Research Publications

A Digital Telehealth System to Compute Myasthenia Gravis Core Examination Metrics: Exploratory Cohort Study. Garbey M, Joerger G, Lesport Q, Girma H, McNett S, Abu-Rub M, Kaminski H. JMIR Neurotech. 2023;2:e43387. doi: 10.2196/43387.

Addressing Outcome Measure Variability in Myasthenia Gravis Clinical Trials. Guptill JT, Benatar M, Granit V, Habib AA, Howard JF, Barnett-Tapia C, Nowak RJ, Lee I, Ruzhansky K, Dimachkie MM, Cutter GR, Kaminski HJ. Neurology. 2023 Apr 19;10.1212/WNL.0000000000207278. doi: 10.1212/WNL.0000000000207278. Online ahead of print.

Comparison of Fixed and Live Cell-Based Assay for the Detection of AChR and MuSK Antibodies in Myasthenia Gravis. Spagni G, Gastaldi M, Businaro P, Chemkhi Z, Carrozza C, Mascagna G, Falso S, Scaranzin S, Franciotta D, Evoli A, Damato V. Neurol Neuroimmunol Neuroinflamm. 2022 Oct 21;10(1):e200038. doi: 10.1212/NXI.0000000000200038. PMID: 36270951; PMCID: PMC9621337

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChRs) in muscles. Double seronegative myasthenia gravis (dSN-MG) is a type of MG where patients do not have detectable AChRs or muscle-specific tyrosine kinase (MuSK) antibodies, which are two of the most common antibody markers for MG. In some patients with dSN-MG, a technique called cell-based assay (CBA) can be used to detect these antibodies. However, research comparing fixed and live CBA is lacking.

In this study, the research group of MGNet Pilot Awardee Valentina Damato, MD, PhD, compared the performance of fixed and live CBAs in serum samples from 192 patients with radioimmunoassay (RIA)-dSN-MG and 100 control subjects. The team also assessed the sensitivity and specificity of these techniques in RIA-positive MG samples.

Results show that fixed CBA represents a valuable alternative to RIA for AChR and MuSK antibody detection in patients with MG. Authors note that fixed CBA could be considered as a first-step diagnostic test, while live CBA can be useful in serologic testing of RIA- and fixed CBA-negative samples.

A prospective natural history study and biorepository for patients with myasthenia gravis (EXPLORE-MG2). Guptill JT, Nowak RJ, Guidon AC, Howard JF, Soliven B, Hammett A, Munro Sheldon B, Li Y, Meece T, Aban I, Cutter G, Kaminski HJ, and the EXPLORE-MG2 Study Team. Neurology. 2022 April P.6005. [Presented as poster at the 2022 American Academy of Neurology (AAN) Annual Meeting in Seattle, WA April 2022]

A prospective natural history study and biorepository for patients with myasthenia gravis (EXPLORE-MG2). Guptill JT, Nowak RJ, Guidon AC, Howard JF, Soliven B, Hammett A, Munro Sheldon B, Li Y, Meece T, Aban I, Cutter G, Kaminski HJ, and the EXPLORE-MG2 Study Team. Muscle Nerve. 2022 May 65:S1;S7-S8. [Presented as poster at the 14th MGFA International Conference on Myasthenia and Related Disorders in Miami, Florida in May 2022]

Adapting Disease Specific Outcome Measures Pilot Trial for Telehealth in Myasthenia Gravis (ADAPT-teleMG): An Innovation in Rare Disesae Study Design During the COVID-19 Pandemic. Guidon AC, Guptill JT, Aban I, Cutter G, Soliven B, Benatar M, Kaminski HJ, Nowak RJ, on behalf of MGNet. Muscle Nerve. 2022 May [Presented as poster at the 14th MGFA International Conference on Myasthenia and Related Disorders in Miami, Florida in May 2022, Presented at the EveryLife Foundation for Rare Diseases 2020 Scientific Workshop]

Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Verschuuren JJ, Palace J, Murai H, Tannemaat MR, Kaminski HJ, Bril V. Lancet Neurol. 2022 Feb;21(2):189-202. doi: 10.1016/S1474-4422(21)00463-4. Erratum in: Lancet Neurol. 2022 Mar;21(3):e3. PMID: 35065041.

Henry Kaminski, MD, principal investigator of the Myasthenia Gravis Rare Disease Network (MGNet), and his colleagues have published a review of the present-day therapy for the autoimmune disease myasthenia gravis (MG). Despite there being only 120,000 patients with MG in the US, the well-understood pathophysiology provides a testing ground for drug development to reduce pathogenic antibody in circulation and for B cell depletion to target autoreactive cells. This review paper discusses a new class of agent, FcRn inhibitors, as well as complement inhibitors, which have recently been approved by the US Food and Drug Administration for use in MG. Challenges remain as a cure remains an elusive goal.

