America Foundation Research Articles

DEVELOPMENT OF NANOPARTICLE-ENCAPSULATED BRD4 INHIBITORS FOR NOVEL EPIGENETIC THERAPEUTICS OF IBD

Abstract BACKGROUND Inflammatory bowel diseases (IBD) are chronic intestinal disorders that are typically categorized as one of two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). We have found that epigenetic regulator bromodomain-containing protein 4 (BRD4) is critical in controlling expression of IBD-associated inflammatory cytokine networks. Targeting BRD4 represents a novel therapeutic strategy by modulating IBD-associated inflammatory networks for effective treatment of IBD. Previously, we have successfully identified highly potent and specific BRD4 inhibitors which significantly suppressed colonic mucosal inflammation and chronicity in several animal models of IBD. One of the most pressing challenges in current IBD research is to develop technologies to enable mucosal targeted drug delivery systems that enhance efficacy and decrease side effects. At current study, we further examined the in vivo efficacy of our nano-encapsulated BRD4 inhibitors on animal models of IBD as well as their in vivo and in vitro safety evaluation. METHODS BRD4 inhibitors were encapsulated into biodegradable nanoparticles by a modified solvent displacement method using a polymeric matrix of PEGylated poly (lactic-co-glycolic acid) (PLGA). Drug metabolism/pharmacokinetic (DMPK) profiling of these Nano-BRD4 inhibitors were examined for their in vivo drug release test and in vitro safety evaluation. In vivo efficacy of Nano-BRD4 inhibitors were evaluated in IBD animal models of both dextran sulfate sodium (DSS)-induced acute or chronic colitis, oxazolone (OXA)-induced colitis and Cbir1 T Cell Transfer-induced colitis. RESULTS Drug release test in vivo and in vitro safety evaluation of Nano-BRD4 inhibitors indicate their good DMPK potential and low toxicity. Oral administration of Nano-BRD4 inhibitors at the dosage of 1 mg/kg effectively block colonic inflammation in both DSS-induced acute or chronic colitis, OXA-induced colitis and Cbir1 T Cell Transfer-induced colitis of mice. Nano-BRD4 inhibitors significantly reduced mucosal inflammation and restores tissue architecture in colon of IBD animal models. Furthermore, Nano-BRD4 inhibitors blocked DSS-, OXA-, and Cbir1 T Cell Transfer-induced induced expression of inflammatory cytokine. CONCLUSION Our nano-encapsulated BRD4 inhibitors effectively block colonic inflammation in our established multiple animal models of IBD. Drug release test in vivo and in vitro safety evaluation of Nano-BRD4 inhibitors indicate their good DMPK potential and low toxicity. Local delivery of nanoparticle-encapsulated BRD4 inhibitors would offer superior epigenetic pharmacotherapy for IBD with higher efficacy, specific delivery, long-lasting release, and a better therapeutic and safety window. FUNDING SUPPORT Litwin IBD Pioneers Program and Entrepreneurial Investing (EI) Initiative award from the Crohn’s & Colitis Foundation of America.

Analysis of length of stay and treatment emergent complications in hospitalized myasthenia gravis patients with exacerbation

IntroductionAIMSMyasthenia Gravis (MG) is an autoimmune neuromuscular disease in which patients suffer from recurrent exacerbation. There are insufficient data measuring the effects of the resources employed before and during acute exacerbation on subsequent disease outcomes. This study aims to identify factors which lead to lengthened hospital stay.MethodsThis is a retrospective chart review of acute MG exacerbations requiring hospitalization. Exacerbations were identified using ICD-9/ICD-10 codes and considered the following variables: age and Myasthenia Gravis Foundation of America (MGFA) class at initial MG diagnosis, age and MGFA class at exacerbation, sex, thymectomy, cause of exacerbation, treatment regimen at time of exacerbation, inpatient treatment regimen, length of hospital stay (LOS), intubation, use of noninvasive ventilation, complications, and disposition.ResultsSeventy patients with 141 hospitalizations were identified. Crisis management characterized by intubation and plasmapheresis positively correlated with LOS (both p < .001). Almost 1/5 hospitalizations required intubation. Previous thymectomy negatively correlated with LOS (p < .05). In contrast, male sex correlated with longer LOS (p < .05). One-third of hospital stays were followed by discharge to a post-acute care facility, 7% home with home health, and 1 hospitalization resulted in death.DiscussionPlasmapheresis, intubation, and male sex were associated with increased LOS in acute MG exacerbation. Intubation appears to be the strongest predictor of LOS. Those with previous thymectomy had shorter hospital stays. The role of thymectomy in the acute setting merits further analysis.

