Worsening of myasthenic symptoms associated with statins.

INTRODUCTION/AIMS: The common presentations of statin intolerance are muscle-specific symptoms. Although statins are one type of drug reported to cause myasthenic worsening, myasthenic worsening has not been recognized as statin intolerance. The purpose of the present study is to investigate in a large cohort the safety profiles of statins in patients with myasthenia gravis (MG). METHODS: A total of 1710 consecutive patients with MG who visited sites associated with the Japan MG registry 2021 group between April and October 2021 were reviewed. Statin-associated myasthenic worsening was defined as worsening of any myasthenic symptoms on statin use and improvement of the symptom by stopping the statin or by undertaking additional treatment with patient and doctor confirmation. RESULTS: Among the 400 patients who used statins, 8 (2%) patients experienced statin intolerance and 6 (1.5%) patients experienced myasthenic worsening. No patients developed MG on the statin. Ptosis was a main symptom of myasthenic worsening in 4 (67%) patients. Atorvastatin was used in all patients with statin-associated myasthenic worsening. The symptoms of statin intolerance and statin-associated myasthenic worsening were improved within 2 months and 3 months, respectively, in all patients by cessation of statin use. DISCUSSION: Regarding statin-associated myasthenic worsening, prevalence was low, and severity was mild; with cessation of statin use, symptoms improved within a few months, and outcomes were generally good. Although statins can be used in MG patients with little concern, statin-associated myasthenic worsening should be noted in addition to the classical statin intolerance associated with statin use.

Real-world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis.

OBJECTIVE: Eculizumab and ravulizumab are complement protein C5 inhibitors, showing efficacy and tolerability for patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG) in phase 3 clinical trials and subsequent analyses. The purpose of the present study was to evaluate the clinical significance of eculizumab and switching to ravulizumab for refractory AChR+ gMG patients in the real-world experience. METHODS: Among the database of Japan MG registry survey 2021, we studied AChR+ gMG patients who received eculizumab. We also evaluated these patients who switched from eculizumab to ravulizumab. Responder was defined as an improvement of at least 3 points in MG-ADL. We performed a questionnaire of preference between eculizumab and ravulizumab. RESULTS: Among 1,106 patients with AChR+ gMG, 36 patients (3%) received eculizumab (female 78%, mean age 56.0 years). Eculizumab was preferentially used in severe and refractory MG patients. The duration of eculizumab treatment was 35 months on average. MG-ADL improved from 9.4 ± 4.9 to 5.9 ± 5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. Of 13 patients who did not continue eculizumab, 6 showed insufficiencies. Early onset MG was most effective. However, 15 patients switching from eculizumab to ravulizumab kept favorable response and tolerability. Questionnaire surveys showed preference for ravulizumab over eculizumab. INTERPRETATION: Eculizumab and switching to ravulizumab showed to be effective for refractory AChR+ gMG patients in clinical settings.

Taste disorders and alopecia in myasthenia gravis.

BACKGROUND: Non-motor symptoms in myasthenia gravis (MG) are rarely confirmed. Although there are some small cohort studies, a large-systemic survey has not yet been performed. METHODS: We investigated the incidence and clinical characteristics of patients with MG who had taste disorders and alopecia using data of 1710 patients with MG enrolled in the Japan MG Registry 2021. RESULTS: Among them, 104 (6.1%) out of 1692 patients and 138 (8.2%) out of 1688 patients had histories of taste disorders and alopecia, respectively. Among the patients with MG, taste disorders were significantly more common in women, those with severe symptoms, refractory MG, or thymoma-associated MG, and were less common in those with ocular MG. The taste disorders often occurred after the onset of MG and often responded to MG treatments. Alopecia was more common in MG patients with a history of bulbar palsy and thymoma, and it often occurred before the onset of MG and sometimes responded to MG treatments. Multivariate logistic regression analysis revealed taste disturbance was associated with worst quantitative MG score and thymoma-associated MG; and alopecia was associated with thymoma-associated MG. CONCLUSION: Clinicians should be aware of the non-motor symptoms in MG, especially in patients with severe myasthenic symptoms and thymoma-associated MG.

Clinical features and outcomes of patients with muscle-specific kinase antibody-positive myasthenia gravis in Japan.

This study included 51 patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) from a Japanese multicenter survey to examine clinical features and outcomes. Median onset age was 37 years and female predominance was observed. All patients developed generalized symptoms and almost all (50/51) patients had bulbar symptoms. About half of the patients met the criteria for refractory MG. The refractory group had a lower age of onset, higher severity scores, and higher maximum daily doses of oral prednisolone compared to the nonrefractory group. The outcomes for MuSK-MG patients in Japan are not favorable, indicating the need for more aggressive treatment.

