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 Efficacy of Erenumab on Migraine-associated Symptoms and Patient-reported Satisfaction Levels: A Retrospective Study in Japan.

Objective In randomized clinical trials and real-world studies, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), including erenumab, have demonstrated efficacy for migraine prevention. However, there have been no real-world studies focusing on erenumab in East Asia that investigated its efficacy on migraine-associated symptoms and patient-reported satisfaction levels. Methods This single-center, observational, retrospective, real-world study examined patients who received at least three doses of erenumab at Keio University Hospital, Tokyo, Japan, between December 2021 and March 2023 as their first CGRP mAb treatment in a real-world setting. The patients were administered 70 mg of erenumab monthly. We assessed changes in monthly migraine days (MMDs), responder rates, migraine-associated symptoms including photophobia, phonophobia, nausea/vomiting, and patient-reported satisfaction levels. In addition, injection site reactions and other adverse events were recorded to investigate safety. Results Nineteen patients were considered eligible for the analysis. At 3 months, erenumab decreased MMDs by 6.6 (95% confidence interval, 2.3-10.8; p<0.01). The 50% responder rate was 42%. A total of 83% (n=15), 56% (n=10), and 71% (n=10) of patients reported either improvement in or disappearance of photophobia, phonophobia, and nausea/vomiting, respectively, and 44% (n=8) and 28% (n=5) answered "very satisfied" and "somewhat satisfied", respectively, with erenumab treatment, leaving only 28% (n=5) as "unsatisfied". Injection site reactions (n=6, 32%) and constipation (n=4, 21%) were frequent adverse events. Conclusion In a real-world setting in Japan, erenumab proved to be effective in not only reducing migraine and headache frequency but also improving migraine-associated symptoms and satisfying the majority of patients.

Efficacy and tolerability of 100†mg of lasmiditan for migraine: A multi-center, prospective observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness and safety of lasmiditan, a new medication for acute migraine attacks, is necessary. METHODS: We performed a prospective, observational, multi-center, real-world study. A total of 48 patients with migraine (44 females, 44.6 ± 12.9 years old) were included in this study. RESULTS: Twenty-three patients (47.9%) reported they were headache-free two hours after taking lasmiditan and were categorized into the responder group. In total, 44 patients (91.7%) experienced at least one side effect within two hours of taking the medication. Dizziness, somnolence, malaise, nausea, and palpitations were reported by 56.3% (n = 27), 45.8% (n = 22), 37.5% (n = 18), 20.8% (n = 10), and 14.6% (n = 7) of patients respectively. Of 48 patients, 20 (41.7%) indicated that they preferred lasmiditan to their previous acute treatment. There were no predictive factors for efficacy. CONCLUSION: This real-world study demonstrated the efficacy and safety of lasmiditan. More than 90% of patients experienced side effects from lasmiditan. Approximately 40% of patients preferred lasmiditan despite the occurrence of side effects.

B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis.

Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%-15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology.

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.

Therapeutic Responses to Efgartigimod for Generalized Myasthenia Gravis in Japan.

Background and Objectives: Efgartigimod, which has been well tolerated and efficacious in individuals with generalized myasthenia gravis (MG), is available in Japan not only for the treatment of anti-acetylcholine receptor-positive (AChR+) but also anti-muscle-specific receptor tyrosine kinase (MuSK+) and seronegative generalized MG. We report details of the use of efgartigimod for generalized MG in clinical practice in Japan. Methods: We included patients with generalized MG in the 2021 survey of Japan Myasthenia Gravis Registry (JAMG-R) study group who received an initial cycle of efgartigimod between May and September 2022. We defined "responders" as patients who achieved a score ≥2 points for MG activities of daily living (MG-ADL) in the first treatment cycle. The MG composite and the Revised scale of the 15-item Myasthenia Gravis-Quality of Life scale (MG-QOL15-r) were also evaluated. Results: Of 1,343 JAMG-R patients, 36 (2.7%) started efgartigimod (female 68%, age 53 years). Their serologic profiles were as follows: AChR+, n = 19 (53%); MuSK+, n = 6 (17%); and seronegative, n = 11 (31%). Twenty-six patients (72%) had refractory MG. There were 81 cycles of efgartigimod during the 26-week observation in 34 patients (average, 2.4 cycles). The mean interval between cycles was 5.9 weeks. A continuous 4-weekly infusion of efgartigimod was performed in 65 (80%) of 81 cycles. In the first cycle, the MG-ADL score of the 34 patients decreased significantly from 10.5 ± 4.3 to 6.9 ± 5.1 (p = 0.003). Similarly, the mean MG composite and MG-QOL15-r decreased from 18.4 ± 13.6 to 11.8 ± 9.6 (p = 0.004) and from 19.2 ± 6.3 to 14.2 ± 8.3 (p = 0.007), respectively. Twenty-one (62%) patients were responders. Therapeutic responses were observed in the subsequent cycles. The duration of effectiveness of efgartigimod was varied among the responders; 4 responders had only a single effective cycle. Significant improvement was observed in the MuSK+ patients. Prednisolone dose of 7 patients was reduced. Our examination of the patients' postintervention status revealed that 6 patients achieved minimal manifestations. COVID-19 occurred in 5 patients. We failed to detect clinical or laboratory findings associated with responders. Discussion: Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.

