Anti-acetylcholine Receptor Antibodies Research Articles

P.044 Efficacy, safety, and tolerability of efgartigimod in AChR-Ab– patients with Generalized Myasthenia Gravis: interim analysis of ADAPT/ADAPT+

Background: Efgartigimod, a human IgG1 antibody Fc-fragment, reduces IgG levels through neonatal Fc receptor blockade. Patients with anti-acetylcholine receptor antibody–negative (AChR-Ab–) generalized myasthenia gravis (gMG) comprise 15%-20% of the gMG population and have limited approved treatment options. We evaluated long-term safety and efficacy of efgartigimod in AChR-Ab– patients from ADAPT/ADAPT+ (open-label extension). Methods: ADAPT evaluated safety and efficacy of efgartigimod versus placebo in AChR-Ab+ (n=129) and Ab– (n=38) patients with gMG. This integrated analysis includes 37 AChR-Ab– patients who received ≥1 dose of efgartigimod in ADAPT/ADAPT+ through October 2020 (median[range] follow-up: 453[85-721] days). Responder status was defined as ≥2-point (MG-ADL) and ≥3-point (QMG) improvement for ≥4 consecutive weeks (with first improvement 1 week after last infusion). Results: Among AChR-Ab– patients in ADAPT (cycle 1), 68.4% (13/19) efgartigimod-treated were MG-ADL responders (placebo, 63.2% [12/19]), and 52.6% (10/19) were QMG responders (placebo, 36.8% [7/19]). In the integrated ADAPT/ADAPT+ analysis (cycle 1), AChR-Ab– patients improved from baseline in MG-ADL/QMG scores, with consistent improvements across multiple subsequent cycles. No clinically meaningful differences in safety or efficacy outcomes between AChR-Ab+ and Ab– patients occurred. Conclusions: Long-term treatment (median >1 year) with efgartigimod was well tolerated and associated with clinically meaningful improvements in MG-ADL/QMG scores in AChR-Ab– patients.

The Case Files

The Case Files

Clinical and immune-related factors associated with exacerbation in adults with well-controlled generalized myasthenia gravis.

To describe the clinical predictors and immune-related factors for exacerbation in adults with well-controlled generalized myasthenia gravis (GMG). We conducted a retrospective analysis of 585 adults with well-controlled GMG from our institution to explore the risk factors for exacerbation. Furthermore, propensity score matching (PSM) was used to compare the proportions of lymphocyte subsets, and the levels of immunoglobulin, complement, and anti-acetylcholine receptor antibody (AChR-ab) in the peripheral blood of 111 patients with exacerbations and 72 patients without exacerbations. A total of 404 patients (69.1%) experienced at least one exacerbation, and the median (interquartile range) time to the first exacerbation was 1.5 years (0.8-3.1 years). Multivariable Cox regression analysis showed that age at onset, disease duration before enrollment, Myasthenia Gravis Foundation of America classification (MGFA) class III vs. class II, MGFA class IV-V vs. class II, AChR-ab levels, anti-muscle specific kinase antibody levels, thymus hyperplasia, prednisone plus immunosuppressants vs. prednisone treatment, and thymectomy were independent predictors for exacerbations [hazard ratio (HR) = 1.011, 1.031, 1.580, 1.429, 2.007, 2.033, 1.461, 0.798, and 0.651, respectively]. Propensity-matched analysis compared 51 patient pairs. After PSM, the peripheral blood proportions of CD3-CD19+ B cells, ratios of CD3+CD4+/CD3+CD8+ T cells, and AChR-ab levels were significantly increased, and the peripheral blood proportions of CD3+CD8+ T and CD4+CD25+CD127low+ regulatory T cells (Tregs) were significantly lower in patients with exacerbation than in those without exacerbation (all p < 0.05). Myasthenia gravis (MG) exacerbations were more frequent in those patients with older onset age, longer disease duration, more severe MGFA classification, positive AChR-ab, and lack of combined immunotherapy or thymectomy treatment. On the other hand, CD3-CD19+ B cells, CD3+CD8+ T cells, Tregs, and AChR-ab in peripheral blood may be involved in the course of GMG exacerbation.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

