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Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. A number of molecules, including ion channels and other proteins at the neuromuscular junction, may be targeted by autoantibodies leading to abnormal neuromuscular transmission. In approximately 85% of patients, autoantibodies, directed against the postsynaptic nicotinic acetylcholine receptor can be detected in the serum and confirm the diagnosis, but in general, do not precisely predict the degree of weakness or response to therapy. Antibodies to the muscle-specific tyrosine kinase are detected in approximately 50% of generalized myasthenia gravis patients who are seronegative for anti-acetylcholine receptor antibodies, and levels of anti-muscle-specific tyrosine kinase antibodies do appear to correlate with disease severity and treatment response. Antibodies to other muscle antigens may be found in the subsets of myasthenia gravis patients, potentially providing clinically useful diagnostic information, but their utility as relevant biomarkers (measures of disease state or response to treatment) is currently unclear.

Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.

The major contribution of this Series is the comprehensive information that they provide about disease mechanisms,1 new drugs in development,2 and known and potential biomarkers.3 Effective and efficient treatment of myasthenia gravis requires close and sustained medical attention. Clinical measures of disease severity in myasthenia gravis are limited by their inherent subjectivity, and most clinical trials in myasthenia gravis show a significant placebo effect on these measures. Caia Image/Science Photo Library Guidelines for reporting research on body fluid biomarkers for neurological disorders have been developed to enhance and accelerate selection of potential biomarkers for clinical development.10 For a biomarker to be useful in confirming the efficacy of a therapeutic modality, it should meet specific criteria, which require more than correlation between the marker and clinical severity.11 For example, although there might be a correlation between antibody concentrations and clinical improvement, a retrospective review of 151 patients with myasthenia gravis reported that acetylcholine receptor antibody concentrations fell in almost all patients who improved clinically, but also in most patients who did not.12 Thus, acetylcholine receptor antibody concentrations were not recommended by the study authors as a biomarker of clinical improvement in myasthenia gravis, although they could be an indicator of adequate immunotherapy.

In this issue of Neurotherapeutics, Li et.al. report a large retrospective study of the beneficial effects of thymectomy on the progression of ocular myasthenia gravis (OMG) to generalized MG (GMG) (Huanhuan et al. in Neurotherapeutics XX, 2021). This paper demonstrates a more than 50% reduction in the risk of GMG when a thymectomy was performed on these patients. The authors conclude with the recommendation that well-designed clinical trials be performed to evaluate the potential that thymectomy in OMG reduces the burden of GMG.

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5–31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13–30]). The mean change in MG-QOL15r was –10·4 (95% CI –18·9 to –1·3) with mycophenolate mofetil and –6·8 (–17·2 to 3·6) with azathioprine (mean difference –3·3, 95% CI –7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI –0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI –4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

ObjectivesTo approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families.DesignRetrospective cohort study.SettingClinics across North America.ParticipantsThe study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis.MethodsPhenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed.ResultsAmong 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members.DiscussionThe familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and increases muscle force following subtetanic nerve input. In an animal model of myasthenia gravis (MG), single oral doses of tirasemtiv improved muscle force and reduced fatigability. The purpose of this study was to determine the effect of single doses of tirasemtiv on skeletal muscle function and fatigability in patients with generalized MG. Thirty-two patients with acetylcholine receptor-antibody positive MG and muscle weakness received single doses of tirasemtiv (250 mg or 500 mg) or placebo in a double-blind, randomized treatment sequence with each treatment separated by at least 1 week. Outcome measures included the Quantitative MG Score (QMG), MG Composite, Manual Muscle Testing, and forced vital capacity. At 6 h after dosing, tirasemtiv produced dose-related improvements from baseline in the QMG score (slope: –0.49 QMG point per 250 mg; p = 0.02) and in percent predicted forced vital capacity (slope: 2.2 % per 250 mg; p = 0.04). QMG improved >3 points in twice as many patients after 500 mg tirasemtiv than after placebo. Both doses of tirasemtiv were well tolerated; there were no premature terminations or serious adverse events. The results of this study suggest that tirasemtiv may improve muscle function in MG and will be used to support further development of tirasemtiv in neuromuscular diseases.

Recent advances in the diagnosis and treatment of acquired myasthenia gravis (MG) are reviewed. Increased awareness about the need for more uniform methods of reporting treatment trials for MG has prompted systematic review of the literature and inspired an effort to develop better classifications and disease-specific outcome measures. New antibodies have been discovered in patients with seronegative MG, possibly defining an immunologically distinct form of the disease. A new immunosuppressant, mycophenolate mofetil, may be an additional and safe option in the treatment of MG. Other work supports the possibility of developing a vaccine against MG suitable for trial in humans.