Serious Bacterial Infections Associated with Eculizumab: A Pharmacovigilance Study.

Objective Molecular-targeted agents, including eculizumab and rituximab, are considered treatment options for refractory myasthenia gravis (MG), but bacterial infections can occur as serious adverse events when using these agents. The present study elucidated the relative risks of bacterial infections associated with eculizumab and rituximab using a pharmacovigilance database. Methods We analyzed eculizumab- and rituximab-associated adverse events reported between 2007 and 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and herein report a refractory MG patient who developed streptococcal toxic shock syndrome during eculizumab treatment. Patients We evaluated a 74-year-old Japanese woman with refractory MG who developed severe bacteremia after receiving eculizumab. Results A total of 44,215 and 108,485 adverse events were reported with eculizumab and rituximab, respectively, from among 13,742,321 individual case safety reports in the FAERS database after data cleaning. We found a strong association between eculizumab and Neisseria infections. In contrast, we found only one case of meningococcal meningitis treated with rituximab. Both eculizumab and rituximab were weakly associated with streptococcal infections. Two cases of streptococcal toxic shock syndrome were associated with rituximab. Conclusion Careful monitoring of serious bacterial infections associated with eculizumab treatment is warranted.

Real-world evidence of fremanezumab for treating migraine in Japan: a retrospective study.

BACKGROUND: There have been very few real-world studies reported in the literature solely focusing on fremanezumab in Asia. This study aimed to evaluate the efficacy and safety of fremanezumab in a real-world setting in Japan. METHOD: This single-centered, observational, retrospective study examined patients with migraines who received four doses of fremanezumab between December 2021 and August 2022 at Keio University Hospital. We assessed the changes in monthly migraine days, responder rates, and migraine-associated symptoms, as well as injection site reactions and adverse events. RESULT: Twenty-nine patients were enrolled, wherein 79.3% were women. Compared with those at baseline, the monthly migraine days decreased by 5.9 days at 4 months. The 50% responder rate was 55.2% at 4 months. A total of 57.9%, 47.8%, and 65.0% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Moreover, injection site reactions were the most common adverse events (55.2%). CONCLUSION: Fremanezumab is effective and safe for migraine prevention in Japan. Fremanezumab also improved migraine-associated symptoms in half of the patients.

Prevalence of Primary Headache in Nurses in Japan: A Cross-sectional Single-center Study.

Objective This study examined the prevalence of migraine in nurses in Japan, which, to our knowledge, has not been documented in English. Methods From April to May 2021, we administered a questionnaire to 229 nurses working at Keio University Hospital to investigate the prevalence and characteristics of headache among nurses in Japan. Headaches were classified as migraine or tension-type headache (TTH) based on the International Classification of Headache Disorders-3 (ICHD-3). Results In total, 80 patients (34.9%) had primary headaches, including 47 (20.5%) with migraine and probable migraine and 33 (14.4%) with TTH and probable TTH. We found a significant difference in the Numerical Rating Scale score, nausea and vomiting, photophobia, phonophobia, and aggravation by routine physical activity between migraine and TTH. The specificities for a migraine diagnosis were 100% and 93.9% for nausea/vomiting and photophobia, respectively. Only 8.8% of patients had their headaches diagnosed by a physician. Conclusion Migraines have a high prevalence (>20%) among nurses and are often under-diagnosed. In many cases, headache-associated symptoms are more important than laterality or other characteristics for the diagnosis. Many nurses are treated for headaches without a correct diagnosis. Further education regarding primary headaches may be necessary for health practitioners as well as society.

Predicting response to CGRP-monoclonal antibodies in patients with migraine in Japan: a single-centre retrospective observational study.

BACKGROUND: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are a favourable option for patients with migraine who experience distressful headache disability and fail to respond to traditional preventive treatment options. However, since CGRPmAb has been available for only 2 years in Japan, the difference between good and poor responders remains unknown. We aimed to investigate the clinical characteristics of patients with migraine in Japan who responded well to CGRPmAb based on real-world data. METHODS: We analysed patients who visited Keio University Hospital, Tokyo, Japan, between the 12th of August 2021 and 31st of August 2022, and were prescribed one of three CGRPmAbs (erenumab, galcanezumab, and fremanezumab) for more than 3 months. We recorded the patients' basic migraine characteristics, such as pain quality, monthly migraine days (MMD)/monthly headache days (MHD), and the number of prior treatment failures. We defined good responders as patients whose MMDs decreased by more than 50% after 3 months of treatment and other patients as poor responders. We compared the baseline migraine characteristics between the two groups and performed logistic regression analysis based on the items that showed statistically significant differences. RESULTS: In total, 101 patients were considered eligible for the responder analysis (galcanezumab: 57 (56%), fremanezumab: 31 (31%), and erenumab: 13 (13%)). After 3 months of treatment, 55 (54%) patients achieved ≥ 50% reduction in MMDs. Comparisons between ≥ 50% responders and non-responders revealed that age was significantly higher (p = 0.003), and MHD and total prior treatment failures were significantly lower (p = 0.027, 0.040, respectively), in responders than in non-responders. Age was a positive predictive factor, and the total number of prior treatment failures and past medical history of immuno-rheumatologic diseases were negative predictive factors of CGRPmAb responsiveness in Japanese patients with migraine. CONCLUSIONS: Patients with migraine who are older, with fewer prior treatment failures and no past history of immuno-rheumatologic disease, may respond well to CGRPmAbs.

Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.

Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.

Real-world evidence of galcanezumab for migraine treatment in Japan: a retrospective analysis.

OBJECTIVE: To evaluate the efficacy and safety of galcanezumab in patients with migraine in a real-world setting in Japan. BACKGROUND: Galcanezumab is the first anti-calcitonin gene-related peptide monoclonal antibody approved in Japan. To the best of our knowledge, no real-world studies on galcanezumab have been published in any international journal from Japan. METHODS: We retrospectively examined patients with migraine who received three doses of galcanezumab between August 2021 and February 2022 at the Keio University Hospital. We assessed changes in monthly migraine days, responder rate, and migraine-associated and premonitory symptoms. We also investigated injection site reactions and adverse events. RESULTS: Fifty-two patients received three doses of galcanezumab during the study period. Compared with those at baseline, the monthly migraine days decreased by 5.9 days (95% confidence interval, 4.2-7.7) at 3 months. The 50% responder rate was 61.5% at 3 months. A total of 64.9%, 50.0%, and 63.9% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Premonitory symptoms without subsequent headache were reported in 62.5% of patients. Moreover, injection site reaction was the most common adverse event (34.6%). CONCLUSION: This study revealed the efficacy and safety of galcanezumab for migraineurs in Japan. Galcanezumab also improved migraine-associated symptoms. However, despite a reduction in headaches, premonitory symptoms without subsequent headache were reported in > 50% of the patients at 3 months.

Anemia in female patients with myasthenia gravis.

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.

Immunodeficiency in patients with thymoma-associated myasthenia gravis.

Thymoma with immunodeficiency is sometimes accompanied by myasthenia gravis (MG), but the clinical characteristics have not been elucidated. This study aimed to characterize its clinical and immunological features. Of the 132 thymoma-associated MG patients, 9 patients presented with immunodeficiency. All suffered from severe pneumonia, and most had invasive thymoma and autoimmune disorders. DRB1*08:03 and DQB1*06:01 alleles were frequently detected. Compared to group without immunodeficiency, they showed no significant differences in the severity of MG, significantly lower IgG concentrations and higher mortality rate. Thymoma-associated MG with immunodeficiency is a distinct subset requiring special attention to prevent infection during the follow-up period.

Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study.

BACKGROUND: Headache is an adverse event of coronavirus 2019 (COVID-19) vaccination. Whether patients with history of headache suffer more from vaccination-induced headaches is unknown. We aimed to uncover if headache patients develop more headaches after COVID-19 mRNA vaccination than healthy controls. METHODS: We performed a questionnaire survey for nursing staff in our hospital from April to May 2021. Based on baseline characteristics, we divided the participants into migraine, non-migrainous headache, and healthy control, and examined the occurrence and features of headache after COVID-19 vaccinations. RESULTS: We included 171 participants (15.2% migraine and 24.6% non-migrainous headache). Headache incidence after vaccinations was significantly higher in the migraine (69.2%) and non-migrainous headache (71.4%) groups than in the healthy control (37.9%) group. The incidence of headaches was significantly higher after the second dose compared to the first (45.6% vs. 20.5%). CONCLUSION: Migraineurs and non-migrainous headache participants developed more headaches compared to the healthy controls after COVID-19 vaccination.

[A case of neuromyelitis optica spectrum disorder in which headache preceded visual field disturbances by 2 months].

A quinquagenarian woman visited our hospital due to experiencing headache around the right upper eyelid for the previous 2 months. T2-weighted MRI of the head showed multiple high-signal-intensity lesions in the corpus callosum and bilateral corona radiata. She was thought to have an autoimmune disease and was treated with steroid pulse therapy, but the light reflex of the right eye diminished and the patient developed inferior horizontal hemianopsia. T2-weighted orbital MRI showed an enlarged right optic nerve, a high-intensity signal in the superior half of the optic nerve, and an enhancing effect. She also tested positive for anti-aquaporin 4 antibodies, so she was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). This case shows that headache can be an initial symptom of NMOSD and that clinicians should consider NMOSD when attempting to diagnose patients presenting with headaches.