Autoimmune alopecia areata due to thymoma without myasthenia gravis: a case report

BackgroundThymoma is associated with autoimmune diseases. Myasthenia gravis is frequently associated with thymoma, but cases of thymoma complicated by alopecia areata are very rare. In this report, we present a case of thymoma associated with alopecia areata, but without Myasthenia gravis.Case presentationA 60-year-old woman had a complaint of rapid progression of alopecia areata. A hair follicular biopsy was performed, which showed the infiltration of CD8-positive lymphocytes. She was prescribed topical steroids for 2 months prior to surgery, but her hair loss was not improved. Screening computed tomography showed a mass in the anterior mediastinum, which was suspected to be a thymoma. Myasthenia gravis was ruled out because she had no relevant symptoms or physical findings, and no anti-acetylcholine receptor antibodies were detected in serum. We performed a transsternal extended thymectomy based on a diagnosis of thymoma Masaoka stage I, without myasthenia gravis. Pathological examination showed Type AB thymoma, Masaoka stage II. The chest drainage tube was removed on postoperative day 1, and the patient was discharged on postoperative day 6. The patient has continued topical steroids and showed improvement 2 months postoperatively.ConclusionsAlthough alopecia areata is a rare complication in thymoma cases without myasthenia gravis, thoracic surgeons need to keep this condition in mind because alopecia reduces the patient's quality of life.

Use of Efgartigimod in Treatment of Myasthenia Gravis Relapse after Possible Recurrence of Invasive Thymoma: A Case Report. (P1-5.011)

<h3>Objective:</h3> NA <h3>Background:</h3> Myasthenia gravis is an autoimmune neuromuscular junction disorder with established association with thymoma. There is no consensus on optimal treatment of recurrent thymoma post-resection. Efgartigimod is a first-in-class FcRn antagonist approved by the FDA in December 2021 for treatment of AChR-antibody-positive adults with generalized MG. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 53-year-old right-handed man presented to us in September 2020 with a 10-month history of recurrent diplopia, ptosis, dysarthria, dysphagia, and bilateral hand weakness. Workup for MG revealed blocking, binding, and modulating AChR antibodies. CT scan of his chest demonstrated an invasive anterior mediastinal mass. He started pyridostigmine, mycophenolate and prednisone, and underwent a sternotomy with thymectomy with sparing of the directly adjacent right phrenic nerve in October 2020. Histopathology revealed a locally invasive Masaoka stage IIIA, pT1bN0M0, WHO type B2 thymoma. He received adjuvant radiotherapy until January 2021. He was weaned off prednisone and pyridostigmine by May 2021. He remained asymptomatic for about 18 months post-thymectomy except for transient dysarthria in September 2021 attributed to missed mycophenolate doses. Patient noticed recrudescence of bulbar and respiratory symptoms around April 2022. Tests showed elevated AChR antibodies but surveillance chest CT scans did not demonstrate tumor recurrence or metastases. His cardiothoracic surgeon remained suspicious of residual thymoma. He started efgartigimod in July 2022 which he tolerated well, resulting in symptom resolution and objective improvement on MG-specific outcome measures (MG-ADL, MG-QoL15r and MGC). His symptoms recurred during a COVID-19 infection a month later, but he rapidly became asymptomatic after completing the second efgartigimod cycle in September 2022. <h3>Conclusions:</h3> Our patient with AChR antibody-positive, thymoma-associated, generalized MG with recurrent symptoms despite mycophenolate treatment, thymectomy and radiotherapy showed a dramatic response to initial cycles of efgartigimod therapy without significant adverse effects. We propose that efgartigimod be considered early in the management of MG patients with recurrent symptoms after thymectomy. <b>Disclosure:</b> Dr. Akemokwe has stock in CVS HEALTH CORP. Dr. Akemokwe has stock in LABORATORY CORP AMERICAN HOLDINGS. Dr. Coskun has nothing to disclose. Dr. Meyerson has nothing to disclose. Dr. Ebong has nothing to disclose.

