International Consensus Guidance for Management of Myasthenia Gravis

Objective To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. Methods In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting “yes”) was used to approve minor changes in grammar and syntax to improve clarity. Results The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. Conclusion This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.

[1]  P. Narayanaswami,et al.  Practice advisory: Thymectomy for myasthenia gravis (practice parameter update) , 2020, Neurology.

[2]  F. Brighina,et al.  Rituximab in AChR subtype of myasthenia gravis: systematic review , 2020, Journal of Neurology, Neurosurgery, and Psychiatry.

[3]  R. Sullivan,et al.  Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum , 2020, Annals of neurology.

[4]  M. Suarez‐Almazor,et al.  Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature , 2019, Journal of Immunotherapy for Cancer.

[5]  R. Gutzmer,et al.  Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy—Review of the Literature and Future Outlook , 2019, Journal of clinical medicine.

[6]  Q. Su,et al.  Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis , 2019, The neurologist.

[7]  M. Benatar,et al.  Long‐term safety and efficacy of eculizumab in generalized myasthenia gravis , 2019, Muscle & nerve.

[8]  A. Marx,et al.  Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial , 2019, The Lancet Neurology.

[9]  S. Yum,et al.  Thoracoscopic thymectomy for juvenile myasthenia gravis , 2019, Pediatric Surgery International.

[10]  D. Lacomis,et al.  Clinical spectrum of neuromuscular complications after immune checkpoint inhibition , 2019, Neuromuscular Disorders.

[11]  F. Zimprich,et al.  High efficacy of rituximab for myasthenia gravis: a comprehensive nationwide study in Austria , 2019, Journal of Neurology.

[12]  M. Freimer.  Faculty Opinions recommendation of International consensus guidance for management of myasthenia gravis: Executive summary. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[13]  M. Freimer.  Faculty Opinions recommendation of Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[14]  M. Nel,et al.  Myasthenic ophthalmoparesis: Time To resolution after initiating immune therapies , 2018, Muscle & nerve.

[15]  Z. Siddiqi,et al.  Rituximab in refractory myasthenia gravis: Extended prospective study results , 2018, Muscle & nerve.

[16]  T. Liewluck,et al.  Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors , 2018, Current Neurology and Neuroscience Reports.

[17]  M. Suarez‐Almazor,et al.  Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease , 2018, Annals of Internal Medicine.

[18]  R. Rojas-García,et al.  The impact of rituximab infusion protocol on the long‐term outcome in anti‐MuSK myasthenia gravis , 2018, Annals of clinical and translational neurology.

[19]  P. Bonomi,et al.  Severe Exacerbation of Myasthenia Gravis Associated with Checkpoint Inhibitor Immunotherapy. , 2017, Journal of neuromuscular diseases.

[20]  Sohita Dhillon.  Eculizumab: A Review in Generalized Myasthenia Gravis , 2018, Drugs.

[21]  G. L. Masson,et al.  Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. , 2017, The Lancet. Neurology.

[22]  S. Topalian.  Targeting Immune Checkpoints in Cancer Therapy. , 2017, JAMA.

[23]  Shigeaki Suzuki,et al.  Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan , 2017, Neurology.

[24]  J. Coward,et al.  Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. , 2017, European journal of cancer.

[25]  R. Tandan,et al.  Rituximab treatment of myasthenia gravis: A systematic review , 2017, Muscle & nerve.

[26]  W. Xu,et al.  Thymectomy is a beneficial therapy for patients with non-thymomatous ocular myasthenia gravis: a systematic review and meta-analysis , 2017, Neurological Sciences.

[27]  F. Bolgert,et al.  Resistant myasthenia gravis and rituximab: A monocentric retrospective study of 28 patients , 2017, Neuromuscular Disorders.

[28]  A. Marx,et al.  Randomized trial of thymectomy in myasthenia gravis. , 2016, Journal of thoracic disease.

[29]  J. Montoya,et al.  Infections associated with the use of eculizumab: recommendations for prevention and prophylaxis , 2016, Current opinion in infectious diseases.

[30]  M. Benatar,et al.  A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis , 2016, Neurology.

[31]  Z. Siddiqi,et al.  Rituximab in refractory myasthenia gravis: a prospective, open‐label study with long‐term follow‐up , 2016, Annals of clinical and translational neurology.

[32]  M. Goldman,et al.  PML in a patient with myasthenia gravis treated with multiple immunosuppressing agents. , 2016, Neurology. Clinical practice.

[33]  M. Benatar,et al.  Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized, controlled trial , 2016, Muscle & nerve.

[34]  J. Wolchok,et al.  Immune Checkpoint Blockade in Cancer Therapy. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  A. Çakcı,et al.  Methotrexate treatment in myasthenia gravis. , 2014, Journal of clinical neuromuscular disease.

[36]  M. Benatar,et al.  A randomized, double‐blind, placebo‐controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis , 2013, Muscle & nerve.

[37]  T. Mineo,et al.  Outcomes after thymectomy in class I myasthenia gravis. , 2013, The Journal of thoracic and cardiovascular surgery.

[38]  Zhenguo Liu,et al.  Extended transsternal thymectomy for the treatment of ocular myasthenia gravis. , 2011, The Annals of thoracic surgery.

[39]  M. Badri,et al.  A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis , 2011, BMC neurology.

[40]  M. Gedizlioğlu,et al.  An unusual complication of immunosuppression in myasthenia gravis: Progressive multifocal leukoencephalopathy , 2009, Neuromuscular Disorders.

[41]  Michael H. Rivner,et al.  120. Methotrexate in myasthenia gravis , 2009, Clinical Neurophysiology.

[42]  R. Brodsky,et al.  Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria , 2007, Nature Biotechnology.

[43]  J. Shrager,et al.  Outcomes after 151 extended transcervical thymectomies for myasthenia gravis. , 2006, The Annals of thoracic surgery.

[44]  J. Shrager,et al.  Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. , 2002, The Annals of thoracic surgery.

[45]  T. de Giacomo,et al.  Thymectomy in the treatment of ocular myasthenia gravis. , 2001, The Journal of thoracic and cardiovascular surgery.

[46]  A. Pujol,et al.  Macroprolactinemia in Childhood and Adolescence: A Cause of Asymptomatic Hyperprolactinemia , 2000, Hormone Research in Paediatrics.

[47]  D B Sanders,et al.  Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. , 2000, Neurology.

[48]  R. Frenck,et al.  Azithromycin compared with rifampin for eradication of nasopharyngeal colonization by Neisseria meningitidis. , 1998, The Pediatric infectious disease journal.

[49]  J. Dichgans,et al.  Ocular myasthenia gravis: response to long-term immunosuppressive treatment. , 1997, Journal of neurology, neurosurgery, and psychiatry.

[50]  B. Daly,et al.  Transsternal radical thymectomy for myasthenia gravis: a 15-year review. , 1989, The Annals of thoracic surgery.

[51]  P. Tonali,et al.  Thymectomy in the treatment of myasthenia gravis: report of 247 patients , 1988, Journal of Neurology.

[52]  D. Dawson.  Progressive multifocal leukoencephalopathy in myasthenia gravis , 1982, Annals of neurology.

[53]  K. Kähler,et al.  Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. , 2019, European journal of cancer.

[54]  B. Burnand,et al.  The RAND/UCLA Appropriateness Method User's Manual , 2001 .