[Thymoma-associated generalized myasthenia gravis complicated with anti-VGKC complex antibody-associated limbic encephalitis: a case report].

We present a case of a 54-year-old woman. She was attending our department for thymoma-associated generalized myasthenia gravis. While she was treated with intravenous immunoglobulins for the exacerbation of myasthenic symptoms, she suddenly lost her consciousness for the first time and continued to have mild disorientation along with anterograde and retrograde amnesia afterwards. The symptoms improved after steroid pulse therapy. After searching for autoantibodies, she was diagnosed with anti-VGKC complex antibody-associated limbic encephalitis. As one-third of cases are complicated by thymoma, anti-VGKC complex antibody-positive limbic encephalitis has the aspect of a paraneoplastic neurological syndrome. In this case, masses suspected to be a recurrence of thymoma were found. In cases of thymoma, involvement of anti-VGKC complex antibodies should be considered when central nervous system symptoms appear, and when anti-VGKC complex antibodies are positive, recurrence or exacerbation of thymoma should be considered.

Impact of Early Treatment with Intravenous High-Dose Methylprednisolone for Ocular Myasthenia Gravis.

The efficacy of intravenous high-dose methylprednisolone (IVMP) in ocular myasthenia gravis (MG) has not been fully established. This study aimed to elucidate the effects of early intervention with IVMP for achieving the therapeutic targets (minimal manifestations [MM] or MM or better status with prednisolone ≤ 5 mg/day [MM5mg]) in ocular MG. In this observational study, we included a total of 1710 consecutive patients with MG enrolled in the Japan MG Registry in 2021. Of these, 204 patients with ocular MG who received immunotherapy were analyzed. The clinical course and time to first achieve MM or MM5mg after starting immunotherapy were compared between the early IVMP group (treated with IVMP within 3 months of treatment initiation) and the non-early IVMP group. Despite having greater clinical severity before immunotherapy and lower oral prednisolone doses throughout the course, the early IVMP group (n = 55) showed a higher rate of achievement of MM (P = 0.0040, log-rank test; hazard ratio 1.58, 95% confidence interval [CI] 1.13-2.20, P < 0.0001) and MM5mg (P = 0.0005, log-rank test; hazard ratio 1.78, 95% CI 1.27-2.51, P < 0.0001) compared with the non-early IVMP group (n = 149). In conclusion, an early intervention with IVMP is likely to increase the probability of achieving a better long-term outcome and reducing the total dose of corticosteroids in ocular MG.

Effectiveness of early cycles of fast-acting treatment in generalised myasthenia gravis.

BACKGROUND: Early fast-acting treatment (EFT) is the aggressive use of fast-acting therapies such as plasmapheresis, intravenous immunoglobulin and/or intravenous high-dose methylprednisolone (IVMP) from the early phases of treatment. EFT is reportedly beneficial for early achievement of minimal manifestations (MM) or better status with ≤5 mg/day prednisolone (MM5mg), a practical therapeutic target for myasthenia gravis (MG). OBJECTIVE: The current study aimed to clarify which specific EFT regimen is efficacious and the patient characteristics that confer sensitivity to EFT. METHODS: We recruited a total of 1710 consecutive patients with MG who enrolled in the Japan MG Registry for this large-cohort study. Among them, 1066 with generalised MG who had received immunotherapy were analysed. Prognostic background factors were matched in a 1:1 ratio using propensity score matching analysis between patients treated with EFT (n=350) and those treated without EFT (n=350). The clinical course and time to first achieve MM5mg after starting immunotherapy was analysed in relation to treatment combinations and patient characteristics. RESULTS: Kaplan-Meier analyses showed that EFT had a significant effect on the achievement of MM5mg (p<0.0001, log-rank test; HR 1.82, p<0.0001). Notably, EFT was efficacious for any type of MG, and the inclusion of IVMP resulted in earlier and more frequent achievement of MM5mg (p=0.0352, log-rank test; HR 1.46, p=0.0380). In addition, early administration of calcineurin inhibitors also promoted MM5mg achievement. CONCLUSION: Early cycles of intervention with EFT and early use of calcineurin inhibitors provides long-term benefits in terms of achieving therapeutic targets for generalised MG, regardless of clinical subtype.

Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.

Association of Smoking and Generalized Manifestations of Myasthenia Gravis.

Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.

Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Arthritis.

A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Oral corticosteroid dosing regimen and long-term prognosis in generalised myasthenia gravis: a multicentre cross-sectional study in Japan.