Abstract CT025: NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience

Abstract Background: FLT3 mutations occur in approximately 30% of AML patients and are associated with aggressive disease. Despite the approval of midostaurin and gilteritinib, the prognosis for FLT3+ patients with relapsed or refractory disease is poor. NMS-088 is a novel, potent FLT3, KIT and CSF1R inhibitor with superior preclinical activity compared with approved FLT3 inhibitors in different FLT3-driven models. In addition, NMS-088 is active on FLT3 resistance mutation F691L. Dose escalation results from a Phase I/II study to establish safety, dose selection and preliminary clinical activity for NMS-088 in patients with R/R AML and CMML are described. Methods: In the Phase I 3+3 escalations, NMS-088 is administered daily for 21 of 28 days (schedule A) or continuously (schedule B). Patients must have R/R AML or CMML unsuitable for standard therapy. The primary objective is the MTD or MAD as assessed by DLTs. Secondary endpoints include safety, PK and ELN response. Results: as of January 26, 44 R/R AML or CMML patients were treated at doses from 20 to 360 mg/day in A or from 120 to 250 mg/day in B. Median age was 64 yrs, 41 pts had AML and 3 pts had CMML, median number of prior lines was 2 (range 1 to 10). FLT3 mutations were present in 24 out of 41 AML pts (20 FLT3-ITD, 2 FLT3 D835 and 2 FLT3-ITD and D835). The majority of pts with FLT3+ AML had received prior FLT3 inhibitors (86.4%). NMS-088 showed manageable safety with no MTD characterized. One pt had DLT (abnormal posture, decreased activity, dyspnea G3 and eyelid ptosis G1) at 360 mg in A (at day 21) and one pt had DLT (eyelid ptosis G3) at 180 mg in B (at day 29), both suggestive for myasthenic syndrome. Three additional pts experienced possible myasthenic syndrome at doses ≥ 180 mg. Overall the most frequent treatment emergent related adverse events (≥10%) were nausea (any grade 20.5%), vomiting (13.6%), asthenia (11.4%). Discontinuations due to related AEs were as follows: 2 DLT pts per protocol, 2 pts due to nausea (G1; day 161 at 270 mg) and myasthenia gravis (G3; day 39 at 300 mg in a pt with baseline AChR antibodies). There was a dose-dependent trend for response. A total of 5 out of 12 evaluable pts with FLT3+ AML treated at dose ≥ 300 mg achieved a response with 2 CRi, 1 CRi/MLFS and 2 MLFS. Remarkably, all these pts had received prior midostaurin and 2 pts received both midostaurin and gilteritinib. Two pts with response withdrew from treatment to receive HSCT (DoR 1.0+ mos each). For other responding pts DoR was 1.3, 2.8 and 7.9 mos. Conclusions: NMS-088 showed clinical efficacy in pts with FLT3+ R/R AML, including pts who have failed prior FLT3 inhibitors. Together with the manageable safety observed, these results warrant further development of this drug including potential as a novel valuable therapeutic option for pts who have exhausted available treatments. The trial is currently opened for enrollment (NTC03922100). Citation Format: Antonio Curti, Alessandro Rambaldi, Chiara Cattaneo, Roberto Cairoli, Matteo Della Porta, Patrizia Chiusolo, Federico Lussana, Marta Ubezio, Valentina Mancini, Isabel Cano, Carmen Besliu, Christian Hove Claussen, Rosalinda Gatto, Patrizia Crivori, Elena Colajori, Alessio Somaschini, Cristina Davite, Antonella Isacchi, Elena Ardini, Lisa Mahnke, Pau Montesinos. NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT025.

Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use.

Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart®) is the first neonatal Fc receptor antagonist approved in several countries worldwide, including the USA and EU for the treatment of generalised myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive, and in Japan for the treatment of gMG regardless of antibody status. In the double-blind, placebo-controlled phase 3 ADAPT trial in patients with gMG, efgartigimod alfa significantly and rapidly reduced disease burden and improved muscle strength and quality of life compared with placebo. The clinical benefits of efgartigimod alfa were durable and reproducible. Furthermore, in an interim analysis of the ongoing open-label phase 3 ADAPT+ extension trial, efgartigimod alfa provided consistent clinically meaningful improvements in patients with gMG. Efgartigimod alfa was generally well tolerated, with most adverse events being mild to moderate in severity.

