Treatment Of Myasthenia Gravis Research Articles

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.

Symptomatic, pharmacological treatment of myasthenia gravis.

Symptomatic, pharmacological treatment of myasthenia gravis.

Congenital myasthenic syndromes: beta adrenergic receptor agonist treatment

Acetylcholinesterase inhibitors, such as pyridostigmine, are the standard symptomatic treatment for myasthenia gravis, and so have naturally been applied to the genetic forms of myasthenia, termed congenital myasthenic syndromes (CMS). Although effective for many CMS in others there was no clear response and in some it was positively harmful. Now, with greater understanding of the mutations and molecular mechanisms underlying CMS, treatments can be tailored for the specific syndrome and depending on diseases severity and patient response this can include utilizing different combinations of the drugs. In CMS, over the last 15-20 years b2-adrenergic receptor agonists have moved from occasional use to a mainstream medication. Many cases show life-transforming improvement both when the b2-adrenergic receptor agonists are used alone or in combination. Here we feature how the identification of DOK7-CMS first highlighted the consistent benefit of b2-adrenergic receptor agonists as medication and how it’s application to many different CMS subtypes evolved. The molecular pathogenic mechanisms for many CMS subtypes are now established and this report will also discuss a hypothetical rationale for which forms of CMS are likely to benefit from the b2-adrenergic receptor agonists.

Promising Antigen-specific Immunotherapy for the Treatment of Myasthenia Gravis

Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated, autoimmune disorder with well-established antigenic targets at the neuromuscular junction. MG autoantibodies mainly target the nicotinic acetylcholine receptor (AChR) and especially epitopes located in the extracellular domain of the α1 subunit (α1-ECD). Today, most therapeutic regimens for MG are non-specific and not curative, requiring chronic treatments that are associated with significant side effects. We aim to develop an antigen-specific therapeutic approach, based on reestablishing tolerance towards the AChR, the dominant autoantigen in MG. To this end, we used a soluble mutated form of the human α1-ECD, which incorporates a major fraction of MG autoreactive T cell epitopes and examined the therapeutic efficiency of intravenous administration in a rat experimental autoimmune MG model. We found that repeated intravenous administration of α1-ECD for up to 12 days led to a robust amelioration of disease symptoms in a dose and time-dependent manner. The observed therapeutic effect of α1-ECD was significantly better than the effect of two current mainstay drugs for MG treatment. There were no signs of toxicity in α1-ECD-treated animals and further studies are underway to fully elucidate the immunological mechanism underlying the treatment effect. Taken together, our preclinical data strongly suggest that intravenous administration of α1-ECD may represent an efficacious and safe strategy to treat MG and thus α1-ECD represents a new drug candidate for clinical application in MG.

Complement inhibition in Myasthenia – from basics to RCT data

Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder causing fatiguable muscle weakness either limited to the ocular muscles or becoming generalised involving the limb and bulbar muscles. Nine out of 10 generalised MG patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). AChR antibodies cause neuromuscular weakness by internalisation of AChR, receptor blockade and by activating the complement pathway. Complement activation causes formation of the membrane attack complex (MAC) leading to degradation of the neuromuscular junction (NMJ). Several animal models have confirmed the role of complement in the pathogenesis of MG, with the experimental models (EAMG) often needing complement inhibitory therapies to prevent or reverse the disease. Various molecules that target the complement system have now been developed to treat myasthenia gravis. The vast majority of the currently studied molecules target the C5 protein, thereby preventing the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include Eculizumab, Zilucoplan, Ravulizumab, Pozelimab, Cemdisiran, Gefurilimab, Danicopan and few others in the pipeline. Eculizumab has been shown in clinical trials to be effective in the treatment of refractory MG, but further sub-group analysis and real-life experience have shown that this can be beneficial in various patients including those receiving regular IVIG, plasma exchange or Rituximab. It was approved for use by FDA in Oct 2017. Ravulizumab is a long-acting monoclonal antibody which has similar mechanism of action to Eculizumab and was approved for use in MG by FDA in April 2022. Zilucoplan is a macrocyclic peptide which binds to C5 and C5b thus preventing terminal complement activation, which can be given subcutaneously (FDA new drug application accepted in Nov 2022). Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Patients would need to be vaccinated against Neisseria meningitidis because of the risk of Gram-negative septicaemia, although no major safety signatures have been noted in the studies so far. Future studies may be able to identify specific biomarkers which might aid in selecting the most appropriate patients who might respond to these therapies.

