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.

Markedly upregulated serum semaphorin 4A as a novel activity marker of myasthenia gravis.

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. Semaphorin 4A (Sema4A) is involved in the activation of T cells in various inflammatory disorders. In this study, we aimed to investigate whether Sema4A is involved in the pathogenesis of MG. We measured serum Sema4A concentrations in 30 treatment-naïve MG patients with acetylcholine receptor (AChR) antibodies, 7 with muscle-specific tyrosine kinase (MuSK) antibodies and 21 normal controls. As a result, serum Sema4A levels were significantly higher in patients with AChR antibody-positive MG and MuSK antibody-positive MG than in controls (p ≤ 0.0001 for both MG groups). Serum Sema4A levels were correlated with AChR antibody levels (Spearman's ρ = 0.39, p = 0.03) and MG Foundation of America clinical classification classes (Spearman's ρ = 0.38, p = 0.04) in patients with AChR antibody-positive MG. In conclusion, high serum Sema4A levels may reflect T-cell activation, and this molecule could be a potential marker of disease activity in MG.

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.

Population-level prokaryotic community structures associated with ferromanganese nodules in the Clarion-Clipperton Zone (Pacific Ocean) revealed by 16S rRNA gene amplicon sequencing.

Although deep-sea ferromanganese nodules are a potential resource for exploitation, their formation mechanisms remain unclear. Several nodule-associated prokaryotic species have been identified by amplicon sequencing of 16S rRNA genes and are assumed to contribute to nodule formation. However, the recent development of amplicon sequence variant (ASV)-level monitoring revealed that closely related prokaryotic populations within an operational taxonomic unit often exhibit distinct ecological properties. Thus, conventional species-level monitoring might have overlooked nodule-specific populations when distinct populations of the same species were present in surrounding environments. Herein, we examined the prokaryotic community diversity of nodules and surrounding environments at the Clarion-Clipperton Zone in Japanese licensed areas by 16S rRNA gene amplicon sequencing with ASV-level resolution for three cruises from 2017 to 2019. Prokaryotic community composition and diversity were distinct by habitat type: nodule, nodule-surface mud, sediment, bottom water and water column. Most ASVs (~80%) were habitat-specific. We identified 178 nodule-associated ASVs and 41 ASVs associated with nodule-surface mud via linear discriminant effect size analysis. Moreover, several ASVs, such as members of SAR324 and Woeseia, were highly specific to nodules. These nodule-specific ASVs are promising targets for future investigation of the nodule formation process.

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.

Activation of the classical complement pathway in myasthenia gravis with acetylcholine receptor antibodies.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction (NMJ) of skeletal muscle. Complement activation is one of the mechanisms by which anti-acetylcholine receptor (anti-AChR) autoantibodies reduce synaptic transmission at the NMJ. In this study, we aimed to examine the activation of the complement pathways, including the classical pathway, as potential contributors to the pathogenesis of MG with anti-AChR antibodies. METHODS: In this single-center, observational study of 45 patients with anti-AChR-antibody-positive generalized MG, serum concentrations of major components of the complement pathways, including C1q, C5, C5a, soluble C5b-9 (sC5b-9), Ba, and complement factor H, were measured using an enzyme-linked immunosorbent assay. A total of 25 patients with a non-inflammatory neurological disorder served as controls. In addition, the relationships of complement activation with clinical characteristics were examined. RESULTS: The patients with MG exhibited lower serum levels of C5 (p = .0001) and higher serum levels of sC5b-9 (p = .004) compared with the control group. At about 6 months (range, 172-209 days) after the start of immunotherapy, serum levels of Ba were significantly higher than baseline levels (p = .002) and were associated with improvement in MG clinical scores. DISCUSSION: Herein, we provide evidence for the activation of the classical complement pathway and its association with disease activity in anti-AChR-antibody-positive generalized MG.

Serum cytokine profiles in myasthenia gravis with anti-muscle-specific kinase antibodies.