Myasthenia Gravis with Idiopathic Inflammatory Myopathy and Sjögren Syndrome, A Triad of Immune-Mediated Diseases

This report illustrates a 73-year-old woman with Sjögren's syndrome and idiopathic inflammatory myopathy with elevated creatine kinase that subsequently deteriorated with an increased dose of steroids, resulting in a myasthenic crisis requiring hospitalization in the intensive care unit; the patient responded successfully to treatment with intravenous immunoglobulin. The patient showed moderate elevation of creatine kinase at the initial diagnosis, with positive anti-Ro/SSA antibodies. Schirmer’s test, anti-Ro52 and anti-Ku antibodies, electromyography, and muscle biopsy were performed to confirm inflammatory myopathy. During the observation in the intensive care unit, creatine kinase increased to 1520 U/L, and a repetitive stimulation test and total anti-acetylcholine receptor antibodies supported the diagnosis of myasthenia gravis. The patient received intravenous immunoglobulin, evolving with clinical improvement. This case is being reported to illustrate the chronic clinical course of a patient with inflammatory myopathy who deteriorated following steroid adjustment, ultimately presenting with myasthenic crisis.

Clinical characteristics, treatment and outcome of nivolumab-induced myasthenia gravis.

To investigate the clinical features of nivolumab-induced myasthenia gravis (MG) and provide evidence for the rational use of nivolumab in the clinic. We collected case reports and case series of nivolumab-induced MG for retrospective analysis by searching Chinese and English databases from 2014 to October 31, 2022. Of the 67 patients included, the median age was 72.5 years (range 34-86), including 44 males (65.7%). MG occurred in the median 2nd treatment cycle (range, 1st-6th) after nivolumab treatment, being mild in 12 patients (17.9%) and moderate to severe in 44 patients (65.7%). Ptosis (n = 48,71.6%), diplopia (n = 34,50.7%), dyspnea (n = 30, 44.8%), limb muscle weakness (n = 30, 44.8%) and dysphagia (n = 27, 40.3%) were the most common symptoms. Fifty-six patients (83.6%) were classified as having generalized myasthenia gravis (GMG), the remaining 11 patients (16.4%) isolated ocular myasthenia gravis (OMG). Twenty-one patients (31.3%) had MG combined with myositis, 10 patients (14.9%) had myocarditis, and 9 patients (13.4%) had both myositis and myocarditis. Forty patients (59.7%) were positive for anti-acetylcholine receptor antibodies. The serum creatine kinase level was significantly increased in 37 patients (55.2%), with a median value of 4000 IU/L (219,14229). After discontinuation of nivolumab and immunosuppressive therapy, 46 patients (68.7%) finally recovered or improved their MG symptoms, while 15 patients (22.4%) did not recover. Eleven patients (16.4%) died of MG complications. MG is a serious and rare adverse reaction to nivolumab. Nivolumab-induced MG should be timely and correctly identified, and immunotherapy should be given.

Methotrexate in generalized myasthenia gravis: a systematic review.

Current myasthenia gravis guidelines recommend the use of azathioprine as first-line steroid sparing agent. However, due to its high cost, compliance to azathioprine is low in developing countries. To determine the efficacy and safety of the cheaper methotrexate as an alternative immunosuppressant, Medline/Pubmed, Embase and Cochrane databases and references were searched for clinical trials and observational studies using the search terms: "Myasthenia OR Myasthenia Gravis OR anti AchR antibody positive Myasthenia Gravis OR anti-MuSK antibody Myasthenia Gravis OR MG" AND "Methotrexate". Of 78 possible articles, only 4 were selected using the following eligibility criteria: population: generalized MG patients; intervention: methotrexate; and outcome: effectiveness, steroid sparing efficacy and adverse effects. Two clinical trials and one observational study noted improvement in different MG outcomes in patients given methotrexate. While one randomized controlled clinical trial concluded that methotrexate has no steroid sparing benefit, a single blinded clinical trial established that methotrexate was a better steroid sparing agent than azathioprine starting at 10th month of use. Adverse effects were rare with non-specific pain and elevated transaminases as the most common complaints. Based on available evidence, MTX may be a safe and effective alternative to AZA as steroid sparing agent in developing countries.