Patient-centered pharmacovigilance: priority actions from the inherited bleeding disorders community.

Patients at the center of product safety Every medical device and therapeutic product has potential benefits and harms. The pharmaceutical and biomedical companies that develop them must demonstrate that they are effective, and the safety risks are limited or manageable, for regulators to approve them for use and sale. After the product has been approved and people are using it in their daily lives, it is important to continue to collect information about any negative side effects or adverse events; this is called pharmacovigilance. Regulators, like the United States (US) Food and Drug Administration, the companies that sell and distribute the products, and healthcare professionals who prescribe them are all required to participate in collecting, reporting, analyzing, and communicating this information. The people with the most firsthand knowledge of the benefits and harms of the drug or device are the patients who use them. They have an important responsibility to learn how to recognize adverse events, how to report them, and to stay informed of any news about the product from the other partners in the pharmacovigilance network. Those partners have a crucial responsibility to provide clear, easy-to-understand information to patients about any new safety concerns that come to light. The community of people with inherited bleeding disorders has recently encountered problems with poor communication of product safety issues, prompting two large US patient organizations, National Hemophilia Foundation and Hemophilia Federation of America, to hold a Safety Summit with all the pharmacovigilance network partners. Together they developed recommendations to improve the collection and communication of information about product safety so that patients can make well-informed, timely decisions about their use of drugs and devices. This article presents these recommendations in the context of how pharmacovigilance is supposed to work and some of the challenges encountered by the community.

Patient-reported burden of myasthenia gravis: baseline results of the international prospective, observational, longitudinal real-world digital study MyRealWorld-MG

ObjectivesMyasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain...

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.

Clinical Profile and Quality of Life in Myasthenia Gravis Using MGQOL15 R(Hindi): An Indian Perspective.

Myasthenia Gravis (MG) is a chronic fluctuating illness, due to the dysfunction of neuromuscular junction which is autoimmune in nature. The disease severely affects the Quality Of Life (QOL). The primary objective of our study was to assess the QOL in patients with MG using Short Form 36 (SF 36) and MGQOL 15 R (Hindi translated). The secondary objective was to assess the correlation of age, sex, illness duration, clinical characteristics, severity, and treatment with the QOL in MG patients. A cross sectional study of 55 MG patients was done to analyse and evaluate the clinical status using Hybrid Myasthenia Gravis Foundation of America (HMGFA), Myasthenia gravis composite score (MGCS) and The Myasthenia Gravis Activities of Daily Living (MG - ADL). QOL was assessed by SF 36 and Hindi version of Myasthenia Gravis Quality of Life 15 - Revised (MG-QOL15R) score. 78.2% patients had generalized MG. The mean MGC and MG-ADL scores were 5.27 and 3.29 (95% CI: 2.24 -4.34) respectively. The mean MGQOL15R score was 6.52 ± 7.7 and the score correlated with the symptoms. The SF 36 scores were the best and the worst in the bodily pain (93.72 ± 13.52) and general health subset (61.81 ± 39.64) respectively. Except for steroid dose, there was no significant correlation between SF36 and other factors. QOL in MG was found to be affected due to the disease. The MGQOL 15 R scores correlated with the clinical features, remission or active status, steroid use and thymectomy. No Significant association was observed between MG QOL scores and various lab parameters and repetitive nerve stimulation (RNS) test results. Higher dose of steroid was associated with poor QOL, while thymectomy was associated with better QOL scores. MGQOL15R (Hindi) is a quick and simple tool to assess the QOL in MG patients.

Evaluating the Construct of Damage in Systemic Lupus Erythematosus.