Myasthenia gravis treatment in the elderly presents with a significant iatrogenic risk: a multicentric retrospective study.

Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. We retrospectively analysed the files of all MG patients with disease onset after age 70years in four French University Hospitals, including clinical, electrophysiological, biological, and treatment data, with an emphasis on TAE. MG outcomes were assessed using the Myasthenia Gravis Foundation of America (MGFA) status scale. We included 138 patients (59% of men) with a mean follow-up of 4.5years (range 1-19). Mean age at diagnosis was 78years (70-93). Anti-acetylcholine receptor antibodies were found in 87% of cases, electrophysiological abnormalities in 82%, and thymoma in 10%. MG outcome was good in a majority of cases, with 76% of treated patients presenting with alleviated symptoms at follow-up. TAE were observed in 41% of patients, including severe TAE in 14% of cases. Seven patients (5.1%) died, including four (2.9%) from MG-related respiratory failure, and three (2.2%) from MG treatment-related complications, i.e., sepsis in 2 cases and brain toxoplasmosis in 1 case. TAE were observed in 53% of patients treated with azathioprine, 23% of patients treated with corticosteroids, and 15% of patients treated with mycophenolate mofetil. This retrospective study demonstrates MG in the elderly presents with a significant iatrogenic risk, including fatal immunosuppressant-related infections.

Measuring the Efficacy of Thymectomy for Pediatric Myasthenia Gravis Across Tertiary Children's Hospitals

BackgroundThymectomy is a treatment for pediatric myasthenia gravis, but the efficacy over time is unknown. Multi-institutional data are also lacking. Therefore, the objective of this study was to determine the efficacy of thymectomy for pediatric myasthenia gravis using medication burden and health care utilization as proxies for disease severity. MethodsThis was a cross-sectional study of the Pediatric Health Information System database among children who underwent thymectomy at one of 49 children's hospitals from 2004 to 2022. Differences in annual median number of doses of myasthenia-related medications, admissions, and health care costs in the year before thymectomy to three years after were compared. A comparison cohort that did not undergo thymectomy was utilized. Medians were compared using the Wilcoxon signed-rank test. Generalized linear regression estimated the effect of surgical approach on outcomes. ResultsA total of451 patients (238 patients who underwent thymectomy and 213 nonthymectomy patients) were identified. Following thymectomy, the decrease in annual median total number of myasthenia-related doses was 12.0 (interquartile range: 6 to 31) (P < 0.001). The decrease in number of annual admissions was 2.0 (1 to 4) (P < 0.001), which represented a cost difference of $5292 ($3533 to $8681) (P < 0.001). No differences were observed in the control cohort. In a generalized linear regression model, surgical approach was not associated with the efficacy of thymectomy (P = 0.55). ConclusionsThymectomy is an effective treatment for pediatric myasthenia gravis, evidenced by the decreased medication burden and health care utilization after surgery. Surgical approach did not influence the success of surgery. Thymectomy should be considered earlier in the treatment algorithm.

FcRN receptor antagonists in the management of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies specifically directed against proteins located within the postsynaptic membrane of the neuromuscular junction. These pathogenic autoantibodies can be reduced by therapies such as plasma exchange, IVIG infusions and other immunosuppressive agents. However, there are significant side effects associated with most of these therapies. Since there is a better understanding of the molecular structure and the biological properties of the neonatal Fc receptors (FcRn), it possesses an attractive profile in treating myasthenia gravis. FcRn receptors prevent the catabolism of IgG by impeding their lysosomal degradation and facilitating their extracellular release at physiological pH, consequently extending the IgG half-life. Thus, the catabolism of IgG can be enhanced by blocking the FcRn, leading to outcomes similar to those achieved through plasma exchange with no significant safety concerns. The available studies suggest that FcRn holds promise as a versatile therapeutic intervention, capable of delivering beneficial outcomes in patients with distinct characteristics and varying degrees of MG severity. Efgartigimod is already approved for the treatment of generalized MG, rozanolixizumab is under review by health authorities, and phase 3 trials of nipocalimab and batoclimab are underway. Here, we will review the available data on FcRn therapeutic agents in the management of MG.