Complement activation profiles in anti-acetylcholine receptor positive myasthenia gravis.

Complement component 5 (C5) targeting therapies are clinically beneficial in patients with acetylcholine receptor antibody+ (AChR-Ab+ ) generalized myasthenia gravis (MG). That clearly implicates antibody-mediated complement activation in MG pathogenesis. Here, classical and alternative complement pathways were profiled in patients from different MG subgroups. In a case-control study, concentrations of C3a, C5a and sC5b9 were simultaneously quantified, indicating general activation of the complement system, whether via the classical and lectin pathways (C4a) or the alternative pathway (factors Ba and Bb) in MG patients with AChR or muscle-specific kinase antibodies (MuSK-Abs) or seronegative MG compared to healthy donors. Treatment-naïve patients with AChR-Ab+ MG showed substantially increased plasma levels of cleaved complement components, indicating activation of the classical and alternative as well as the terminal complement pathways. These increases were still present in a validation cohort of AChR-Ab+ patients under standard immunosuppressive therapies; notably, they were not evident in patients with MuSK-Abs or seronegative MG. Neither clinical severity parameters (at the time of sampling or 1 year later) nor anti-AChR titres correlated significantly with activated complement levels. Markers indicative of complement activation are prominently increased in patients with AChR-Ab MG despite standard immunosuppressive therapies. Complement inhibition proximal to C5 cleavage should be explored for its potential therapeutic benefits in AChR-Ab+ MG.

Small Volume Plasma Exchange as an Alternative to Conventional Plasma Exchange and Intravenous Immunoglobulin for Myasthenic Crisis: A Case Report

Myasthenic crisis is a life-threatening condition. At times it manifests as the initial presentation of the underlying myasthenia gravis. Rapidly acting therapies for treatment of this condition are plasma exchange and intravenous immunoglobulin. We report a case of myasthenic crisis in a young female, presenting with respiratory failure and bulbar symptoms. She had significantly raised titres of anti-acetylcholine receptor antibody. She was treated with multiple sessions of small volume plasma exchange. This modification of conventional plasma exchange significantly reduces costs and is potentially an effective alternative to conventional plasma exchange and intravenous immunoglobulin in resource-poor settings.

A Case of Generalized Myasthenia Gravis Exacerbated by COVID-19

AbstractMyasthenia gravis (MG) is a rare, long-term neuromuscular disorder that can affect individuals of any age. In Japan, the Omicron variant of coronavirus disease 2019 (COVID-19) began spreading in 2022, and many cases of neurological symptoms caused by the virus have been reported. Although COVID-19 has been reported to exacerbate MG in adults, there are no reports on the effects of COVID-19 on the MG symptoms of pediatric patients. We report the case of a 6-year-old girl with a 3-year history of MG who presented to our hospital with symptom exacerbation after COVID-19 infection. Four days before admission, she developed fever with a runny nose and cough. Three days before admission, she developed severe bilateral blepharoptosis and progressive limb weakness, and 2 days before admission, she was diagnosed with COVID-19 by SARS-CoV-2 antigen test. Physical examination revealed moderate blepharoptosis and mild bilateral upper and lower limb weakness. We diagnosed her with worsening MG due to COVID-19, and she was administered 400 mg/kg intravenous immunoglobulin (IVIG) daily for 5 days with continued oral corticosteroids and tacrolimus. The patient's symptoms improved promptly after admission and, at discharge 7 days after admission, her symptoms had significantly improved. During the 1-month outpatient follow-up period, she remained stable and the anti-acetylcholine receptor (AchR) antibody level was reduced to 14.6 nmol/L (from 18.5 nmol/L on admission). Our case suggests that COVID-19 exacerbates MG in both children and adults.

