Muscle-specific Tyrosine Kinase Research Articles

Coexistence Of Anti-Musk-Positive Bulbar Myasthenia Gravis And Myotonic Dystrophy Type 1: The First Case Report from Turkey

Muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG) is an acute-onset subtype of MG that primarily affects the fasciobulbar muscles and begins with progressive velopharyngeal and respiratory symptoms such as early respiratory crises, swallowing, and speaking difficulties. Myotonic dystrophy Type 1 (DM1) is an autosomal dominantly inherited autoimmune neuromuscular disease characterized by distal-dominant muscle weakness, cardiovascular pathologies, and corneal disorders. In this case report, we discussed 42-year-old female patient with a previous diagnosis of DM1, and diagnosed with MuSK-MG as a result of electroneuromyographic and antibody tests upon the development of bulbar symptoms and thymus hyperplasia. The patient underwent video-assisted thymectomy, and medical treatment was started with a combination of pyridostigmine and methylprednisolone. The coexistence of anti-MuSK positive MG with thymoid hyperplasia and DM 1 has not been reported so far, and it has been predicted that both diseases may trigger each other through neuroinflammatory mechanisms on an autoimmunergic basis.

MuSK Myasthenia Gravis-Potential Pathomechanisms and Treatment Directed against Specific Targets.

Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies target structures within the neuromuscular junction, affecting neuromuscular transmission. Muscle-specific tyrosine kinase receptor-associated MG (MuSK-MG) is a rare, often more severe, subtype of the disease with different pathogenesis and specific clinical features. It is characterized by a more severe clinical course, more frequent complications, and often inadequate response to treatment. Here, we review the current state of knowledge about potential pathomechanisms of the MuSK-MG and their therapeutic implications as well as ongoing research in this field, with reference to key points of immune-mediated processes involved in the background of myasthenia gravis.

Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

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.

Efgartigimod in generalized myasthenia gravis: A real-life experience at a national reference center.

Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening). Eight patients were positive for acetylcholine receptor antibody, four for muscle-specific tyrosine kinase antibody, and two for lipoprotein-related protein 4 antibody, and five were classified as triple negative. Efficacy of EFG was assessed by the Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Composite, and Quantitative Myasthenia Gravis scales. Fifty-three percent of patients needed three treatment cycles, 26% needed four, and 21% needed five along the 14-month clinical follow-up. Meaningful improvement was observed at the end of each cycle with the clinical scores adopted. EFG had a dramatic effect on disease course, as during the year before treatment eight of 19 patients (42%) were hospitalized, and 15 of 19 (79%) needed treatment with plasma exchange or immunoglobulins; three of 19 (16%) were admitted to the intensive care unit. During EFG, none of the patients was hospitalized and only one patient required plasma exchange and intravenous immunoglobulins. No major side effects or infusion-related reactions occurred. We observed that EFG was safe and modified significantly the course of the disease along a 14-month follow-up. Our experience strengthens the role of FcRn inhibition as an effective new tool for long-term treatment of gMG.

Exploring the depths of IgG4: insights into autoimmunity and novel treatments.

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

Independent risk factors for in-hospital outcome of myasthenic crisis: a prospective cohort study.