The Systemic Lupus International Collaborating Clinics (SLICC), American College of Rheumatology (ACR), and the Lupus Foundation of America are developing a revised systemic lupus erythematosus (SLE) damage index (the SLICC/ACR Damage Index [SDI]). Shifts in the concept of damage in SLE have occurred with new insights into disease manifestations, diagnostics, and therapy. We evaluated contemporary constructs in SLE damage to inform development of the revised SDI. We conducted a 3-part qualitative study of international SLE experts. Facilitated small groups evaluated the construct underlying the concept of damage in SLE. A consensus meeting using nominal group technique was conducted to achieve agreement on aspects of the conceptual framework and scope of the revised damage index. The framework was finally reviewed and agreed upon by the entire group. Fifty participants from 13 countries were included. The 8 thematic clusters underlying the construct of SLE damage were purpose, items, weighting, reversibility, impact, time frame, attribution, and perspective. The revised SDI will be a discriminative index to measure morbidity in SLE, independent of activity or impact on the patient, and should be related to mortality. The SDI is primarily intended for research purposes and should take a life-course approach. Damage can occur before a diagnosis of SLE but should be attributable to SLE. Damage to an organ is irreversible, but the functional consequences on that organ may improve over time through physiological adaptation or treatment. We identified shifts in the paradigm of SLE damage and developed a unifying conceptual framework. These data form the groundwork for the next phases of SDI development.

Myasthenia gravis complicated by the development of COVID-19: an analysis of case series

Myasthenia gravis (MG) is an autoimmune disease characterized by increased dynamic muscleweakness. Patients with myasthenia gravis are united by the phenomenon of deterioration of the clinicalcondition after infection, refusal of treatment or taking certain medications, surgical intervention, exposureto heat and stress. In the context of the COVID‑19 (Coronavirus disease 2019) pandemic, the study ofpatients with myasthenia gravis and a new infectious disease may reveal new pathogenetic patterns andchange the therapeutic strategy.&#x0D; Objective — to identify clinical and paraclinical, therapeutic regularities in patients with MG and COVID‑19.&#x0D; Methods and subjects. From April 2021 to November 2021, the course of MG against the background ofCOVID‑19 in 11 patients was analyzed. The control group consisted of 7 patients with COVID‑19, butwithout MG. General clinical, neurological, instrumental, laboratory and statistical examination methods,scales Myasthenia Gravis Foundation of America (MGFA), The Quantitative Myasthenia Gravis Score (QMGS), Myasthenia Gravis Activities of Daily Living (MG‑ADL), The National Early Warning Score 2 (NEWS2) and questionnaires were used.&#x0D; Results. In the experimental and control groups, the level of SpO2 when breathing atmospheric air wascorrelated with the presence of bronchial asthma (BA) (r = –0.791), diabetes mellitus (DM) (r = –0.553),hypertension (r = –0.301). A positive correlation (r = 0.271) was found between the presence of MG and the level of SpO2 when breathing atmospheric air, which may be associated with the intake of pyridostigmine anda decrease in muscle mass in patients with MG. Presence of a relationship between the NEWS2 indicatorwith DM (r = 0.501), BA (r = 0.483), obesity (r = 0.376), hypertension (r = 0.352), multinodular goiter (r = 0.204), hydrothorax (r = 0.204) and MG (r = 0.120). In the myasthenia group, a relationship was established between the duration of treatment for COVID‑19 and body mass index (BMI) (r = 0.523), age (r = 0.504), pyridostigmine intake (r = –0.243) and weight (r = 0.228). NEWS2 in the experimental group was correlated with pyridostigmine intake (r = –0.386), weight (r = 0.355) and BMI (r = 0.256). Duration of treatment for COVID‑19 was associated with duration of MG (r = 0.570), obesity (r = 0.572), and BMI (r = 0.526). NEWS2 is related to the level of SpO2 when breathing atmospheric air (r = — 0.907), hemoglobin (r = –0.847) and vital capacity of the lungs (VC) (r = –0.699). Obesity (r = 0.787), anemia (r = 0.684) and BA were correlated with NEWS2. The finding of an inverse correlation between NEWS2 and pyridostigmine intake (r = –0.684) was promising. Soft palate paresis (r = –0.614), dysphagia (r = –0.614) and nasality (r = –0.545) were correlated with a decrease in VC. A correlation was found between VC and the NEWS2 (r = –0.699). The duration of COVID‑19 (r = –0.646) and patient age (r = –0.626) were correlated with VC.&#x0D; Conclusions. MG with the addition of COVID‑19 tends to worsen the course, progress of muscle weakness,development of respiratory failure and hypoxia. Aggravating factors are age, duration of MG, duration ofCOVID‑19, BMI, concomitant pathology (DM, hypertension, BA, obesity, anemia). Constitutional features(lower BMI and weight) may contribute to shortening the duration of treatment. Taking pyridostigmineallows to reduce not only the duration of treatment, but also the risk of worsening of the condition, whichmay be associated with the suppression of the inflammatory process when taking an anticholinesteraseagent.&#x0D;