Severity and antibodies profile of seropositive myasthenia gravis

Background: Myasthenia gravis (MG), an autoimmune disease, affects the neuromuscular junction. The impaired neuromuscular transmission results in fatigable muscle weakness among MG patients. Positive antibodies are found among MG patients. Aims: The main aim of this study is to evaluate the correlation of MG severity with their anti-muscle-specific kinase (MUSK) and anti-acetylcholine receptor (AChR) antibody status. Moreover, the study also identifies the correlation between the antibodies profile and the severity of a seropositive MG. Setting and Design: This retrospective cross-sectional study was conducted in the tertiary center of the western region of Saudi Arabia named King Abdullah Medical City (Makkah) over 8 years, from January 2011 to December 2019. Materials and Methods: This retrospective cross-sectional study was conducted in Saudi Arabia in King Abdullah Medical City (Makkah) over 8 years, from January 2011 to December 2019 was reviewed. Seventeen patients out of 27 MG patients came out to be seropositive. The correlation was investigated between severity and antibody status. Statistical Analysis: Data were collected in an Excel sheet, and statistical analysis was performed using SPSS 21 software. Results: The results showed that most patients (87.5%) were positive for AChR antibodies only, while others (12.5%) were positive for anti-MUSK and anti-AChR. Thymoma and crisis were observed in 100% with dual seropositivity and 21% with single seropositivity. Conclusion: The study concluded that a severely aggressive course of MG is present among patients. However, detailed clinical trial studies are required for conforming MG severity and dual seropositivity.

Efgartigimod: a breakthrough medicine for myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction origin that causes persistent fatigue and weakening of voluntary muscles. MG is the most prevalent neuromuscular junction disorder, with an estimated 150–200 new cases per million individuals per year. Patients with MG presently lack a specific and effective long-term therapeutic option. Patients with generalized MG who test positive for anti-acetylcholine receptor antibodies have demonstrated a positive response to Efgartigimod therapy. Thus, the clinical trial of Efgartigimod for the treatment of generalized MG is a significant step toward the availability of an internationally licensed medicine for the ailment.

Clinical Experience With Efgartigimod in Generalized Myasthenia Gravis: Results From a Case Series of US-Based Patients Participating in an Expanded Access Program

Objective To describe the efgartigimod treatment regimens and response among 6 US-based patients with generalized myasthenia gravis (gMG) enrolled in an Expanded Access Program (EAP). Background For some patients with gMG, available therapies do not provide sufficient symptom relief and can cause serious side effects. Efgartigimod, a human IgG1 antibody Fc-fragment (natural ligand of the neonatal crystalline fragment receptor [FcRn]), has increased affinity to FcRn vs endogenous IgG. Efgartigimod reduces IgG recycling and increases IgG degradation. Efgartigimod received FDA approval in 2021 for the treatment of gMG in adults who are anti-acetylcholine receptor (AChR) antibody positive. Design/Methods In the efgartigimod EAP (NCT04777734), gMG patients had access to open-label efgartigimod. Eligible patients (=18 y) met clinical criteria of the Myasthenia Gravis Foundation of America classifications II–IV and had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score =5 points (&gt;50% attributed to non-ocular symptoms). During the first two, fixed-treatment cycles, patients received 4 weekly infusions of efgartigimod 10 mg/kg. During the 4-week inter-treatment period, patients received their ongoing treatments and no efgartigimod infusions. Baseline demographic characteristics and safety data were collected. Treating physicians had the option to assess and track clinical function and burden of disease among treated patients. Results As of the cutoff date (Dec 17, 2021), 8 patients have been enrolled in the US; follow-up data are available for 6 (3 males and 3 females; median age 59 y). 83% (5/6) of patients received at least 2 treatment cycles and 4–5 infusions per cycle. Symptom improvements were noted. Four patients reported 6 AEs: fatigue (resolved), tachycardia and headache (both resolved), dyspnea and diplopia (both not resolved), and back spasms (status unknown). Conclusions We report on 6 patients with gMG who received efgartigimod as part of an EAP. Detailed patient narratives will be presented.

