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Methotrexate Not Effective in Generalized Myasthenia Gravis
by S. Andrew Josephson
Update to Chapter 461: Myasthenia Gravis and Other Diseases of the Neuromuscular Junction
Patients with myasthenia gravis (MG) are typically treated with immunosuppressive medications in addition to pyridostigmine. Corticosteroids are the mainstay of treatment, but their long-term use is limited by a number of potential side effects. As a result, patients are usually quickly started on a steroid-sparing immunosuppressive agent in order to reduce the dose of corticosteroids required. While azathioprine and cyclosporine have some evidence to support their use in this setting, trials of other medications including mycophenolate mofetil have not shown benefit. Methotrexate is a commonly used inhibitor of dihydrofolate reductase that is well tolerated and used in many autoimmune conditions. Therefore a recent trial of methotrexate in MG was a potentially important advance (Pasnoor et al, 2016).
The authors conducted a 12-month, randomized, double-blind, placebo-controlled trial across 19 sites in North America. Eligible patients were older than 18 years with positive acetylcholine receptor antibodies and a clinical diagnosis of generalized MG. Those with contraindications to methotrexate or those who had taken a steroid-sparing agent within the past 3 months were ineligible. Patients also had to be taking a stable dose of prednisone for at least 1 month prior to enrollment and then were randomized to a dose of up to 20 mg weekly of oral methotrexate or placebo. Based on a standard protocol, prednisone was then tapered in the setting of clinical improvement or increased with clinical worsening. The primary outcome examined was the 9-month prednisone area under the dose-time curve (AUDTC) in the two groups between months 4 and 12.
A total of 50 patients were randomized in the trial, with a mean age of around 67 years and a male predominance (70%). Baseline mean and median prednisone dose were balanced between the 2 groups. The authors found no significant difference in the AUDTC between methotrexate and placebo (p = .26). The estimated between-group difference corresponded to only around 1.9 mg/day less prednisone in the methotrexate group. A number of secondary outcomes were examined at 12 months, including composite MG scores and activities of daily living scores—and again no significant differences were found between the groups. Using the standard weaning protocol, the average daily prednisone dose decreased in both of the groups.
There were no methotrexate-related serious adverse events observed, and the rate of elevated liver function tests was similar in the two groups. However, 8 of the participants withdrew during the course of the study (7 assigned to placebo) for various reasons, including worsening symptoms (n = 3), myalgias, comorbid illness, elevated liver function tests, death (stroke), and travel problems. All analyses were performed using an intent-to-treat plan.
This study failed to demonstrate that methotrexate reduced the dose of corticosteroids in patients with myasthenia gravis. As the authors point out, the study illustrated many of the pitfalls of these types of investigations in MG—including selecting an appropriate outcome measure and the observation that steroids are likely a very effective therapy used in all patients at the time of diagnosis, making many add-on trials difficult due to inadequate power, inadequate effect, or both. For now, physicians should not use methotrexate as a first-line steroid-sparing medication in their patients with generalized MG.
– Josephson SA. Methotrexate Not Effective in Generalized Myasthenia Gravis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo JL. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. https://accessmedicine.mhmedical.com/updatesContent.aspx?gbosid=280830§ionid=79756727. Accessed August 09, 2016.
Reference
Pasnoor M et al.: A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 87:57, 2016. [PubMed® abstract]
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Publicado en Actividades Académicas, Actualización medica, actualizaciones, Curso de Educación Continua, Neurologia |