Heterogeneity of Acetylcholine Receptor Autoantibody-Mediated Complement Activity in Patients With Myasthenia Gravis. Obaid AH, Zografou C, Vadysirisack DD, Munro-Sheldon B, Fichtner ML, Roy B, Philbrick WM, Bennett JL, Nowak RJ, O'Connor KC. Neurol Neuroimmunol Neuroinflamm. 2022 Apr 26;9(4):e1169. doi: 10.1212/NXI.0000000000001169. PMID: 35473886.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Clinical assays—laboratory tests used to diagnose and monitor patients—only measure autoantibody binding. Therefore, these tests often provide limited insight on disease burden and therapeutic response. To address these limitations, Dr. Kevin C. O’Connor and colleagues at Yale University developed a new assay for evaluating acetylcholine receptor autoantibody–mediated complement activity. Results suggested that a subset of patients lacks association between membrane attack complex formation and autoantibody binding or disease burden. Authors note that this assay provides a better understanding of autoantibody mechanisms and may improve predictions for treatment response. Ultimately, these measurements could help assess disease progression and provide more individualized treatment plans.

Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study. Chia R, Saez-Atienzar S, Murphy N, Chiò A, Blauwendraat C; International Myasthenia Gravis Genomics Consortium, Roda RH, Tienari PJ, Kaminski HJ, Ricciardi R, Guida M, De Rosa A, Petrucci L, Evoli A, Provenzano C, Drachman DB, Traynor BJ. Proc Natl Acad Sci U S A. 2022 Feb 1;119(5):e2108672119. doi: 10.1073/pnas.2108672119.

Novel pathophysiological insights in autoimmune myasthenia gravis. Masi G, O'Connor KC. Curr Opin Neurol. 2022 Aug 5. doi: 10.1097/WCO.0000000000001088. Epub ahead of print. PMID: 35942663

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Affected receptors cannot properly receive nerve signals, impacting voluntary muscle contractions. Generalized muscle weakness and fatigue with prolonged activity are characteristic symptoms, which improve with rest. In this review article, authors summarize recent insights into the development of MG relating to the immune system, including the mechanisms of various MG disease subtypes. They also describe the wide range of treatment options now available to patients with MG, which have uncovered significant differences in clinical responses between subtypes. These differences could help clinicians choose specific therapeutic strategies. Authors conclude that improved understanding of autoantibodies is revealing the mechanisms that guide the development of MG. In the future, authors note that studies on the differences in immunology among MG patients will be key to developing effective, individualized therapies.

Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy. Fichtner ML, Hoehn KB, Ford EE, Mane-Damas M, Oh S, Waters P, Payne AS, Smith ML, Watson CT, Losen M, Martinez-Martinez P, Nowak RJ, Kleinstein SH, O'Connor KC. Acta Neuropathol Commun. 2022 Oct 28;10(1):154. doi: 10.1186/s40478-022-01454-0. PMID: 36307868; PMCID: PMC9617453.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. A small number of individuals with MG have autoantibodies that target muscle-specific tyrosine kinase (MuSK), which is an enzyme that is crucial to the development and maintenance of the neuromuscular junction. Most patients with MuSK MG can experience remission with CD20-mediated B cell depletion therapy (BCDT). However, relapse is common. In this study, researchers explored the factors that lead to relapse after BCDT in patients with MuSK MG. The team studied autoantibody-producing B cells over the course of BCDT, identifying MuSK-specific B cells from nine patients. Researchers isolated two MuSK-specific B cells from two patients who were experiencing relapse after BCDT. Next, the team explored the molecular properties of these B cells and collected longitudinal samples from the patients. Findings showed that a reservoir of pathogenic, autoantibody-producing B cell clones survived BCDT and reemerged several months before relapse. Authors state that this study provides a better understanding of MuSK MG relapse, as well as a possible biomarker for relapse prediction.

The best and worst of times in therapy development for myasthenia gravis. Benatar M, Cutter G, Kaminski HJ. Muscle Nerve. 2022 Nov 2. doi: 10.1002/mus.27742. Epub ahead of print. PMID: 36321730.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. The US Federal Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN)-inhibitors, a type of therapy for autoimmune diseases, for treatment of MG. Several other therapies are also in late stage clinical trials or under regulatory review. However, questions remain about which patients are most likely to benefit from which therapies and how effective the treatments will be. In this review article, researchers discuss therapy development for MG, including the most critical needs for clinical trial readiness and biomarker development. Authors provide a summary of Myasthenia Gravis Rare Disease Network (MGNet) meetings held during the MG Foundation of America International Conference, where these topics were discussed. Authors conclude with a series of recommendations to guide focused research in the most critical areas of therapy development for MG, welcoming ongoing discussion.

Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease. Cleanthous S, Mork AC, Regnault A, Cano S, Kaminski HJ, Morel T. Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes. Mandel-Brehm C, Fichtner ML, Jiang R, Winton VJ, Vazquez SE, Pham MC, Hoehn KB, Kelleher NL, Nowak RJ, Kleinstein SH, Wilson MR, DeRisi JL, O'Connor KC. J Immunol. 2021 Oct 15;207(8):2005-2014. doi: 10.4049/jimmunol.2100225. Epub 2021 Sep 20.

Myasthenia gravis (MG) is a B cell mediated autoimmune disorder that affects neuromuscular transmission. Patients with MG experience severe muscle weakness and increased fatigability. MG pathology is directly facilitated by IgG isotype autoantibodies. Diversity of immunoglobin G V regions (IgG-Vs) is critical for immunity. Recently, the presence of N-linked glycosylation of IgG-Vs (IgG-VN-Glyc) has been shown to contribute to diversity. In autoimmune disorders, researchers have observed higher frequencies of IgG-VN-Glyc when compared to healthy individuals. To test the boarder specificity of elevated IgG-VN-Glyc, MGNet investigators studied patients with distinct subtypes of MG: AChR and MuSK. The investigators focused on examining the B cell repertoire and total IgG, applying complementary sequencing and proteomic-based approaches. When compared with healthy donors, MGNet investigators found that the frequency of IgG-VN-Glyc motifs was increased in the total B cell receptor (BCR) repertoire of patients with MG. The investigators also found that the fraction of total IgG-VN-Glyc in MG serum is elevated, and the presence of IgG-VN-Glyc did not alter binding of several MG patient-derived monoclonal antibodies (mAbs). These findings contribute to efforts to understand the basic biology of IgG-VN-Glyc and its association with disease.

Telemedicine visits in myasthenia gravis: Expert guidance and the Myasthenia Gravis Core Exam (MG-CE). Guidon AC, Muppidi S, Nowak RJ, Guptill JT, Hehir MK, Ruzhansky K, Burton LB, Post D, Cutter G, Conwit R, Mejia NI, Kaminski HJ, Howard JF Jr. Muscle Nerve. 2021 Sep;64(3):270-276. doi: 10.1002/mus.27260. Epub 2021 Jul 7.

Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis. Fichtner ML, Vieni C, Redler RL, Kolich L, Jiang R, Takata K, Stathopoulos P, Suarez PA, Nowak RJ, Burden SJ, Ekiert DC, O'Connor KC. J Exp Med. 2020 Dec 7;217(12):e20200513. doi: 10.1084/jem.20200513.

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology. Fichtner ML, Jiang R, Bourke A, Nowak RJ, O'Connor KC. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776. eCollection 2020.

Complement Inhibitor Therapy for Myasthenia Gravis. Albazli K, Kaminski HJ, Howard JF Jr. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917. eCollection 2020.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America. Green JD, Barohn RJ, Bartoccion E, Benatar M, Blackmore D, Chaudhry V, Chopra M, Corse A, Dimachkie MM, Evoli A, Florence J, Freimer M, Howard JF, Jiwa T, Kaminski HJ, Kissel JT, Koopman WJ, Lipscomb B, Maestri M, Marino M, Massey JM, McVey A, Mezei MM, Muppidi S, Nicolle MW, Oger J, Pascuzzi RM, Pasnoor M, Pestronk A, Provenzano C, Ricciardi R, Richman DP, Rowin J, Sanders DB, Siddiqi Z, Soloway A, Wolfe GI, Wulf C, Drachman DB, Traynor BJ. BMJ Open. 2020 Sep 18;10(9):e037909. doi: 10.1136/bmjopen-2020-037909.

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses. Jiang, R., M. L. Fichtner, K. B. Hoehn, P. Stathopoulos, R.J. Nowak, S. H. Kleinstein, K. C. O’Connor . JCI Insight. 2020 Jul 23;5(14):e136471. doi: 10.1172/jci.insight.136471

Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Meffre E, O'Connor KC. Immunol Rev. 2019 Nov;292(1):90-101. doi: 10.1111/imr.12821. Epub 2019 Nov 12.