Recommendations Published for Myasthenia Gravis Management

Pushpa Narayanaswami, MD, MB, BS

Based on the latest evidence found in the literature, the Myasthenia Gravis Foundation of America’s (MGFA) appointed task force have published new recommendations for the management of myasthenia gravis (MG), updating the 2016 formal consensus-based guidance.

The panel, which featured Pushpa Narayanaswami, MD, MB, BS, associate professor, Beth Israel Deaconess Medical Center, Harvard University, and 15 other international experts, provided updates on recommendations for thymectomy, as well as new recommendations for the use of rituximab, eculizumab, and methotrexate.

Topics informing new recommendations were selected based on a review of studies of treatment of MG published since 2013. Recommendations were also developed to inform early immunosuppression in ocular MG and the management of MG associated with immune checkpoint inhibitor (ICI) treatment.

Thymectomy

The authors collected data from the randomized, rater-blinded MGTX trial which enrolled patients <65 years of age with acetylcholine receptor antibody positive (AChR-Ab+) generalized non-thymomatous MG of <5 years duration. Using that data, the investigators concluded that thymectomy should be considered early in the disease for patients with generalized MG with AChR-Ab+, aged 18–50 years, to improve clinical outcomes and to minimize immunotherapy requirements and need for hospitalizations.

The procedure should also be strongly considered for those who fail to respond to an initial trial of immunotherapy and should only be performed when a patient is deemed stable and safe, they noted.

Endoscopic and robotic approaches to thymectomy which have shown a good track record for safety and may yield similar results to more aggressive approaches, were unchanged from the 2016 consensus guidance. Consideration for thymectomy in patients with generalized MG without detectable AChR-Ab if they fail to respond to immunosuppressive (IS) therapy was also left unchanged.

Ocular MG

Evidence for recommendations on ocular MG was drawn from a small randomized, controlled trial (RCT), and a retrospective case study of 110 patients with ocular MG who underwent extended transsternal thymectomy.

The panel recommended that ophthalmoparesis or ptosis in ocular MG that is not responding to anti-cholinesterase agents should be treated with immunosuppressant agents if symptoms are functionally limiting. Additionally, corticosteroids should be used as the initial IS agent in ocular MG.

Results from a single small RCT demonstrated that corticosteroids may be effective for ocular MG and may avoid adverse effects associated with high-dose corticosteroids. Lastly, patients with AChR-Ab+ with ocular MG who don’t respond well to acetylcholinesterase medicines and who either prefer not to take IS therapy or are refractory to IS agents may be offered thymectomy.

Rituximab

Rituximab, an anti-CD20 monoclonal antibody, had 1 unchanged recommendation from the 2016 consensus guidance and 1 new recommendation.

The authors concluded that the drug should still be considered as an early therapeutic option in patients with MG with MuSK-Ab who have an unsatisfactory response to initial immunotherapy. However, they noted that the efficacy of rituximab in patients with refractory AChR-Ab MG is uncertain. It may be an option if patients fail or do not tolerate other IS agents.

Methotrexate

Studies on the use of methotrexate in MG are limited and the available data do not provide convincing evidence of efficacy, according to the authors.

Narayanaswami et al. recommended that although the evidence from RCTs is lacking, oral methotrexate can be considered as a steroid-sparing agent in patients with generalized MG who have not tolerated or responded to steroid-sparing agents that are better supported by RCT data.

Eculizumab

Eculizumab, a humanized monoclonal antibody against the terminal C5 complement molecule, had recommendations supported by a phase 2 RCT and the phase 3 REGAIN study. The authors concluded that eculizumab should be considered in the treatment of severe, refractory, AChR-Ab+ generalized MG. Due to the limited data on cost and efficacy comparing eculizumab and other treatments, the drug should be considered after trials of other immunotherapies have been unsuccessful in meeting treatment goals.

Previously established recommendations of the Advisory Committee on Immunization Practice (ACIP) or other local guidelines regarding immunization meningococcal meningitis should be followed prior to treatment with eculizumab. The group did noted that future research on the efficacy of eculizumab in other MG populations (MG with thymoma, seronegative MG), and in other stages of disease (MG crises, exacerbations, early therapy in non-refractory AChR-Ab+ MG) is needed.

Immune Checkpoint Inhibitors

Candidates for ICIs should discuss the risk of MG and other immune-mediated neurologic illnesses. There is currently no evidence to support or refute the utility of AChR antibody testing in patients without MG prior to starting ICIs, according to Narayanaswami et al.

MG associated with ICIs is generally severe, with a high rate of respiratory crises. Those with pre-existing MG are not constituted to an absolute contraindication to the use of ICIs, at least in patients with well-controlled disease (minimal manifestation [MM] status or better).

Patients with pre-existing MG should avoid combined therapy (anti-CTLA-4 plus anti-PD1/PD-L1 monoclonal antibodies), given the higher potential for severe immune-related adverse events (irAEs). Additionally, it is mandatory to closely monitor this patient subgroup, particularly for respiratory and bulbar function. Despite a less than satisfactory therapeutic response to ICIs in patients receiving immunosuppressants, MG treatment should be maintained and may even be restarted in patients whose MG is in remission prior to treatment with ICIs.

Early aggressive treatment with high-dose steroids in combination with plasma exchange or intravenous immunoglobulin (IVIg) may be required in patients who develop overt MG while on ICIs. Oncologic status should be the ultimate determinant when deciding to withdraw ICIs.

"This continues to be a living document, which will require periodic review and updates to reflect new information relevant to the management of MG,” Narayanaswami et al concluded.

REFERENCE

Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis. Neurology. Published online November 3, 2020. doi: 10.1212/WNL.0000000000011124.