Is the treatment of myasthenia gravis improving?

In this issue of Neurology ®, Mendoza et al.1 report the validation of a patient- acceptable symptom state (PASS) in myasthenia gravis (MG). But can the answer yes/no to a simple question serve a purpose? In MG, the immune system mounts an attack against proteins present in the postsynaptic neuromuscular junction membrane, which leads to weakness and fatigability in skeletal muscles.2 This weakness may also include muscles controlling breathing, producing life-threatening morbidity. Indeed, the outlook for a patient diagnosed with MG in the first part of the 20th century was certainly grim, with a mortality rate in the 30% range. Over the last century, treatment has improved in several incremental steps. In 1934, Mary B. Walker published her seminal discovery of amelioration of muscle fatigue with acetylcholinesterase blockers, but mortality rates in MG crises (and cholinergic crises due to overuse of these medications) remained high even after the introduction of supported ventilation.3 In the 1960s to 1970s, the uncovering of the autoimmune basis of MG provided a rationale for using corticosteroids, other oral immunosuppressants, and later immunoglobulins. These still represent a cornerstone in MG treatment, with oral immunosuppressants such as azathioprine, mycophenolate, or cyclosporin introduced to reduce the risks of steroid-induced side effects.4 However, changes in clinical practices have been guided mostly by empirical evidence rather than findings from randomized trials. For example, it was not until 2016 that thymectomy, after some 75 years of use, was shown in a randomized study to improve 3-year outcomes in acetylcholine receptor antibody–positive nonthymomatous MG. One of the dual primary outcomes in the international thymectomy trial was reduction in the Quantitative Myasthenia Gravis Scale (QMGS) score.5 In contrast, several trials of oral immunosuppressants as add-on therapy to prednisone using the QMGS score as outcome have failed to show benefit over the control arm.6 This could relate at least in part to the QMGS being a provider-administered test of strength in different muscle groups that does not take into account differences in individual capacities. As part of the effort to move to a more patient-centered approach, the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale was used as the primary outcome in the Safety and Efficacy of Eculizumab in the Refractory Generalized Myasthenia Gravis (REGAIN) trial, which formed the basis for regulatory approval of eculizumab, a C5 complement blocker, for refractory acetylcholine receptor antibody–positive nonthymomatous MG.7 Although improvement of the MG-ADL score in the active treatment arm failed to reach significance over placebo in a worse-rank analysis, the study showed significant benefit with the QMGS and a quality of life scale (Myasthenia Quality of Life [MG-QoL15]). The REGAIN study exemplifies the need for, and difficulty of, capturing relevant changes in a patient-centered way, an issue also relevant in real-world practice. Most MG clinical experts hold the opinion that with current treatments we adequately control MG symptoms reasonably well in the majority of patients, a clear advance from times past.