Vibrance-mg: Clinical Trial of Nipocalimab in Pediatric Myasthenia Gravis

Objective We describe an open-label study of nipocalimab to determine the effect of nipocalimab in pediatric participants with gMG. Background Nipocalimab is a high affinity, 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. Data from Vivacity-MG, a Phase 2, multicenter, randomized, double-blind, placebo-controlled study of nipocalimab demonstrated safety, tolerability, and efficacy of nipocalimab in adult generalized myasthenia gravis (gMG) (clinicaltrials.gov NCT03772587). Design/Methods This global study will enroll at least 12 participants, aged 2 to &lt;18, with a diagnosis of gMG and an insufficient clinical response to ongoing, stable standard-of-care therapy, as reflected by a Myasthenia Gravis Foundation of America (MGFA) Class of IIa/b through IVa at screening. Participants must have a positive serologic test for either acetylcholine receptor or Muscle Specific Tyrosine Kinase pathogenic autoantibody. The study will consist of a screening period of up to 4 weeks, a 24-week open-label Active Treatment Phase where participants will receive nipocalimab intravenously every two weeks, and a Long-term Extension phase; after last dose, a safety follow-up assessment will be conducted at 8 weeks. The primary outcome is the effect of nipocalimab on total serum IgG, safety and tolerability, and PK in pediatric participants with gMG. Results Study enrollment will begin in 2022. Conclusions The vibrance-mg study will assess the PK/PD, safety and activity of Nipocalimab in pediatric gMG.

Vivacity MG Phase 3 Study: Clinical Trial of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis

Objective We describe Vivacity-MG3. our pivotal Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Nipocalimab Administered to Adults With gMG (NCT04951622). Background Nipocalimab is a high affinity, 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. Data from Vivacity-MG, a Phase 2 randomized placebo-controlled study of nipocalimab in adult generalized myasthenia gravis (gMG), demonstrated safety, tolerability, and efficacy of nipocalimab (clinicaltrials.gov NCT03772587). Design/Methods This global study will enroll approximately 180 participants with gMG, aged 18 and older, with an insufficient clinical response to ongoing, stable standard-of-care therapy, as reflected by a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of &gt;/= to 6 at screening and baseline, and a Myasthenia Gravis Foundation of America (MGFA) Class of IIa/b–IVa/b at screening. The study will consist of a screening period of up to 4 weeks, a 24-week double-blind placebo-controlled phase where participants will be randomly assigned in a 1:1 ratio to receive either placebo or nipocalimab intravenously every two weeks, and an open label extension phase of variable duration. The primary outcome is the average change in MG-ADL score from baseline to weeks 22, 23 and 24 of the double-blind placebo-controlled phase. Results Study enrollment began in July 2021 and is ongoing. Conclusions The ongoing Vivacity MG Phase 3 study will assess the efficacy, safety, and PK/PD of Nipocalimab in adult gMG.