Choices and Challenges With Treatment of Myasthenia Gravis in Pregnancy: A Systematic Review.

Myasthenia gravis (MG) is an autoimmune disease affecting young women in their second and third decades, coinciding with their reproductive years. We aim to explore the choices and challenges in the treatment of MG in pregnancy. Cochrane, PubMed, Google Scholar, and Embase were the four databases systematically searched for studies with patients reporting pregnancy outcomes for women with MG during pregnancy using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) technique. Quality assessment was done using the Joanna Briggs Institute critical tool (JBI, Adelaide, Australia) for methodological quality. From 2000 to 2023,40 studies fromdatabase search results were considered.There is a substantial risk of complications with MG, especially if it appears during pregnancy. In particular, widespread weakness is a cause of severe, life-threatening disorders, but several treatment options are available.

Eculizumab treatment alters the proteometabolome beyond the inhibition of complement.

Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.

P.036 Are there sex differences in the treatment of myasthenia gravis? a single centre cohort study

Background: Females with generalized myasthenia gravis (gMG) report lower quality of life (QoL) compared to males. Our objective was to determine whether sex differences in treatment and time to treatment initiation may contribute to this difference. Methods: We performed a single centre retrospective study of people diagnosed with gMG. We used multivariable logistic and Cox regression models to assess the association between sex and study outcomes, adjusting for duration from onset to diagnosis, age at diagnosis, thymoma, and antibody status. Results: 179 people with gMG were included. Mean age at diagnosis was 58.4 years, mean follow-up was 4.8 years, and 58.1% were male. There was no association between sex and odds of starting prednisone (adjusted odds ratio [aOR]=0.58, 95% confidence interval [95%CI]=0.28-1.19, p=0.14) or steroid sparing agents (aOR=0.72, 95%CI=0.39-1.35, p=0.31). Similarly, sex was not associated with time to starting prednisone (adjusted hazard ratio [aHR]=0.74, 95% confidence interval [95%CI]=0.52-1.06, p=0.10) or steroid sparing agents (aHR=0.82, 95%CI=0.55-1.22, p=0.33). Females were more likely to start plasmapheresis (aOR=3.15, 95%CI=1.09-9.07, p=0.03). Conclusions: We found no sex differences in first and second line immunotherapy for gMG that might explain differences in QoL. Females were more likely to initiate plasmapheresis, which may reflect greater disease severity.

P.035 Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies

Background: Several case series describe patients with refractory acetylcholine receptor antibody-positive (AChR) myasthenia gravis (MG) treated with hematopoietic stem cell transplant (HSCT). In this report, we describe four patients with anti-muscle-specific kinase (MuSK)MG treated with HSCT. Methods: We reviewed the records of all patients undergoing HSCT for MG in the Alberta Blood and Bone Marrow Transplant Program and identified 4 patients with anti-MuSK MG. Results: All 4 patients had severe disease (Myasthenia Gravis Foundation of America score IVb-V) and were refractory to multiple treatments, including rituximab. 3 patients improved with no clinical manifestations or mild symptoms and remained as such for 2, 3.5, and 5.5 years. In these 3 patients, adverse events ranged from treatable infections and transient dyspnea to persistent fatigue and premature menopause. The average worst Myasthenia Gravis Activities of Daily Living (MG-ADL) scores improved from 14.7 before to 0.3 after HSCT while their mean worst Myasthenia Gravis Quality of Life Questionnaire (MG-QoL15) scores improved from 26.7 to 0. The fourth patient developed pneumonia and passed away from respiratory failure 8 weeks post-transplant. Conclusions: In patients with severe refractory anti-MuSK MG, it may be reasonable to consider HSCT but with an appreciation of the associated risks.

Neonatal Fc Receptor Inhibitor Therapeutics in Neuromuscular Disease.