Myasthenic crisis (MC) is a life-threatening condition for myasthenia gravis (MG). Therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) efficaciously treat patients with MC. However, not every MC responds well to rescue therapies, and the determinants for outcome with the evidence from prospective cohorts are still lacking. To explore the risk factors for in-hospital outcomes in patients with MC. Using a national neuromuscular center-based cohort of MG with prospective follow-ups from the crisis to the post-crisis phase, we finally included 90 MC episodes from 76 independent patients who received a standard regimen of rescue therapies. The mean admission age was 52.89 ± 15.72 years. With a female predominance of 63.16% (48/76) and a high proportion of thymoma-associated MG (TMG) of 63.16% (48/76), the overall in-hospital mortality was 2.63% (2/76) and the average duration for mechanical ventilation (MV) use was 17.09 ± 13.36 days (0-53 days). In contrast to the patients with anti-acetylcholine receptor (AChR) antibodies, muscle-specific tyrosine kinase (MuSK)-associated MC exhibited a shorter MV support (5.20 ± 5.07 versus 17.40 ± 13.24 days, p = 0.023), length of intensive care units (ICU) stay (6.00 ± 4.64 versus 19.16 ± 17.54 days, p = 0.046), and hospital stay (16.00 ± 4.12 versus 34.43 ± 20.48 days, p = 0.011). Thymoma [odds ratio (OR): 0.200, 95% confidence interval (CI): 0.058-0.687, p = 0.011], partial pressure of carbon dioxide (PCO2) in blood gas before MV (OR: 1.238, 95% CI: 1.015-1.510, p = 0.035), and pneumonia (OR: 0.204, 95% CI: 0.049-0.841, p = 0.028) were identified as independent risk factors for prolonged MV use. TMG patients with thymoma burden exhibited a notable longer MV use (22.08 ± 17.54 versus 8.88 ± 6.79 days, p = 0.001), a prolonged hospital stay (40.40 ± 26.13 versus 23.67 ± 13.83 days, p = 0.009) compared with non-TMG. Even with complete thymoma resection (R0), TMG exhibited an unfavorable outcome versus non-TMG. With timely rescue therapies and prospective follow-ups, the in-hospital outcome of MCs was substantially improved. Thymoma, PCO2 in blood gas before MV, and pneumonia were identified as independent risk factors for prolonged MV use.

Triple-seronegative myasthenia gravis: clinical and epidemiological characteristics.

Myasthenia gravis (MG) is an autoimmune disease usually caused by antibodies against the acetylcholine receptor (AChR-Abs), muscle-specific tyrosine kinase (MuSK-Abs), or low-density lipoprotein receptor-related protein 4 (LRP4-Abs). However, there are MG patients who do not have these antibodies and are thus said to have triple-seronegative (triple-SN) MG. This study aims to describe the frequency and clinical and epidemiological characteristics of patients with triple-SN MG. This was a retrospective cross-sectional study carried out through the analysis of medical records. Descriptive and analytical statistical analysis was performed comparing subgroups of myasthenic patients, classified according to serological profile. The sample population consisted of 93 MG patients: 85 were positive for antibodies, 80 (86%) with AChR-Abs, 5 (5.4%) with MuSK-Abs, and no MG patients with LRP4-Abs. Eight patients (8.6%) had triple-SN MG; they had a median age at disease onset of 30 years (21-45). Their most common initial symptoms were ptosis, diplopia, and generalized weakness. Most patients presented with mild symptoms at their last visit, reflecting a median MG composite scale score of 4 (0-6), and 75% of patients had an adequate response to treatment. Our study showed a low frequency of triple-SN MG in Brazilian MG patients. Triple-SN MG was predominant in females, who presented with ptosis, diplopia, and generalized weakness, and most patients had an adequate response to immunosuppressive treatment. There was no significant difference between triple-SN MG and the other subgroups.

Rituximab as a sole steroid-sparing agent in generalized myasthenia gravis: Long-term outcomes.

Rituximab, a B-cell depleting monoclonal antibody, represents an option for the treatment of refractory myasthenia gravis (MG). Its use is more established in muscle-specific tyrosine kinase positive (MuSK +) patients, while its role in managing acetylcholine receptor positive (AChR +), or double seronegative (DSN) patients, remains less clear. This study evaluates the long-term effectiveness and safety of rituximab in MG of various serotypes. We conducted an open-label study of MG patients receiving rituximab. Adults with generalized refractory MG, either anti-AChR + or DSN, and anti-MuSK + , refractory or not, who had follow-up > 12months were selected. Change in quantitative myasthenia gravis (QMG) score at last follow-up, compared with baseline was a primary outcome, as well as factors affecting response to treatment. Secondary outcomes included, long-term safety, the steroid-sparing effect and relapse rates post-rituximab. Thirty patients (16 anti-AChR + , 6 anti-MuSK + , 8 DSN) followed for a mean of 33.3months were included. Mean scores pre-rituximab compared to last follow-up significantly decreased (p < 0.001), from 11 ± 4.1 to 4.3 ± 3.8, and from 1.9 to 0.3 regarding QMG and relapse rate per patient/year, respectively, while in 93.1% a daily steroid dose ≤ 10mg was achieved. Antibody status was the only factor independently influencing several endpoints. Throughout the study period no crises or deaths occurred. The present study supports that rituximab is an effective and well tolerated treatment for refractory anti-AChR + and DSN MG patients, while anti-MuSK + remains the group experiencing the greater benefits.