The Religious, Scientific, Cultural, and Economic Foundations of America

Historian Lynn White wanted to understand why the Western civilization had exploited nature so much that its own quality of life--even its survival--was now at stake. White concluded that the answer is: the Judeo-Christian tradition.The environmental movement began in the early 1960s, with far-reaching changes in American values and attitudes, that were powering a growing interest in wilderness and its preservation.By destroying pagan animism, Christianity made it possible to exploit nature in a mood of indifference to the feelings of natural objects. Severed from the human community and its ethical protection, nature was fully exposed to human greed.Aristotle’s scientific philosophy of nature—animate and alive—dominated Western thought for two thousand years after his death. But thanks to the Scientific Revolution of the 16th and 17th centuries, the notion of an organic and spiritual universe was replaced by that of the world as a machine, and the word machine became a dominant metaphor of the modern era. It was around 1850, that Western Europe and North America arranged a marriage between science and technology that signified the Baconian creed of power over nature. Its acceptance as a normal pattern of action may mark the greatest event in human history since the invention of agriculture. Perhaps the most profound legacy of the Scientific Revolution is the principle of reductionism that encourages an atomistic and disintegrated view of nature. As a result, we have the Faustian bargain of Hydrogen bombs that pose an existential threat to the universe. Individualism is first on the list of American cultural heritage. Next is the “Bootstrap philosophy.” This phrase has become part of American mythology, and the nation’s attitude toward helping those in society that have been left behind; and we lecture them to lift themselves up by their bootstraps. Next are the negative attitudes toward government that are unjustified. Then there is the free-market crusade that has led to American economic decline. And next, this is their promised Utopia for what ails America: “Privatization, deregulation, downsizing, shrinking entitlements, and lower taxes.”Smith’s explanation of the paradox of the interplay between supply and demand, is an important scientific contribution to society. But, why then did he cross that line, and enter the domain of metaphysics with his proclamation that “consumption is the sole end and purpose of all production”?Yet, he put no limits on consumption and left the door of overconsumption wide open.Smith says that in an unfettered market--propelled by competition among self-interested sellers and buyers--the invisible hand will then allocate goods efficiently.However, one of the best-kept secrets in economics is that there is no case for the “invisible hand.”Finally, Adam Smith ignored the Industrial Revolution? This is because his static theory could not handle innovation.

Impact of the COVID-19 pandemic on patients with myasthenia gravis: A survey of the Myasthenia Gravis Foundation of America MG patient registry.

Factors associated with coronavirus disease 2019 (COVID-19) infection among the myasthenia gravis (MG) population are incompletely understood. This study aimed to characterize the behavior of MG patients during the pandemic and to examine risk factors associated with COVID-19 infection. A "COVID-19 Survey" was sent to MG Patient Registry participants in the summer of 2020 (CSS20) and winter of 2021 (CWS21). Survey results were summarized descriptively. Demographics, disease characteristics, medication use, and survey results were compared between those reporting COVID-19 diagnosis (COVID), COVID-19 like symptoms without diagnosis (COVID-Like), and asymptomatic participants. A total of 454 and 665 participants completed the CSS20 and CWS21 surveys respectively; 326 participants completed both. Most continued follow-up visits and MG treatments. The frequency of COVID-like symptoms was similar between CSS20 and CWS21, while COVID-19 exposure (6% vs. 27%), COVID-19 testing among symptomatic individuals (35% vs. 78%), and COVID-19 diagnosis (0.2% vs. 6%) were higher in the CWS21. Cough, fever, fatigue, myalgia, anosmia/ageusia, and hospital and intensive care unit (ICU) admissions were more frequent in the COVID compared to the COVID-Like group. COVID-19 exposure (odds ratio [OR] 7.88), number of people in the household (OR 1.31), and report of MG exacerbation before the pandemic (OR 2.6) were independently associated with COVID-19 infection. COVID-19 affected MG patients increasingly through the early pandemic. While face-to-face contact with a COVID-19 infected individual was an obvious risk factor, MG patients who had more people in the household and unstable disease were at elevated risk for COVID-19 infection.

The best and worst of times in therapy development for myasthenia gravis.

Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized myasthenia gravis, and several other therapies are in late-stage clinical trials or under regulatory review. However, questions about which patients are most likely to benefit from which therapies, and the relative effectiveness of these very expensive drugs, has resulted in uncertainty around the place that they should occupy in the existing therapeutic armamentarium. MGNet (a Rare Diseases Clinical Research Consortium funded by the National Institute of Neurological Diseases and Stroke) held two meetings during the 14th International Conference of the Myasthenia Gravis Foundation of America to discuss the most critical needs for clinical trial readiness and biomarker development in the context of therapy development for myasthenia gravis. Herein we provide a summary of these discussions, but not a consensus opinion, and offer a series of recommendations to guide focused research in the most critical areas. We welcome ongoing discussion through comments on this work.

Impact of Thymectomy on Crisis Incidence and Quality of Life amongst Generalised Myasthenia Gravis Patients.

Thymectomy, combined with corticosteroids, immunosuppressive agents, and cholinesterase inhibitors, has been accepted as the standard treatment for myasthenia gravis (MG) patients. Data on the effect of thymectomy on occurrence of myasthenic crisis are few. To assess the long-term impact of thymectomy in patients with generalized Myasthenia gravis (GMG) in terms of occurrence of myasthenia crisis and quality of life. A retrospective analysis of 274 clinical records of patients diagnosed with myasthenia gravis (MG) in Nizam's institute of medical sciences (NIMS), a tertiary level teaching hospital between January 2000 and December 2015 was done. Severity of the disease was assessed using Myasthenia Gravis Foundation of America (MGFA) classification and quantitative myasthenia gravis (QMG) score. Myasthenia crisis was diagnosed in our patients when they required ventilator assistance due to respiratory failure caused by muscle weakness (MGFA class V). Quality of life (QoL) was assessed. Of 230 cases included in the final analysis, 108 (46.9%) underwent thymectomy. Posttreatment crisis occurred in 53.3% of the nonthymectomy subjects, and 25.9% of thymectomy group (P < 0.001). In multivariate logistic regression analysis, after controlling for the effect of gender, age at diagnosis and grade of the disease, the odds ratio of myasthenic crisis in people with thymectomy was 0.186.(95% CI 0.087 to 0.387, P = 0.001). No statistically significant differences were observed in quality of life scores between thymectomy and nonthymectomy groups, either before (P = 0.86) or after surgery (P = 0.939). The odds of myasthenia crisis was lesser in people, who underwent thymectomy even after controlling for MGFA grade and other potential confounders but no significant differences in quality of life were found with thymectomy.

Correlation between neutrophil-to-lymphocyte ratio and severity of myasthenia gravis in adults: A retrospective study

BackgroundThe study aimed to explore the clinical value of neutrophil-to-lymphocyte (NLR) in evaluating myasthenia gravis (MG) severity and the correlation between NLR and the Quantitative Myasthenia Gravis Score (QMGS). MethodsThis study included 128 patients with MG and 116 healthy controls. We completed Myasthenia Gravis Foundation of America (MGFA) classification for patients with MG, and defined MGFA I, II, and III as mild MG and MGFA IV and V as severe MG. The NLR of the patients were calculated, and statistical analysis was performed, with statistical significance set at P < 0.05. When pairwise comparisons between patients with mild MG, severe MG, and the healthy controls were performed, P < 0.017 was considered statistically significant under Bonferroni correction. ResultsNLR was significantly higher in patients with severe MG than in those with mild MG [2.90(2.41–5.83) vs 1.72(1.38–2.51), P = 0.000] and in the healthy controls [2.90(2.41–5.83) vs 1.65(1.34–1.91), P = 0.000]. NLR was independently associated with severe MG. The cut-off value of NLR for differentiating mild MG from severe MG was 2.37, and the sensitivity and specificity were 0.900 and 0.815, respectively. The results of Spearman test showed that NLR was positively correlated with QMGS in mild MG. NLR tended to be correlated QMGS in patients with severe MG, but the difference was not statistically significant. ConclusionNLR may be a helpful marker for identifying patients with severe MG. NLR can also be used to further evaluate disease severity, especially for mild MG.

