, manipulating acetylcholine receptor antigen presentation or suppressing acetylcholine receptor-specific B-cells or plasma cells work in experimental MG, but have not yet been attempted properly for the human disease, or they do not work. Apart from the 10-15% of patients with paraneoplastic MG, the cause of the disease is not known. Until curative or antigen-specific therapy become available, the well-established treatment gives good-to-excellent results in most patients, with acceptable quality of life and no increased mortality. Acute and intensive care treatment during MG exacerbation is a cornerstone in the treatment.
We assessed the performance of items from the Quantitative Myasthenia Gravis (QMG), MMT (Manual Muscle Test), and MG-ADL (Myasthenia Gravis - Activities of Daily Living) scales, using data from two recently completed treatment trials of generalized MG. Items were selected that were relevant to manifestations of MG, meaningful to both the physician and the patient, and responsive to clinical change. After the 10 items were chosen, they were weighted based on input from MG experts from around the world, considering factors such as quality of life, disease severity, risk, prognosis, validity, and reliability. The MG Composite is easy to administer, takes less than 5 minutes to complete, and requires no equipment. Weighting of the response options of the 10 items should result in ordinal scores that better represent MG status and are more responsive to meaningful clinical change. To better determine its suitability for clinical use and for treatment trials, the MG Composite will be tested prospectively at several academic medical centers and will be used as a secondary measure of efficacy in pending clinical trials of MG.
ANCA are markers for systemic vasculitis such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA) and are usually of the IgG isotype. However, IgM ANCA may rarely occur in isolation, and in these circumstances, we have found that they are associated clinically with a syndrome of pulmonary hemorrhage and systemic vasculitis. How frequently IgM ANCA may occur in conjunction with IgG has not previously been investigated. We report here a study of 24 consecutive patients with IgG ANCA-positive systemic vasculitis (14 WG, 10 MPA) in whom we determined whether IgM ANCA occurred in association with IgG ANCA, and if so, whether this had clinical importance. Eight patients were found to have IgM ANCA as well as IgG ANCA, and of these, seven presented with severe pulmonary hemorrhage. None of the IgM ANCA-negative patients presented with pulmonary hemorrhage. Although the occurrence of pulmonary hemorrhage in ANCA positive vasculitis was closely correlated with the presence of IgM ANCA, the antigen specificity of these IgM autoantibodies was variable, since both myeloperoxidase (4 patients), PR3 (3 patients), and an unknown ANCA antigen (1 patient) were found to be targets. We conclude that knowledge of ANCA isotype may have important clinical and therapeutic implications for the management of patients with systemic vasculitis.
We assessed the health-related quality of life (HRQoL) of patients with myasthenia gravis (MG) and correlated it with the physician's measurements of MG. Patients with MG were evaluated by means of (1) self-administered questionnaires, (2) clinical examination, (3) Osserman classification, (4) anti-AChR antibody, and (5) neurophysiology. Relationships between patient-oriented assessment and conventional clinical-neurophysiological and serological findings were evaluated. A total of 46 patients, inpatients and outpatients (mean age 50.7 years, range 11-77 years, 17 males, 29 females) with MG diagnosis were studied. The Osserman scale and clinical examination findings were significantly related to the physical aspects of HRQoL. Mental aspects of the quality of life were not progressively involved as muscle deficit progressed, but even in a mild clinical picture, the mental aspects were deteriorated. Patient-oriented measures proved that the patient's quality of life was impaired especially with regard to physical aspects. Our data demonstrated that clinical measurements are related to the HRQoL. The results may be useful in developing a disease-specific patient-oriented tool.
The incidence of myasthenia gravis (MG) from 1970 through 1999 was studied in an area with 2.3 million inhabitants. The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6). The two onset types of MG may thus be distinct disorders. The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors.
Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms.
Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage.
Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells.
There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.
To correlate muscle biopsy findings with prebiopsy and postbiopsy clinical course and response to therapy in polymyositis (PM) and sporadic inclusion body myositis (IBM).
Existence of pure PM has recently been questioned; subsequently, the definition and criteria for diagnosing PM were debated.
Patient records, follow-up information, and muscle biopsies were analyzed in 107 patients whose biopsies were initially read as PM and IBM.
The patients fell into three groups by combined biopsy and clinical criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy diagnosis of PM but clinical features of IBM. For the three groups, the respective mean periods from disease onset to end of follow-up were 5.9, 8.5, and 9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM, and 1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of each group. Nineteen PM patients had no associated autoimmune disease or marker. Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27 PM, and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy improved 22 of 27 PM patients but had only transient beneficial effects in 2 of 32 IBM and 1 of 14 PM/IBM patients.
1) Sixteen of 43 patients (37%) with biopsy features of polymyositis (PM) had clinical features of inclusion body myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically affected muscles of IBM patients challenges biopsy criteria for IBM, or the IBM markers appear late in some patients, or their distribution in muscle is patchy and restricted compared with that of the inflammatory exudate. 3) The muscle biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85% of the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced by combined evaluation of the clinical and pathologic findings.
Between 1940 and 2000 a total of 1976 patients with myasthenia gravis (MG) were studied. Diagnosis was made by improvement in weakness after anticholinesterase medication. The historical developments in diagnosis and treatment of MG are reviewed. We analyzed the clinical course of MG as influenced by age, gender, thymectomy, thymomectomy, and the presence of antibodies to acetylcholine receptors (AChR). The clinical course of MG was significantly influenced by age and gender, and these need special attention in managing patients. The most severe level of weakness and high mortality occurred during the first 1 to 2 years of the disease, after which many patients experienced improvement. For treating MG patients the usefulness of thymectomy remains to be proven, and novel drugs need to be developed to increase the number as well as normal functioning of the AChRs and other components of the neuromuscular system.
There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes.
A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies.
Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength.
The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.
We have defined myasthenia gravis (MG) in the elderly as onset after the age of 50 years. MG is diagnosed more often today than previously. The increase is mainly found in patients over the age of 50 years. Neurologists therefore see more old patients with MG now than before. Prevalence of the early-onset form of MG seems to be unchanged. Recent data indicate that MG may still be substantially underdiagnosed in very old people. Ptosis, diplopia, weakness of the facial muscles, and problems of articulation are important clinical signs in MG and are easier to detect in a youthful appearance. Since ageing causes a decrease in the total eyelid area with sagging of the lower eyelids, a ptosis may be more difficult to diagnose in the elderly. In addition, diplopia may not be detected because of reduced vision due to macular degeneration or cataract formation. Ocular symptoms of MG are therefore more easily missed in the elderly. Thymomatous MG is more common among older patients than it is in younger onset. The mean age at onset of MG for thymoma cases is 50-60 years. Approximately 10-15% of all MG patients have a thymoma, and around 40% of all thymoma cases are associated with MG. During normal aging, the thymus tissue becomes atrophic and replaced with fat. Recent data on MG thymus pathology suggest that lymphocyte accumulation indicating residual thymus may also be found in the elderly, and that there is little qualitative difference between the young and the old thymus from MG patients. The mean concentration of antibodies to acetylcholine receptor (AChR) is lower in MG in the elderly than in early-onset or thymoma-associated MG. Seronegative MG is less common among older patients. Approximately 30% of patients with late-onset, nonthymoma MG have antibodies to titin, while such antibodies are extremely scarce in early-onset MG. Titin antibodies in MG patients seem to be associated with a higher frequency of DR7 antigen and a decrease of DR3 antigen. The antibody response in MG may therefore be influenced by the genetic background.