OBJECTIVE: We examined the correlation between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL ≤5 mg/day lasting >6 months (the treatment target) in patients with generalised myasthenia gravis (MG). METHODS: We classified 590 patients with generalised MG into high-dose (n=237), intermediate-dose (n=187) and low-dose (n=166) groups based on the oral PSL dosing regimen, and compared the clinical characteristics, previous treatments other than PSL and prognosis between three groups. The effect of oral PSL dosing regimen on the achievement of the treatment target was followed for 3 years of treatment. RESULTS: To achieve the treatment target, ORs for low-dose versus high-dose regimen were 10.4 (P<0.0001) after 1 year of treatment, 2.75 (P=0.007) after 2 years and 1.86 (P=0.15) after 3 years; and those for low-dose versus intermediate-dose regimen were 13.4 (P<0.0001) after 1 year, 3.99 (P=0.0003) after 2 years and 4.92 (P=0.0004) after 3 years. Early combined use of fast-acting treatment (OR: 2.19 after 2 years, P=0.02; OR: 2.11 after 3 years, P=0.04) or calcineurin inhibitors (OR: 2.09 after 2 years, P=0.03; OR: 2.36 after 3 years, P=0.02) was associated positively with achievement of treatment target. CONCLUSION: A low-dose PSL regimen with early combination of other treatment options may ensure earlier achievement of the treatment target in generalised MG.

Social disadvantages associated with myasthenia gravis and its treatment: a multicentre cross-sectional study.

OBJECTIVES: To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. OUTCOME MEASURES: All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. RESULTS: We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. CONCLUSIONS: Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.

Early fast-acting treatment strategy against generalized myasthenia gravis.

INTRODUCTION: In this study we sought to clarify the effects of early fast-acting treatment (EFT) strategies on the time course for achieving the treatment target in generalized myasthenia gravis (MG). METHODS: This retrospective study of 923 consecutive MG patients analyzed 688 generalized MG patients who had received immunotherapy during the disease course. The time to first achieve minimal manifestations (MM) or better while receiving prednisolone at ≤5 mg/day for ≥6 months (MM-or-better-5mg) up to 120 months after starting immunotherapy was compared between EFT and non-EFT patients. RESULTS: Achievement of MM-or-better-5mg was more frequent and earlier in the EFT group (P = 0.0004, Wilcoxon test; P = 0.0001, log-rank test). Multivariate Cox regression analysis calculated a hazard ratio of 1.98 (P < 0.0001) for utilization of EFT. Dosing regimens of oral steroids in EFT produced no differences in the time course. CONCLUSIONS: EFT strategies are advantageous for early achievement of MM-or-better-5mg. Muscle Nerve 55: 794-801, 2017.

Response to treatment of myasthenia gravis according to clinical subtype.

BACKGROUND: We have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment. METHODS: A total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti-muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared. RESULTS: As a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status. CONCLUSIONS: Differences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.

Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

Usefulness of 11C-methionine-positron emission tomography for the diagnosis of progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disease of the brain caused by the JC virus that occurs mainly in immunocompromised patients. The prognosis is very poor. As the lesion looks like non- specific leukoencephalopathy, making a diagnosis at the early stage is very difficult. We report three PML cases in which there was a mismatch between (11)C-methionine-positron emission tomography (MET-PET) uptake and (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake. All three cases demonstrated the hyper-uptake of MET around the white matter lesions and hypo-uptake of FDG inside the lesions. We speculate that the infection had ended inside the white matter lesions of these patients, while JC virus infection was ongoing around the lesions, resulting in the increase of methionine metabolism, and the glucose metabolism was reduced or intermediate because inflammatory cells infiltrate PML lesions rarely. Two patients who were diagnosed and treated with mefloquine while the JC virus was at a low level in the cerebrospinal fluid are still alive. We suggest the usefulness of MET-PET for the early diagnosis of PML and early treatment with mefloquine.

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction, and prednisolone (PSL) and immunosuppressive drugs are available for treatment. Tacrolimus, a macrolide that suppresses the immune system, is used as a second-line treatment for MG. There have been several reports of the effects of tacrolimus over a few years of follow-up. Here, we report data from 9 patients with steroid-dependent generalized MG treated with low-dose tacrolimus (2-3 mg/day) for 5 years. Following treatment with tacrolimus, mean MG-activities of daily living score improved from 4.6 at baseline to 3.3 at 5 years after initiation of treatment. Mean dose of PSL could also be reduced, from 24.0 mg/day at baseline to 10.2 mg/day at 5 years, although there were no cases of total withdrawal of PSL. By contrast, 5 of the 9 patients experienced exacerbation of symptoms and transient increases in PSL dose during the 5-year period. Tacrolimus is an important option for treatment of MG; however, careful management is needed for long-term treatment with this drug.