MuSK-CAART: A novel precision cellular therapy for muscle-specific tyrosine kinase myasthenia gravis

Chimeric autoantibody receptor (CAAR) T cells are a novel genetically-engineered T cell immunotherapy that aims to durably eliminate antigen-specific B cells while sparing healthy B cells, ideally leading to safe and lasting remission of B cell-mediated autoimmune diseases with a one-time infusion. We describe the preclinical development of muscle-specific tyrosine kinase CAAR T cells (MuSK-CAART) for the treatment of MuSK myasthenia gravis, a debilitating autoantibody-mediated disease that causes potentially life-threatening muscle weakness.

A novel MUSK mutation in a patient with CMS9

Congenital myasthenic syndromes (CMS) are a relatively rare cause of fatigable muscle weakness often with significant ocular, bulbar and respiratory impairment1. Mutations in the gene encoding muscle specific tyrosine kinase (MuSK) can lead to abnormal endplate and acetylcholine receptor functioning and cause an autosomal recessive post-synaptic CMS (CMS9). Only 23 patients with CMS9 have been characterized in the literature since the initial description in 20042. Here, we report a newly diagnosed case of CMS9 in a 23-year-old female who harbored a novel c.296G&gt;T (Cys99Phe) mutation in the MUSK gene, thereby expanding the phenotypic/genotypic characterization of this rare disorder.

Pregnancy in MuSK-positive myasthenia gravis: A single-center case series.

Myasthenia gravis (MG) with muscle-specific tyrosine kinase (MuSK) antibodies (MMG) is predominantly seen in women of childbearing age. Our objective in this study was to describe the course of MMG during pregnancy and within 6 months postpartum, and to document any effect on fetal health. A retrospective review was performed of medical records of patients with MMG seen in the Duke Myasthenia Gravis Clinic from 2003 to 2022. MMG patients with onset of MMG symptoms before or during pregnancy as well as within 6 months postpartum were reviewed. A total of 14 pregnancies in 10 patients were included in our study cohort. Initial MG symptoms developed during pregnancy or within 6 months postpartum in six patients. Four patients had two pregnancies, three of whom developed MG during their first pregnancy. In the patients diagnosed before pregnancy, MG symptoms increased in five of eight patients during pregnancy or postpartum. Four patients required rescue therapy with plasma exchange or intravenous immunoglobulin during pregnancy or postpartum. One patient had a cesarean section after prolonged labor due to failure of progression. There were no other complications of pregnancy or delivery, and all infants were healthy at delivery. As in non-MuSK MG, women with MMG may also have worsening or may develop initial MG symptoms during pregnancy or within 6 months postpartum. More aggressive medical therapy may be required for pregnant patients with MMG. Further study is needed to identify the mechanism and risk of worsening of MMG during pregnancy or postpartum.

Myasthenia in adults, children, and adolescents: what's new?