Clinical Characteristics of Double SeroPositive Myasthenia Gravis

Objective This study aims to delineate the clinical phenotype of DSP-MG and assess the histopathological correlation with thymoma. Background Double SeroPositive Myasthenia Gravis (DSP-MG), a rare autoimmune disease that affects neuromuscular transmission, is characterized by antibodies against both AChR and MuSK receptors. This is the second study to be conducted in the world which attempts to define the clinical phenotype of DSP-MG patients. Design/Methods This is a retrospective case series conducted at a tertiary care hospital in South India conducted between February 2018 and October 2021. All patients who were diagnosed with DSP-MG based on typical clinical presentation and positive titres of both Anti- AChR and Anti-MuSK antibodies were included in the study. Results This study consisted of 13 DSP-MG patients (7 Females, Mean age- 60.77 +/-14.24). The presentation was generalized in 9 patients, bulbar in 3 and ocular in 1 patient. Severity of the disease was assessed using the Modified Osserman System wherein 5 patients were Grade 4, 4 patients in grade 3, 3 patients in grade 2 while 1 patient was grade 1. The muscle groups affected first were the limbs (n = 6), ocular (n = 5), bulbar (n = 3) and respiratory (n = 1). MDCT done in 11 patients showed thymoma in five and thymic hyperplasia in 1. Four patients underwent thymectomy whose histopathology showed Type A, B2 (n = 2) and AB thymomas. Four patients had associated thyroid dysfunction and 3 patients were found to have developed MG post stroke. All 13 patients improved with Anticholinesterases, 9 patients were administered immunosuppressants, 3 patients were given IVIg and a single patient underwent plasmapheresis. Conclusions Our study shows that DSP MG is more similar to the clinical phenotype of AChR-MG, rather than MuSK-MG that has been previously defined in literature.

Dynamic nomogram for predicting generalized conversion in adult-onset ocular myasthenia gravis

PurposeTo explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients.MethodsA retrospective, observational cohort study was performed for 435 OMG patients with onset age older than 14 years old. Multivariate Cox regression was used to identify the independent factors affecting generalized conversions that then were incorporated into the construction of the nomogram.ResultsTwo hundred thirty-seven patients (54.5%) had transformed into GMG after a median of 1.1 years (range 0.1-–9.1 years). The 6-, 12-, and 24-month generalized conversion rates were 31.7%, 49.8%, and 65.4%, respectively. Multivariable analysis showed that the early-onset age, male sex, concomitant autoimmune diseases (AID), positive results of anti-acetylcholine receptor antibodies, repetitive nerve stimulation abnormalities, the presence of thymoma, and prednisone treatment were significantly associated with the generalized conversions (hazard ratio [HR] = 0.598, 0.686, 1.554, 1.541, 2.020, 2.510, and 0.556, respectively). A nomogram was established to predict the possibility of generalization-free survival (GFS) in adult-onset OMG patients, and the model demonstrated good predictive performance with a C-index of 0.736 (95% confidence interval 0.703 ~ 0.769). Moreover, subgroup analyses were performed based on the presence or absence of prednisone therapy, and the results indicated that prednisone therapy has better prevention of generalized conversions in male, non-thymoma patients, and patients without other AID.ConclusionA new predictive nomograph and web-based survival calculator we developed show favorable applicability and accuracy in predicting long-term GFS in adult-onset OMG patients.

Seronegative Myasthenia Gravis Presenting as Dysphagia in a Young Male- A Diagnostic Dilemma

21year old gentleman presented with insidious onset, gradually progressive dysphagia for 2 weeks. There was no other associated signs or symptoms. Initial blood workup, radiological investigations and diagnostic interventions were non-contributory. In the meantime, dysphagia worsened and was found to be progressive with advancement of the day. Oesophageal manometric studies showed gradual weakening of peristaltic contractions after a string of repetitive swallows. Repetitive nerve stimulation test and edrophonium test were suggestive of Myasthenia Gravis; Anti-acetylcholine receptor antibody and anti-MuSK antibody were negative. He was initiated on Pyridostigmine and had improvement of dysphagia after a few days. He has now achieved remission. Hence, we present a curious case of Seronegative Myasthenia Gravis in a young gentleman who presented with only dysphagia recovered with Pyridostigmine.