This study measured the serum levels of of 15 cytokines in 15 patients with anti-muscle-specific kinase antibody-positive MG (MuSK-MG) using a multiplex suspension array system. Fifteen patients with non-inflammatory neurological diseases served as controls. Compared with controls, patients with MuSK-MG showed higher levels of Th1- (IFN-γ), Th2- (IL-25, IL-31, and IL-33), Th17- (IL-22), Treg-related cytokines (IL-10), and soluble CD40 ligand (sCD40L). Higher serum Th2-related cytokines (IL-25 and IL-31) levels were correlated with less MG Foundation of America (MGFA) class. These suggest that Th2-related cytokines have protective effects, whereas sCD40L and others may facilitate the disease.

Effects of BL 23 (Shenshu) acupuncture on serum cytokine levels in healthy adults: A randomized double-blind sham-controlled phase 1 study.

The purpose of this study was to evaluate the safety and efficacy of BL 23 (Shenshu) acupuncture on serum cytokine levels. Sixteen healthy adults were randomized into the BL 23 acupuncture group or pseudo-acupuncture group and changes of serum cytokines were analyzed. The changes in IL-13, TNF-α, and GM-CSF levels were different between the BL 23 acupuncture group and pseudo-acupuncture group (P < 0.05). No adverse events associated with acupuncture were observed. In conclusion, BL 23 acupuncture can suppress immune responses via decreases in TNF-α and suppression of increases in IL-13 and GM-CSF. This study elucidated some of the mechanisms of the acupuncture effect.

Genetic population structures of common scavenging species near hydrothermal vents in the Okinawa Trough.

Deep-sea mining of hydrothermal deposits off the coast of Japan is currently under consideration, and environmental baseline studies of the area are required to understand possible impacts. The aim of this study is to clarify population structures of dominant benthic megafaunal species near hydrothermal vent fields in the Okinawa Trough, using a population genetics approach. We examined dominant deep-sea scavenging species including eels, several amphipods, and a decapod and performed population genetic analyses based on the mitochondrial cytochrome c oxidase subunit I region. Several sites were sampled within Okinawa Trough to examine intra-population diversity while two other locations 1400-2400 km away were chosen for inter-population comparisons. For synaphobranchid eels Simenchelys parasitica and Synaphobranchus kaupii, our results showed significant intra-population diversity but no inter-population genetic differentiation, suggesting strong genetic connectivity and/or large population sizes. In addition, single nucleotide polymorphism analysis also confirmed strong genetic connectivity for Simenchelys parasitica. Among scavenging amphipods, we detected seven putative species using molecular phylogenetic analysis. We evaluated population structures of the most abundant species of amphipods and a decapod species (Nematocarcinus lanceopes). Our results provide basic information on the genetic population structures of benthic megafaunal species near hydrothermal vent fields, which can be used to select candidate species for future connectivity analysis with high-resolution genetic markers and aid understanding of the potential population impacts of environmental disturbances.

Minimal symptom expression achievement over time in generalized myasthenia gravis.

OBJECTIVES: Minimal symptom expression (MSE), defined as myasthenia gravis (MG) activities of daily living profile (MGADL) score 0 or 1, has been recently used as an indicator of treatment goal in MG. However, no study has determined when MSE is achieved. The current study aimed to investigate the timing and incidence of MSE achievement in generalized MG patients. METHODS: Eighty-five patients with acetylcholine receptor antibody-positive generalized MG were included. They were followed-up maximum 3 years after starting immunotherapy, and we reviewed the MGADL score, prednisolone dose, and achievement of MSE and minimal manifestations (MM) or better status. RESULTS: MSE was achieved in 37.6, 45.2, 55.8, 60.3, and 57.1% of the patients at 3, 6, 12, 24, and 36 months after treatment, respectively. Most patients who achieved MSE showed MM or better status at any phase. In addition, more than 2 years after the starting treatment, about 80% of patients who achieved MSE showed MM or better status with an oral prednisolone dose of 5 mg/day or less (MM-5 mg). Noteworthy, during the early stage of treatment, the proportion of patients who achieved MSE was higher than that who achieved MM-5 mg. CONCLUSION: From the early phases of immunotherapy, MSE is a good marker of therapeutic goal in patients with generalized MG.

Role of soluble forms of follicular helper T-cell membrane molecules in the pathogenesis of myasthenia gravis.