Therapy of myasthenia gravis (MG) is increasingly oriented to the patient's antibody status. In addition to symptomatic therapy, steroids, classic long-term immunosuppressive therapies and thymectomy are regularly used. In recent years, new therapeutic approaches have been developed that particularly benefit acetylcholine receptor (AChR) antibody (Abs) positive patients with highly active disease. While the C5 complement inhibitor eculizumab was reserved for treatment-refractory generalized courses of AChR-Abs positive MG, two new drugs, the neonatal Fc receptor inhibitor efgartigimod and the more advanced C5 complement inhibitor ravulizumab, have recently been approved as add-on therapy for AChR-Abs positive generalized MG (gMG). In highly active courses of MG with Abs against the muscle-specific receptor tyrosine kinase (MuSK), the use of rituximab should be considered early in the course of the disease. The efficacy of the new drugs in children and adolescents with juvenile MG (JMG) is currently being tested in clinical trials. The new guideline recommends the use of modern immunomodulators based on astep-by-step approach depending on disease activity. With the German Myasthenia Register (MyaReg), the changing therapeutic landscape and quality of life of patients with myasthenic syndromes can be assessed, thus providing real-world data on the care of MG patients. Despite treatment based on the previous guideline, many MG patients suffer considerable impairment to their quality of life. With the new immunomodulators, there is the possibility of early intensified immunotherapy, which, in contrast to long-term immunosuppressants, can lead to arapid improvement in the course of the disease.

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.

Ocular Myasthenia Gravis: A Current Overview.

Ocular myasthenia gravis (OMG) is a neuromuscular disease characterized by autoantibody production against post-synaptic proteins in the neuromuscular junction. The pathophysiological auto-immune mechanisms of myasthenia are diverse, and this is governed primarily by the type of autoantibody production. The diagnosis of OMG relies mainly on clinical assessment, the use of serological antibody assays for acetylcholine receptors (AchR), muscle-specific tyrosine kinase (MusK), and low-density lipoprotein 4 (LPR4). Other autoantibodies against post-synaptic proteins, such as cortactin and agrin, have been detected; however, their diagnostic value and pathogenic effect are not yet clearly defined. Clinical tests such as the ice test and electrophysiologic tests, particularly single-fiber electromyography, have a valuable role in diagnosis. The treatment of OMG is primarily through cholinesterase inhibitors (pyridostigmine), and steroids are frequently required in cases of ophthalmoplegia. Other immunosuppressive therapies include antimetabolites (azathioprine, mycophenolate mofetil, methotrexate) and biological agents such as B-cell depleting agents (Rituximab) and complement inhibitors (eculizumab). Evidence is scarce on the effect of immunosuppressive therapy on altering the natural course of OMG. Clinicians must be vigilant of a myasthenic syndrome in patients using immune-check inhibitors. Reliable and consistent biomarkers are required to assess disease severity and response to therapy to optimize the management of OMG. The purpose of this review is to summarize the current trends and the latest developments in diagnosing and treating OMG.

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells.

Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

Development and Application of a Cell-Based Assay for LRP4 Antibody Associated With Myasthenia Gravis

Among patients with double-seronegative myasthenia gravis (dSN-MG) who do not have detectable antibodies against acetylcholine receptor or muscle-specific tyrosine kinase, autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4-Ab) have been detected recently. The purpose of this study was to develop an in-house cell-based assay (CBA) to detect LRP4-Ab and to apply it to samples from patients with MG. The complementary DNA of LRP4 fused into a vector plasmid containing GFP was transfected into human embryonic kidney 293 (HEK293) cells. LRP4 expression in the transfected HEK293 cells was assessed using the reverse-transcription polymerase chain reaction (RT-PCR), Western blotting, and immunocytochemistry. The CBA included 252 sera collected from 202 patients with MG and 38 with other neuromuscular diseases, and 12 healthy controls. The transfected HEK293 cells were incubated using sera and antihuman immunoglobulin G antibodies conjugated with Alexa Fluor 594. The presence of LRP4-Ab was determined based on the fluorescence intensity and the localization in fluorescence microscopy. The expressions of the mRNA and protein of LRP4 in the transfected HEK293 cells were confirmed using RT-PCR and Western blotting, respectively. Immunocytochemistry indicated LPR4 expression on the cell membrane. Among 202 patients with MG including 53 with dSN-MG, LRP4-Ab were positive in 3 patients who were all double seronegative. LRP4-Ab were not detected in the patients with other neuromuscular diseases or the healthy controls. A CBA for detecting LRP4-Ab associated with MG has been developed, and was used to find LRP4-Ab in the sera of patients with MG.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Plasma Myokine Profiles in Patients With AChR- and MuSK-Ab-Positive Myasthenia Gravis.

