New Consensus Guidance on Myasthenia Gravis

July 12, 2016

A new international consensus guidance for the management of myasthenia gravis has been released.

The guidance, published online in Neurology on June 29, is intended to be a guide for clinicians caring for patients with myasthenia gravis worldwide.

Lead author, Donald B. Sanders, MD, Duke University Medical Center, Durham, North Carolina, explained to Medscape Medical News that many different therapies are used for myasthenia gravis, but few "if any" good clinical trials have provided the data necessary for guidelines based on a high level of evidence.

"So it was felt that a consensus of experts with wide experience of treating the condition would be useful," Dr Sanders said. "These guidance statements have thus been determined that way. This is the first such guidance issued on myasthenia gravis."

The hope is that this document will provide a reference for clinicians who don't see many patients with myasthenia gravis, he added. "This is a relatively rare disease, so most neurologists would not see it very often, and as it is so heterogeneous there is not only one way to treat it. It is important to identify the correct subset of the disease and to use the therapy appropriate for that subset. Doctors who do not have much experience of this condition need guidance on that."

He pointed out that the document also provides guidance on therapies not approved for myasthenia gravis. "Many medicines used in myasthenia gravis are unapproved for such use. Third-party payers need some justification to pay for these therapies."

Consensus Approach

Dr Saunders explained that the method of reaching consensus — known as the RAND/UCLA approach — involves expert members of the panel voting anonymously on each item, which is then given a score between 1 and 9 based on the vote: 9 being highly appropriate and 1 being highly inappropriate.

The panel is then asked to comment on the recommendation, and then the process is repeated up to three times until a consensus is reached. "We managed to reach consensus on most items this way," he said.

The document notes that acquired myasthenia gravis is a disorder of neuromuscular transmission, resulting from binding of autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and the disease is estimated to affect more than 700,000 people worldwide.

The increasing use of immunomodulating therapies has been a major factor in improving the prognosis for patients with this condition in recent years, but the various treatment options must be weighed in the context of individual patient factors.

The document makes the following consensus guidance treatment statements:

  • Pyridostigmine should be part of the initial treatment in most patients. The dose should be adjusted as needed on the basis of symptoms. The ability to discontinue pyridostigmine may indicate that the patient has met treatment goals and may guide the tapering of other therapies, the authors say. Corticosteroids or immunosuppressive therapy should be used in all patients who have not met treatment goals after an adequate trial of pyridostigmine.

  • A nonsteroidal immunosuppressive agent should be used alone when corticosteroids are contraindicated or the patient declines them or can be used initially in conjunction with corticosteroids when the risk for steroid side effects is high based on medical comorbidities. A nonsteroidal immunosuppressive agent should be added to corticosteroids when significant steroid side effects develop, response to steroids is inadequate, or the steroid dose cannot be reduced because of symptom relapse.

  • Nonsteroidal immunosuppressive agents that can be used include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus. There is widespread variation because of the sparse literature comparing these agents. Expert consensus and some clinical trial evidence support the use of azathioprine as a first-line immunosuppressive agent. Evidence also supports the use of cyclosporine, but potential serious adverse effects and drug interactions limit its use. There is no good evidence for mycophenolate and tacrolimus, but both are widely used.

  • Patients with refractory myasthenia gravis should be referred to an expert in management of the condition, and the following therapies may also be used: chronic intravenous immunoglobulin and plasma exchange, cyclophosphamide, and rituximab (for which evidence of efficacy is building, but for which formal consensus could not be reached).

  • Immunosuppressive agent dosage and duration of treatment: Once patients achieve treatment goals, the corticosteroid dose should be gradually tapered. In many patients, continuing a low dose of corticosteroids long term can help to maintain the treatment goal. For nonsteroidal immunosuppressive agents, once treatment goals have been achieved and maintained for 6 months to 2 years, the dose should be tapered slowly to the minimal effective amount. Dosage should be adjusted no more frequently than every 3 to 6 months. Tapering of drugs is associated with risk for relapse, which may necessitate upward adjustments in dose. The risk for relapse is higher in patients who are symptomatic or after rapid taper. It is usually necessary to maintain some immunosuppression for many years, sometimes for life.

  • Patients must be monitored for potential adverse effects and complications from immunosuppressive drugs. Changing to an alternative agent should be considered if adverse effects and complications are medically significant or create undue hardship for the patient.

Dr Sanders pointed out that one important subset of patients that need to be identified are those with antibodies to muscle-specific kinase, who often do not respond to cholinesterase inhibitors. "These patients can be identified with a blood test and need a different treatment," he said.

He noted that one item the panel could not agree on was the use of azathioprine in pregnant women.

"There was a pretty strong feeling in favor of this," he noted. "It is allowed almost everywhere else in the world, but in the US azathioprine has been considered teratogenic and there is concern about medico-legal liability, although this concern does not appear to be shared elsewhere. In the US this is still embedded in our culture."

He reported that although most panel members believed azathioprine was not teratogenic, there was a "strongly held minority view that it was so in the end we have published the result of the votes." This shows a median score of 8 for use of azathioprine in pregnancy, "so a strong degree of approval but the range was 1 to 9, showing that at least one person voted that the recommendation was highly appropriate least one person voted that it was highly inappropriate. So we have provided information but we are leaving the final decision to the treating physician."

Dr Sanders believes this approach to formulating guidance should be used in other conditions. "There are many diseases in which there is wide variability with many different possible therapies. The goal is to put all those various different therapies into balance."

He acknowledges, however, that this is not a completely accepted approach as yet. "We had a challenge to get journals to accept this approach — it was a long and arduous process to get this paper published. But we now hope this guidance will be endorsed by organizations such as the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine."

A "Highly Commendable Effort"

In an accompanying editorial, Marinos C. Dalakas, MD, Thomas Jefferson University, Philadelphia, Pennsylvania, notes that myasthenia gravis requires long-term maintenance therapy but the immunosuppressive agents used are "variably applied, even among MG [myasthenia gravis] experts, depending on mentorship, immunotherapy background, and the way we assess existing trials."

He says, "Convening an experienced panel to provide consensus guidance on how best to treat MG is therefore helpful."

Dr Dalakas describes the current guidance document as "a highly commendable effort," adding that the authors have "acknowledged that other experts may have opposing views and assured readers that their goal was to offer guidance and not to dictate formal legally binding guidelines or to influence payment and insurance decisions. Accordingly, the consensus is an overall helpful guide for the practicing neurologist."

He points out that this is a living document that should be frequently updated with results from upcoming trials — most importantly, the just-completed thymectomy trial.

Consensus on MG treatment remains an unfinished business and so diversity of opinion may continue for some time," he concludes.

The guidance was supported by a grant from the Myasthenia Gravis Foundation of America. Dr Sanders is a consultant for Accordant Health Services, Cytokinetics, GlaxoSmithKline, and Jacobus Pharmaceutical Co. Dr Dalakas has disclosed no relevant financial relationships.

Neurology. Published online June 29, 2016. Full text Editorial

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