The Neonatal Fc Receptor (FcRn) is integral to a wide variety of processes including IgG recycling, serum albumin turnover, and bacterial opsonization. Thus, targeting FcRn will increase antibody degradation including pathogenic IgGs. FcRn inhibition provides a novel therapeutic mechanism by which autoantibody titers are reduced resulting in clinical improvement and disease abatement. The FcRn targeting mechanism is similar to that of intravenous immunoglobulin (IVIg) in which saturated FcRn facilitates accelerated pathogenic IgG degradation. Recently, the FcRn inhibitor efgartigimod was approved for the treatment of myasthenia gravis. Subsequently, clinical trials of this agent have been conducted for numerous inflammatory conditions involving pathogenic autoantibodies. These disorders include the Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and inflammatory myositis. Other disorders traditionally treated with IVIg may also benefit from FcRn inhibition in certain contexts. This manuscript discusses the mechanism of FcRn inhibition, preclinical data, and the results of clinical trials of this agent for a wide range of neuromuscular diseases.

When is a thymectomy appropriate for treating myasthenia gravis?

When is a thymectomy appropriate for treating myasthenia gravis?

Application of Clinical Practice and Scientific Research in Undergraduate Teaching of Myasthenia Gravis

Objective: Under theoretical guidance, undergraduates learned the diagnosis, differential diagnosis and treatment of Myasthenia Gravis (MG)through clinical practice and scientific exploration. Methods: Theoretical basis was Chinese guidelines for the diagnosis and treatment of myasthenia gravis (2020 edition). Under the guidance of teachers, undergraduates cooperated with each other and learned step by step. Phase 1 was clinical trainee, determine the location and nature of the lesion through neurological examination and medical history. Phase 2 was classroom learning, simulate nerve conduction and repetitive nerve stimulation (RNS) to explore the differential diagnosis of diseases with similar clinical features. Phase 3 was classroom learning, watch the video of the neostigmine trial, explore the diagnosis and treatment of MG on the theoretical basis. Results: Phase 1, according to the localization signs and disease changes, the location and nature of the lesions were preliminarily determined. Phase 2, peripheral nerve disease, neuromuscular junction disease, and myopathy were differentiated by nerve conduction and RNS. Phase 3, according to the pathogenesis of MG, organize and understand the diagnostic criteria and target therapy provided in the guideline to guide the diagnosis and long-term treatment of MG. Conclusion: In undergraduate teaching, teachers provided appropriate teaching environment, theoretical support and teaching methods. Teachers guided undergraduates to participate in clinical practice and scientific exploration. During the learning process of MG, undergraduates train clinical thinking and establish scientific research awareness.

Real world study on prevalence, treatment and economic burden of myasthenia gravis in Italy

The purpose of this study was to investigate the epidemiology, management, and economic burden of myasthenia gravis in settings of real clinical practice. The analysis used administrative databases covering around 12 million subjects across Italy and included all adult patients with hospitalization discharge diagnosis or active exemption code for myasthenia gravis or with ≥1 pyridostigmine prescription from 2011 to 2018. The estimated prevalence of myasthenia gravis during 2018 was in the range 13.5–29.3/100,000 people (depending on the criteria applied), corresponding to 8190–17,728 alive patients, when reproportioning data to the entire Italian population. Overall 4397 patients with myasthenia gravis (mean age 61.7 years, 46.6% males) were included. A large pyridostigmine use was observed (84.0%–46.8% from 1st to 3rd year of follow-up), followed by corticosteroids (54.5%–44.6% from 1st to 3rd year of follow-up) and non-steroidal immunosuppressants (16% over follow-up). Total direct healthcare costs for myasthenia gravis were 4-times higher than those of the general population (€3771 and €869, respectively), and up to 9-fold increased when considering patients with exacerbation (€7827). These findings showed the epidemiologic burden of myasthenia gravis and the complexity of the therapeutic management for the affected patients, with large use of treatments and elevated healthcare expenditures.

Myastenia gravis: features of epidemiology, pathogenesis, treatment and relation to thymomas

Мyasthenia gravis is a common disease, for adequate treatment of which early detection, knowledge of its clinical manifestations and possible methods of therapy is required. This review provides up-to-date information regarding the issues of myasthenia gravis. The aim of the paper: to systematize the latest scientific data on the pathogenesis, genetic characteristics, methods of treatment of myasthenia gravis, as well as to identify the relationship between myasthenia gravis and other diseases. The following databases were used to search for published studies: Pubmed, Web of Science, EBSCOhost and Scopus. The search was carried out in the time period from the date of establishment of the corresponding database until October 2022. Following search terms were used: “myasthenia gravis”, “myasthenia treatment”, “myasthenia epidemiological features”, “myasthenia and thymoma “myasthenia pathogenesis””. Тhe main studies on the epidemiology of myasthenia gravis are indicated, the key clinical forms and their pathogenetic characteristics, the relationship between myasthenia gravis and thymoma, and the main methods of treatment are also given.

