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A task force of the Myasthenia Gravis Foundation of America recently published a formal consensus statement intended to be a treatment guide for clinicians caring for myasthenia gravis (MG) patients worldwide. Its development was stimulated by the fact that there is generally no accepted standard of care for MG, and no one treatment is best for all MG patients. Also, there are few randomized trials of treatments in current use, and the generalizability of the few trials that have been successful may be difficult. Fifteen international experts in MG participated in the consensus process, which used a simple consensus to develop preliminary definitions and the RAND/UCLA Appropriateness Method to quantify agreement on treatment guidance statements for seven topics: symptomatic and immunosuppressive treatment, intravenous immunoglobulin and plasma exchange, impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG with muscle-specific tyrosine kinase antibodies, and MG in pregnancy. The executive summary of the guidance statement was published with open access to facilitate access by patients and healthcare professionals, and the full statement, with extensive background information, is available online. The guidance statement is a living document that will require updates as new treatments and new information on current treatments become available., (© 2018 New York Academy of Sciences.)

Recently competed clinical trials of therapeutics for myasthenia gravis have varied widely in design, but also perhaps in less explicit ways. We explore ways in which these design characteristics may have influenced recruitment and results, as well as the implications for forthcoming studies. Trial eligibility criteria may inadvertently select for incident versus prevalent cases or patients with relatively mild versus more severe disease. Trial enrichment with patients who have relatively mild disease may limit the sensitivity of the trial to detect a therapeutic effect. Enrichment for patients with more severe disease may introduce confounds caused by regression toward the mean. Overly narrow eligibility may limit the generalizability of results. An exclusive focus on incident cases may hamper recruitment, as may many other factors, such as access to the experimental therapeutic treatment outside of the trial or following completion of the double-blind treatment period. We illustrate how other design characteristics (e.g., treatment duration, strategy for steroid tapering, selection of the primary outcome, and principal analytic approach) may affect the sensitivity of a trial to demonstrate therapeutic effects. Finally, we consider the importance of placebo effects, being careful to differentiate these from therapeutic effects observed in the placebo group, and discuss how the use of combined outcome measures may minimize placebo effects., (© 2017 New York Academy of Sciences.)

Efficacy of Prednisone in the Treatment of Ocular Myasthenia (EPITOME) is a multicenter, randomized, double blind, placebo-controlled trial that is being conducted under the auspices of the Muscle Study Group. EPITOME is the first randomized control trial in patients with ocular myasthenia and aims to evaluate the efficacy and tolerability of prednisone over a period of four months in patients with newly diagnosed ocular myasthenia whose symptoms have failed to remit in response to a trial of cholinesterase inhibitor therapy., (© 2012 New York Academy of Sciences.)

Biomarkers are defined as characteristics (e.g., proteins, RNA, single nucleotide polymorphisms, imaging) that are objectively measured and evaluated as indicators of pathogenic processes or pharmacologic responses to therapeutic intervention. Biomarkers are important in clinical trials where the robust biomarker reflects the underlying disease process in a sensitive and reliable manner. For myasthenia gravis (MG), acetylcholine receptor and muscle-specific kinase antibodies, as well as single-fiber electromyography, serve as excellent biomarkers for diagnosis but do not adequately substitute for clinical evaluations to predict treatment response. New technologies are emerging that enable broad biomarker discovery in biological fluids. Biomarker evaluation is ideally done in the context of longitudinal clinical trials. The MGTX trial has collected plasma and serum for RNA and protein analysis and thymus, which will allow robust biomarker discovery. The ultimate goal will be to identify candidates for a reliable substitute for a clinically meaningful end point that is a direct measure of the effectiveness of a therapy in the context of a continuum of disease natural history and a patient's overall well-being., (© 2012 New York Academy of Sciences.)

The primary study [MGTX] aims to answer three questions: does extended transsternal thymectomy combined with the prednisone protocol, when compared with the prednisone protocol alone: (1) result in a greater improvement in myasthenic weakness, (2) result in a lower total dose of prednisone, thus decreasing the likelihood of concurrent and long-term toxic effects, (3) enhance the quality of life by reducing adverse events and symptoms associated with the therapies? Inclusion criteria are MGFA Class 2, 3, or 4; acetylcholine receptor antibody positive; age at least 18.0 years and <60.0 years; MG history of <3 years. Patients can be prednisone naïve or not. The National Institute for Neurological Disorders and Stroke awarded funding for MGTX in September 2005, and NIH awarded funding for the ancillary Biomarkers study (BioMG) in February 2006. Diverse regulatory obstacles have been encountered in this international study, but we now have a total of over 70 centers in 22 countries (North America, South America, Europe, Australasia, South Africa) either actively recruiting or at various levels of readiness.

Antibodies to muscle-specific receptor tyrosine kinase (MuSK-Ab) are detected in approximately 40% of generalized acetylcholine receptor (AChR) antibody-negative myasthenia gravis (MG). Based on a growing number of clinical series, a MuSK-Ab-positive phenotype is emerging. While these clinical patterns are not wholly distinct from either AChR-Ab-positive or seronegative (both AChR-Ab and MuSK-Ab-negative) MG, they are still helpful in identifying these patients. MuSK-Ab-positive MG patients are predominantly female with more prominent cranial and bulbar involvement and more frequent crises than other MG populations. Disease onset tends to be earlier, generally by the third or fourth decade. MuSK-Ab-positive patients are more likely to display poor tolerance of or a lack of improvement with anticholinesterase agents. The yield of repetitive nerve stimulation with conventional limb muscles is lower in these patients, but at least three-quarters demonstrate abnormalities on recording of facial-innervated muscles. Similarly, single-fiber electromyography of distal limb muscles tends to have a lower yield of abnormality in MuSK-Ab-positive patients than either AChR-Ab-positive or seronegative MG, whereas jitter is increased in nearly all MuSK-positive patients when proximal limb or cranial musculature is studied.

Thymectomy has been regularly used in the management of nonthymomatous autoimmune myasthenia gravis (MG), but its benefits have not been established in a randomized, controlled trial. The widespread use of thymectomy in MG patients without thymoma is largely based on retrospective, nonrandomized case series that have produced a consensus that the procedure is sometimes beneficial. Still, the benefits and utilization of thymectomy are actively debated among MG experts. In this paper, we describe the development of a multicenter, international trial to determine whether extended transsternal thymectomy reduces corticosteroid requirements for patients with generalized AChR antibody-positive nonthymomatous MG.