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BackgroundEarly 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).ObjectiveThe current study aimed to clarify which specific EFT regimen is efficacious and the patient characteristics that confer sensitivity to EFT.MethodsWe 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.ResultsKaplan-Meier analyses showed that EFT had a significant effect on the achievement of MM5mg (pConclusionEarly 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.

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.

Hypercoagulability associated with malignant tumors causes thrombosis, termed Trousseau's syndrome, but is rarely associated with benign gynecological tumors, such as myoma and adenomyosis. We herein report a 47-year-old Japanese woman with uterine adenomyosis who developed multiple cerebral infarcts during menstruation. Edoxaban was initially used for prevention but failed to prevent recurrence of thrombosis. However, hysterectomy and bilateral salpingo-oophorectomy resulted in the successful prevention of recurrence of cerebral infarct for five years without antiplatelet or anticoagulant agents. In our patient, the surgical removal of adenomyosis was highly effective for preventing thrombosis in a patient with adenomyosis.

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.

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.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.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.From the early phases of immunotherapy, MSE is a good marker of therapeutic goal in patients with generalized MG.

Myasthenia gravis (MG) is an autoimmune disease with autoantibodies against the mainly nicotinic acetylcholine receptor (AChR). High mobility group box1 (HMGB1) acts as a danger signal and drives the pathogenesis of autoimmune-mediated diseases. However, the role of HMGB1 in the pathogenesis of MG is not fully understood. Therefore, in this study, we analyzed serum levels of HMGB1 and immunohistochemical HMGB1 staining of muscle tissues in the passive transfer MG model to investigate the role of HMGB1 in MG. As a result, serum HMGB1 levels tended to be higher and the quantitative score of muscle pathology showed greater HMGB1 deposition (P = 0.02) along with sparser AChR staining and more severe inflammation in the passive transfer MG rats (n = 6) than those in control rats (n = 6). These findings indicate that HMGB1 is an important mediator and biomarker for inflammation in the pathogenesis of MG and can be a therapeutic target in MG.

INTRODUCTION In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS MG patients showed a significantly greater MCD mean (MG: control, 26.3 μs; 13.5 μs [median]; P

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). 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. 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. 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.

ObjectiveTo 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.MethodsWe 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.ResultsThe 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).ConclusionsHigh 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.

OBJECTIVE To investigate changes in serum complements and their regulators in the pathogenesis of myasthenia gravis (MG). METHODS Forty-four patients with acetylcholine receptor antibody-positive MG, as well as 20 patients with non-inflammatory neurological disorders were enrolled. Serum complements (C3, C4 and soluble C5b-9) and complement regulators (vitronectin, clusterin and properdin) were extensively analysed by enzyme-linked immunosorbent assay and their associations with clinical profiles of MG were examined. RESULTS Serum C3, C4 and clusterin levels were not significantly different between patients with MG and controls. The patients with MG had higher soluble C5b-9 (P = 0.09) and vitronectin (P = 0.001) levels than the controls; moreover, vitronectin levels decreased after treatment (P = 0.09). Serum properdin (P = 0.03) levels were lower in the patients with MG than in the controls, and negatively correlated with the MG Activities of Daily Living score (rs = -0.26, P = 0.09) and with the presence of bulbar palsy (P = 0.04). CONCLUSION Our results show that activation of complements and an altered complement network could contribute to the inflammatory pathogenesis of MG.

Summary Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40 patients with anti-acetylcholine receptor antibody-positive MG and 30 controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ = 0·45; P = 0·004) and MG Foundation of America classification (Spearman's ρ = 0·37; P = 0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

ObjectivesCurrently, no established biomarkers exist for presymptomatic sporadic Creutzfeldt-Jakob disease (sCJD). The purpose of this study was to raise awareness about sCJD cases showing abnormalities on brain MRI diffusion-weighted imaging (DWI) before symptom onset and demonstrate temporal changes in DWI abnormalities during the preclinical period.MethodsWe described the clinical presentation including the results of MRI—performed multiple times in the preclinical period—and the diagnostic workup of a middle-aged man with sCJD.ResultsMRI of the brain performed 27 months before symptom onset revealed an extremely localized lesion on DWI in the right occipital cortex. Follow-up MRI scans showed propagation of DWI abnormalities along the cortices without the appearance of neurologic symptoms/signs. After symptom onset, the patient's neuropsychiatric condition rapidly deteriorated. Elevated total tau protein levels and positive 14-3-3 protein were observed in the CSF, and periodic synchronous discharges using electroencephalography resulted in the diagnosis of sCJD.DiscussionCJD should be considered in differential diagnoses when localized DWI signal abnormalities propagate along the cortices over time, even in the absence of typical CJD symptoms. DWI signal abnormalities on brain MRI scans may be highly sensitive diagnostic markers for CJD, even in the preclinical stage.