Characteristics of Repetitive Nerve Stimulation (Rns) and Correlation with Severity and Quality of Life of Myasthenia Gravis Patients

Background: Myasthenia gravis is a rare autoimmune disease due to neuromuscular junction (NMJ) disorders. The diagnosis of myasthenia gravis is based on cardinal clinical symptoms, including fluctuating weakness, worsening with activity, and improving with rest. In addition to clinical signs and antibody tests, other tests that are also crucial for diagnosis are electrodiagnostic examination (EDX) such as repetitive nerve stimulation (RNS) and single fibre electromyography (SFEMG). Recent studies have focused on assessing patients' severity and quality of life, essential for determining the prognosis and subsequent treatment plans. Objective: To evaluate the characteristic of RNS and its correlation with rigor and quality of life of myasthenia gravis patients. Methods: Inclusion criteria: patients diagnosed with myasthenia gravis, aged 18-65 years, willing to participate in the study. Exclusion criteria include a history of neuropathy, motor neuron disease, or myopathy and dropping out of the study. Patient demographic data were collected. The results of the RNS examination were divided into two categories, normal and abnormal. MG severity was assessed by the Myasthenia gravis foundation of America (MGFA) classification, and the patient's quality of life was assessed by Myasthenia Gravis Quality of Life 15 (MG-QOL 15). Results: Of the 24 samples, 69.1% of RNS were positive. The most sensitive muscle for assessing RNS is the anconeus muscle, followed by the trapezius and nasal. There was no significant relationship between RNS features and severity and the quality of life of myasthenic Gravis patients. Conclusion: Onconeus muscle is the best location for assessing RNS. Although the number of patients with normal RNS had lower severity and better quality of life, there was no statistically significant relationship. Further studies with larger samples and longer follow-ups are needed.

Rituximab in Myasthenia Gravis- Experience from a Low- and Middle-Income Country (LMIC) Setting.

Myasthenia gravis (MG) is an immune-mediated disorder of the neuromuscular junction. About 10% are refractory to immunosuppressive therapy. To analyze the response of patients with generalized MG to rituximab. A retrospective review of patients with MG who received rituximab was carried out (n = 13, M:F = 6:7, mean age: 44.84 ± 15.73 years). Myasthenia Gravis Foundation of America (MGFA), MGFA post-intervention status (MGFA-PIS), and Myasthenia Gravis Status and Treatment Intensity (MGSTI) were assessed before and after rituximab. The duration of MG was 104.07 ± 92.25 months. Before rituximab, the MGFA was IIA/IIB/IIIA/IIIB/IVB/V in 1/1/2/6/2/1 patients and MGSTI was four in eight patients and six in three patients. The mean duration of follow up was 20.92 ± 14.06 months (range, 4 to 42 months). Dose reduction or discontinuation of cholinesterase inhibitors could be achieved 12 patients. Complete stable remission (CSR) and pharmacologic remission (PR) were achieved in one and four patients respectively and five patients had minimal manifestations. Most patients attained level 0, 1 or 2 MGSTI at last follow up. No rituximab infusion-related adverse events were noted. Three patients had exacerbation of MG between one to five weeks after rituximab administration. Three patients died, one each due to a cardiac event unrelated to MG or treatment, complications related to myasthenic crisis, and coronavirus disease. Rituximab was effective in bringing about remission in MG and can be considered as a first-line agent. However, it has to be administered under close supervision as some patients develop exacerbation of MG akin to steroid-induced worsening.

Decreased initial compound muscle action potential amplitudes in myasthenia gravis

Objective We aimed to investigate the hypothesis that amplitudes of compound muscle action potential (CMAP) elicited by single stimulation decrease by baseline neuromuscular blocking in myasthenia gravis (MG), and to examine correlation of CMAP amplitudes with baseline muscle weakness. Methods One hundred ninety-four consecutive patients who underwent repetitive 3 Hz nerve stimulation tests (RNST) at our laboratory were included in the study. Of these, 109 patients were diagnosed as suffering from MG, and the remaining 85 with other disease served as the non-MG controls. RNST was performed on the nasalis, trapezius, and abductor digiti minimi (ADM) muscles. CMAP amplitudes elicited by the first stimulation were compared between the two groups. In MG patients, we studied the correlation of CMAP amplitudes with MG Foundation of America (MGFA) class, total scores of manual muscle testing (MMT), and 4th decrement (%) of RNST. Results Compound muscle action potential amplitudes in MG were significantly lower than in controls (p < 0.05 in all muscles tested). Decreases in CMAP amplitudes were more prominent in generalized than in ocular MG (p < 0.05), and in patients with MGFA III–V classes than in those with 0–II (p < 0.01 in the trapezius and ADM). CMAP amplitudes partially correlated with total MMT scores and MG-ADL scale scores. Additionally, CMAP amplitudes elicited by the first stimulation correlated with the 4th decrement of RNST (p < 0.01 in all muscles tested). Conclusion Compound muscle action potential amplitudes are reduced in MG, presumably by baseline neuromuscular transmission block, and could reflect persistent muscle weakness, rather than fatigue, in MG patients.