This study examined the role of Tfh and Treg associated molecules also known as checkpoint molecules, their ligands, and IL-21 in myasthenia gravis (MG) pathogenesis. Serum levels of sPD-1, sPD-L1, sICOS, sICOSLG, sCTLA4, and IL-21 were measured in 39 patients with acetylcholine receptor (AChR) antibody-positive generalized MG and 27 controls. sPD-1 and IL-21 levels were higher in MG patients than in controls. Additionally, sPD-1 levels correlated positively with the levels of IL-21, sICOSLG, sCTLA4, and AChR antibody titers. sICOS are correlated with MGADL and AChR antibody titers. These Tfh associated molecules could be used as biomarkers of MG disease activity.

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.

Serum pentraxin 3 concentration correlates with disease severity in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is an antibody-mediated inflammatory disease affecting post-synaptic membranes of neuromuscular junctions, and objective biomarkers of MG disease activity are lacking. Pentraxin 3 (PTX3) is an acute-phase inflammatory glycoprotein in the same family as C-reactive protein that is associated with disease activity in several autoimmune disorders. Thus, we investigated whether circulating PTX3 is a useful biomarker of MG activity. METHODS: Serum PTX3 was measured in 40 patients with MG who were positive for anti-acetylcholine receptor antibody, and in 30 healthy and disease controls, using a commercial enzyme-linked immunosorbent assay kit. In patients with MG, the correlation of serum PTX3 levels with disease severity scales at serum sampling, including MG Foundation of America (MGFA) classification, MG activity of daily living (MG-ADL) score, and quantitative MG (QMG) score, were investigated. RESULTS: Although there was no significant difference in serum PTX3 between the MG and control groups (mean, 3346 pg/mL in MG group vs. 2870 pg/mL in control group, P = 0.56), serum PTX3 moderately correlated with all disease severity scores (MGFA classification: Spearman's ρ = 0.53, P = 0.0004; MG-ADL score: Spearman's ρ = 0.45, P = 0.004; QMG score: Spearman's ρ = 0.50, P = 0.004). CONCLUSION: Our results suggest that circulating PTX3 may reflect the extent of neuromuscular junction damage and might be involved in the pathogenesis of MG.

Immunoadsorption apheresis versus intravenous immunoglobulin therapy for exacerbation of myasthenia gravis.

Immunoadsorption apheresis (IA) or intravenous immunoglobulin (IVIg) is used to treat exacerbation of myasthenia gravis (MG). This study aimed to compare the efficacy and safety between IA and IVIg for MG patients with anti-acetylcholine receptor (AChR) antibodies. We retrospectively studied 19 AChR antibody-positive generalized MG patients who underwent IA (n = 9) or IVIg treatment (n = 10). We reviewed the MG activities of daily living profile (MG-ADL) scores at baseline, 1 and 3 months after the treatment. Adverse events during the treatment period were also reviewed. The MG-ADL scores showed significantly greater improvement from the baseline in the IA group than in the IVIg group (1 month: -7 vs -3, P = .035; 3 months -9 vs -2.5, P = .016). An adverse event that led to the discontinuation of the treatment was observed in only one patient in the IVIg group (anaphylactic reaction). Our data suggest that the IA treatment is safe and more efficacious than the IVIg treatment for aggravation of anti-AChR-positive MG. Larger prospective studies are required to confirm the finding.

High levels of serum interleukin-6 are associated with disease activity in myasthenia gravis.

Myasthenia gravis (MG), a neuromuscular junction disorder, is caused by pathogenic autoantibodies. Interleukin-6 (IL-6) plays important roles in T helper 17 (Th17), T follicular helper (Tfh), and B cell activations as well as in antibody production. This study aimed to evaluate the clinical significance of serum IL-6 level as a biomarker of disease activity in patients with anti-acetylcholine receptor (AChR) antibody-positive MG. In the present study, serum IL-6 levels were measured in 93 treatment-naïve patients with anti-AChR antibody-positive MG and compared with those in 101 controls. Moreover, correlations between serum IL-6 levels and clinical characteristics were analyzed. Serum IL-6 levels were significantly higher in patients with anti-AChR antibody-positive MG than in controls (median [interquartile range], 2.5 [1.5-8.3] pg/mL vs. 1.5 [1.5-3.2] pg/mL, P < 0.001). The serum levels were correlated with the MG Foundation of America clinical classification (Spearman's ρ = 0.27; P < 0.01) and decreased following immunosuppressive treatment in parallel with disease activity (P = 0.01). In conclusion, IL-6 is involved in the pathogenesis of anti-AChR antibody-positive MG and could be a therapeutic target in MG.