B Cell Targeting mAb–siRNA Conjugates Reduced Autoantibody in Experimental Myasthenia

Abstract Conjugates of monoclonal antibodies (mAbs) and siRNA have been used for target cell-specific gene repression. B cells are integrally involved in the anti-Acetylcholine receptor autoantibody-mediated pathogenic development of autoimmune myasthenia gravis (MG). Here we show that simultaneous targeting of the critical receptors expressed on pathogenic B-cell subsets with the optimized dose of mAb-siRNA conjugates markedly depleted target B cells and substantially reduced pathogenic autoantibody in a mouse model of MG. The results show the potential of mAb-conjugates in the treatment of myasthenia gravis. Supported by grants from AFM-Telethon, France

Therapeutic Strategies for Myasthenia Gravis

For years, the treatment of myasthenia gravis (MG) included high-dose oral steroids. This improved the mortality rate, but the adverse aspects of this treatment have become apparent. To overcome these statuses, an early fast-acting treatment strategy was advocated in the 2010s. Although this strategy improved the patients' quality of life, there are still many patients experiencing impaired activities of daily living. A certain number of so-called "refractory MG" patients also exist. Molecular-targeted drugs for MG have recently been developed. To date, three such drugs are available in Japan.

Myasthenia Gravis Treatments Are Associated with Negative Patient Sentiment in Digital Conversation Data (P7-8.013)

<h3>Objective:</h3> To explore patient experiences with treatments for Myasthenia Gravis (MG) via digital conversations with a focus on corticosteroids and Immunoglobulin (Ig) therapies. <h3>Background:</h3> MG is a rare, chronic autoantibody disease that requires long-term treatment and is associated with high disease and treatment burden and reduced quality of life. <h3>Design/Methods:</h3> One year (8/2021–8/2022) of conversations focused on MG and treatments, specifically corticosteroids and Ig, originating from US internet protocol addresses were tagged based on self-identification in the conversations or on public profiles. Advanced search techniques together with artificial intelligence powered algorithms were used to extract and organize data by topics into a large, unstructured dataset. Sentiment analysis via natural language processing was conducted to categorize conversations as positive, negative or neutral and analyzed to derive the most frequent drivers of each sentiment. <h3>Results:</h3> Among 13,234 conversations extracted from topical sites, message boards, social networks and blogs, 19% were related to MG treatments. Most conversations had negative sentiment (59%), 39% were neutral, and 1% were positive. Among corticosteroid and Ig treated individuals, respectively, posts with negative (69% and 61%) and neutral (31% and 39%) sentiments were the norm, with virtually no “positive” conversations. “Treatment issues” was the dominant driver of negative sentiment among the corticosteroid and Ig related conversations. When posting about “barriers to treatment”, corticosteroid related conversations were most frequently about lack of effectiveness and side effects, while patients discussing Ig treatments most frequently focused on side effects and cost/insurance. <h3>Conclusions:</h3> Digital conversations reveal a high degree of negativity and concern related to MG treatment, specifically, corticosteroids and Immunoglobulin therapies. There is a need for new treatments that provide effectiveness through symptom control with few side effects. By capturing patient voice, this study reinforces limitations of current treatments and highlights the need for improved options for individuals with MG. <b>Disclosure:</b> Dr. Pesa has received personal compensation for serving as an employee of Janssen. Dr. Pesa has stock in J&amp;J. Dr. Chaudhry has received personal compensation for serving as an employee of Johnson &amp; Johnson. Dr. Chaudhry has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mrs. Brethenoux has received personal compensation for serving as an employee of Cien+ . Mr. Furey has nothing to disclose. The institution of Mrs. Gil Valletta has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Janssen. The institution of Mrs. Gil Valletta has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for A- Speakers. The institution of Mrs. Gil Valletta has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for The Cleveland Clinic. Mrs. Gil Valletta has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for United Health Group. Mrs. Gil Valletta has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Zumiez. Miss Gonzalez Quijano has nothing to disclose. Mr. Lorenzo has nothing to disclose.