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.

Immune-mediated necrotizing myopathy (IMNM) is a pathologically defined diagnosis of idiopathic inflammatory myopathies. Adequate studies on cytokines of IMNM is lacking. We measured serum levels of 27 cytokines/chemokines in 22 IMNM patients, 10 sporadic inclusion body myositis (IBM) patients, and 23 other neurological disorders (ONDs) patients. In IMNM patients, the correlations between clinical features and cytokine/chemokine levels, and changes in cytokine/chemokine levels after immunosuppressive therapy were examined. Compared with ONDs patients, IMNM patients had significantly increased serum levels of several cytokines. In particular, IP-10 and MIP-1α levels were prominently increased, decreased after immunosuppressive-therapy, and correlated with serum creatine kinase levels. IP-10 and MIP-1α could play important roles in the IMNM pathogenesis.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

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).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.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.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.

Summary Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti-AChR antibody-positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti-AChR antibody-positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)-17; a Th17-related cytokine, IL-21 (a Tfh-related cytokine), the B-cell-activating factor (BAFF; a B cell-related cytokine) and a proliferation-inducing ligand (APRIL; a B cell-related cytokine) have been reported to be up-regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Abstarct Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. The neuromuscular junction damage associated with MG is caused by anti-acetylcholine receptor (AChR) antibody and complements. Recently, eculizumab (an anti-C5 monoclonal antibody) was approved for patients with anti-AChR antibody-positive generalized refractory MG. Here, we report a Japanese man with MG who well responded to eculizumab, but experienced acute severe worsening of myasthenic symptoms 2 months after its discontinuation. Plasmapheresis did not improve his symptoms; hence, eculizumab was re-administered, resulting in a dramatic response within a week. This is an informative case because eculizumab discontinuation in patients with MG has been very rarely reported. If eculizumab treatment is clinically well effective and AChR antibody titer does not decrease, clinicians should be aware that acute and critical deterioration of MG may occur after the eculizumab discontinuation.

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.

Complement-dependent disruption of motor endplate is detected in anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). We measured serum AChR α1 subunit protein levels, which may be associated with neuromuscular damage, in 55 patients with MG (47 were seropositive and 8 were negative) and in 20 controls. Serum AChR α1 subunit protein concentrations were higher in patients with anti-AChR antibody-positive MG than those in controls (P = .04), were negatively correlated with MG activities of daily living score (P = .01), and tended to be higher in ocular MG than in generalized MG. AChR α1 subunit protein elevation may be related to seropositive MG pathogenesis, especially in the ocular type.

BACKGROUND AND PURPOSE Thymectomy is an effective treatment for myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies. We rarely encounter patients who develop MG after surgery for thymic tumors. This study aimed to investigate the characteristics and frequency of post-thymectomy onset (PostTx) MG. METHODS We reviewed the clinical information of thymoma-associated MG in 158 patients. Of these, 18 (11%) patients with PostTx MG were identified. RESULTS The presence of anti-AChR antibodies (82%) and electrophysiological abnormalities (50%) was confirmed before thymectomy in patients with PostTx MG. The clinical characteristics of PostTx MG were similar to those of pre-thymectomy onset (PreTx) MG. In PostTx MG, the duration between thymectomy and MG onset were distributed as

High-dose intravenous methylprednisolone (IVMP) is often used as a treatment for generalized myasthenia gravis (MG); however, little is reported about the efficacy of IVMP in ocular MG. We evaluated the efficacy and safety of IVMP therapy and compared results with those of conventional oral prednisolone (PSL) treatment in ocular MG. We retrospectively studied 18 patients with ocular MG. Clinical course and safety during 6 months in 10 patients who were treated with IVMP were compared with those of 8 who were treated with PSL. IVMP (1000 mg/day) was administered one to three times within 6 months, whereas oral PSL was administered at the dose of 5–10 mg/day. The score for MG activities of daily living profile (MGADL) was assessed at baseline and at 1, 3, and 6 months after treatment. Patients who received IVMP showed faster improvements than those receiving PSL; the median changes in the ocular scores on the MGADL was −2 versus 0 at 1 month (p = 0.03), −3 versus −1 at 3 months (p = 0.07), and −3 versus −2 (p = 0.86) at 6 months. No patient in either group developed initial worsening of symptoms or generalized weakness. In conclusion, IVMP results in more rapid improvement than oral PSL therapy and can be a treatment option for ocular MG.