Usefulness of subcutaneous immunoglobulin therapy in the management of myasthenia gravis: a retrospective cohort study.

IntroductionTo describe the efficacy of subcutaneous immunoglobulin (SCIg) in patients with myasthenia gravis (MG).MethodsThis was a retrospective study conducted in the neuromuscular referral center of Bordeaux (between January 1, 2014 and March 31, 2021) with MG patients treated with SCIg. The main outcome was SCIg efficacy assessed by the before and after SCIg Myasthenia Gravis Foundation of America (MGFA) clinical classification, the duration of hospitalization and the number of days of orotracheal intubation (OTI).ResultsSixteen patients were included in the study (11 females; 5 males). Nine patients were still treated with SCIg at the end of the study (March 31, 2021) and then underwent prospective follow-up. The average age of the patients was 56.1 (19–83) years. The median duration of MG at onset of SCIg was 37.4 months. Eight patients (50%) remained stable (4 in stage MGFA-IV and 4 in MGFA-III). Eight patients (50%) improved: 3 from MGFA-IV to MGFA-III, 1 from MGFA-IV to MGFA-II, 1 from MGFA-IV to MGFA-I, 2 from MGFA-III to MGFA-II and 1 from MGFA-III to MGFA-I (no patient worsened). The duration of disease progression did not appear to affect the response to SCIg therapy. The number of hospital days per month was significantly reduced after SCIg compared to before, and the number of days in intensive care unit and the number of days of OTI were also reduced. Only minor adverse effects were noted, and 80% of patients were in favor of continuing SCIg.ConclusionsSCIg is a well-tolerated and useful treatment in MG, offering interesting perspectives in the management of MG patients. However, further large-scale prospective studies are needed to confirm these results.

Effects of 3,4-diaminopyridine on myasthenia gravis: Preliminary results of an open-label study.

Background: 3,4-diaminopyridine (3,4-DAP) can lead to clinical and electrophysiological improvement in myasthenic syndrome; it may thus represent a valuable therapeutic option for patients intolerant to pyridostigmine. Objective: to assess 3,4-diaminopyridine (3,4-DAP) effects and tolerability in patients with anti-AChR myasthenia gravis. Method: Effects were monitored electrophysiologically by repetitive nerve stimulation (RNS) and by standardized clinical testing (QMG score) before and after a single dose administration of 3,4-DAP 10 mg per os in 15 patients. Patients were divided according to their Myasthenia Gravis Foundation of America (MGFA) class into mild and severe. Results: No significant side effects were found, apart from transient paresthesia. 3,4-DAP had a significant effect on the QMG score (p = 0.0251), on repetitive nerve stimulation (p = 0.0251), and on the forced vital capacity (p = 0.03), thus indicating that it may reduce the level of disability and the decremental muscle response. When the patients were divided according to the MGFA classification, 3,4-DAP showed a positive effect in the severe group, either for the QMG score (p = 0.031) or for the RNS decrement (p = 0.031). No significant difference was observed in any of the outcome measures within the mild group (p > 0.05). A direct effect of 3,4-DAP on nicotinic ACh receptors (nAChRs) was excluded since human nAChRs reconstituted in an expression system, which were not affected by 3,4-DAP application. Conclusion: Our results suggest that 3,4-DAP may be a useful add-on therapy, especially in most severe patients or when immunosuppressive treatment has not yet reached its full effect or when significant side-effects are associated with anticholinesterase.