Marked Respiratory Failure in an Ambulant Patient with Immune-mediated Necrotizing Myopathy and Anti-Kv1.4 and Anti-titin Antibodies.

We herein report a case of seronegative immune-mediated necrotizing myopathy (IMNM) concurrent with anti-Kv1.4 and anti-titin antibodies. A 72-year-old Japanese woman presented with a 29-year history of fluctuating high serum creatine kinase (CK) levels followed by intermittent ptosis and respiratory muscle weakness. This case highlights the fact that marked respiratory muscle weakness requiring intubation can be seen in an ambulant patient with IMNM. Marked respiratory muscle weakness, rhabdomyolysis-like acute elevation of CK levels, and anti-striational muscle antibodies may be a characteristic constellation of findings in a distinct subgroup of patients with inflammatory myopathy with myasthenia gravis or similar symptoms.

Long-term outcomes and prognostic factors in generalized myasthenia gravis.

OBJECTIVE: This study aimed to investigate the timing of meeting the criteria for a status of "minimal manifestation (MM) or better" and the factors that influenced whether "MM or better status" or "MM or better status with an oral prednisolone (PSL) dose of 5 mg/day or less (5-mg MM)" was met in patients with acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (MG). METHODS: We performed a retrospective study in 93 patients with AChR antibody-positive generalized MG who were followed for 3 years after the start of immunotherapy. We reviewed clinical data, such as MG-related symptoms, the MG activities of daily living profile (MGADL) score, immunotherapy including the dose of PSL, and achievement of the status of MM or better at baseline and 3, 6, 12, 24, and 36 months after treatment. RESULTS: An MM or better status was achieved in 60% of the patients 3 months and in 90% of the patients 2 years after initiating immunotherapy. At 2 years, 60% of the patients had achieved the treatment goal, which was an "5-mg MM". More frequent plasmapheresis and higher dose of PSL within 3 months after immunotherapy initiation were associated with difficulty in achieving the 5-mg MM status at 2 years. CONCLUSION: Approximately 60% of the MG patients achieved the treatment goal within 2 years after treatment. PSL dose and the cumulative number of plasmapheresis procedures at 3 months after immunotherapy initiation may help identify treatment-resistant patients with MG.

Rate of change in acetylcholine receptor antibody levels predicts myasthenia gravis outcome.

OBJECTIVE: To investigate the association between changes in anti-acetylcholine receptor antibody (AChR Ab) levels induced by immunosuppressive treatment and myasthenia gravis (MG) prognosis at 1-year post-treatment in patients with MG. METHODS: We included 53 consecutive AChR Ab-positive patients with MG whose AChR Ab levels were remeasured within 100 days of initiating immunosuppressive treatment (median remeasuring time post-treatment: 71 (55-84) days). The AChR Ab level reduction rate (RR-AChRAb, %/day) adjusted for the time between treatment initiation, and AChR Ab level remeasurement was calculated as follows: (pretreatment-post-treatment AChR Ab level)/pretreatment AChR Ab level/days between therapy initiation and AChR Ab level remeasurement ×100. Participants were divided into two groups based on the cut-off value of RR-AChR Ab, determined using receiver operating characteristic analyses for achieving minimal manifestation (MM) or better status at 1-year postimmunosuppressive treatment. The Myasthenia Gravis Foundation of America postintervention status and MG activity of daily living (MG-ADL) score at 1-year post-treatment were compared between the two groups. RESULTS: The RR-AChRAb cut-off value was 0.64%/day. The high RR-AChRAb group had a higher ratio of MM or better status (90% vs 65%, p=0.03) and lower MG-ADL score (median; 1 vs 2, p=0.04) than the low RR-AChRAb group. Kaplan-Meier analyses showed the early MM achievement in the high RR-AChRAb group (p=0.002, log-rank test). CONCLUSIONS: High RR-AChRAb is associated with a favourable outcome at 1-year post-treatment. AChR Ab remeasurement within 100 days of therapy may be useful for predicting AChR Ab-positive MG outcomes at 1-year post-treatment.