Myokines include cytokines secreted by muscle fibers, which are the final targets of myasthenia gravis (MG). This pilot study investigated whether myokine plasma concentrations are altered in patients with MG and assessed the association between the concentration of each myokine and disease severity. We compared the plasma concentrations of 15 myokines in 63 patients with acetylcholine receptor antibody (Ab)-positive MG and 14 with muscle-specific tyrosine kinase Ab-positive MG (MuSK MG) with those in 15 healthy controls. Plasma myokine concentrations were measured using a Luminex multiplex assay kit with magnetic beads that contained Abs for 15 myokines. Correlations between myokine concentration and clinical scale results were analyzed. The concentration of fractalkine in plasma was higher in MG (median [interquartile range]=419.6 [38.7-732.5] pg/mL) than in controls (158.5 [0.0-313.2] pg/mL, p=0.034). The leukemia inhibitory factor concentration was also found to be higher in MuSK MG (29.9 [8.7-40.1] pg/mL) than in healthy controls (7.6 [0.0-15.6] pg/mL, p=0.013). Fatty-acid-binding protein 3 (FABP3) concentrations in plasma were positively associated with clinical parameters for MG severity, including scores on the Quantitative Myasthenia Gravis score (p=0.008), Myasthenia Gravis Activities of Daily Living (p=0.003), and Myasthenia Gravis Composite (p=0.024) scales. FABP3 concentration in plasma tended to decrease after treatment in patients without additional relapse but increased in those with further relapse. The plasma myokine profile was significantly altered in patients with MG. FABP3 concentration may be useful in assessing disease severity and predicting the treatment response.

Serum Autoantibody Lowering by the Anti-FcRn Monoclonal Antibody, Nipocalimab, Correlates With Clinical Improvement in Generalized Myasthenia Gravis Patients

Objective To evaluate the relationship between clinical improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores and the pharmacodynamic effects of IgG autoantibody lowering induced by nipocalimab in the Vivacity MG Phase 2 study. Background Nipocalimab is a fully human, aglycosylated, effectorless IgG1 anti-FcRn monoclonal antibody that targets the neonatal Fc receptor (FcRn) with high affinity, thereby lowering IgG pathogenic antibodies in autoimmune disease. Design/Methods The relationship between the reduction in acetylcholine-receptor (AChR)- and Muscle-Specific-Tyrosine-Kinase (MuSK)- autoantibodies with improvement in MG-ADL scores were explored across the four nipocalimab dose arms in the Vivacity MG Phase 2 Study in generalized myasthenia gravis (gMG) patients. Results Of the 68 patients enrolled, 54 were randomized to one of the four nipocalimab dosing arms. 51 (94%) were seropositive for anti-AChR, 3 (6%) for anti-MuSK. Nipocalimab was well-tolerated and achieved substantial, dose-dependent and rapid reductions in serum total IgG, including all IgG subtypes and anti-AChR autoantibodies. These reductions were associated with dose-dependent, durable and rapid MG-ADL responses in all nipocalimab-treated groups. A similar trend in IgG4 reduction was noted, though the sample size of MuSK positive patients was small. Conclusions The results support the rapid, dose-dependent and predictable effect of nipocalimab in lowering pathogenic autoantibodies and inducing clinical improvement in patients with gMG. In addition, the close correlation between serum IgG, anti-AChR and clinical response suggest the potential of using serial serum IgG levels as a biomarker in management of gMG patients treated with nipocalimab; this will be tested in the ongoing Phase 3 gMG trial.