A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis

Mamatha Pasnoor(University of North Carolina at Chapel Hill), Jianghua He(University of North Carolina at Chapel Hill), Laura Herbelin(University of North Carolina at Chapel Hill), Ted M. Burns(University of North Carolina at Chapel Hill), Sharon Nations(University of North Carolina at Chapel Hill), Vera Bril(University of North Carolina at Chapel Hill), Annabel K. Wang(University of North Carolina at Chapel Hill), Bakri Elsheikh(University of North Carolina at Chapel Hill), John T. Kissel(University of North Carolina at Chapel Hill), David Saperstein(University of North Carolina at Chapel Hill), J. Aziz Shaibani(University of North Carolina at Chapel Hill), Carlayne E. Jackson(University of North Carolina at Chapel Hill), Andrea Swenson(University of North Carolina at Chapel Hill), James F. Howard(University of North Carolina at Chapel Hill), Namita Goyal(University of North Carolina at Chapel Hill), William David(University of North Carolina at Chapel Hill), Matthew Wicklund(University of North Carolina at Chapel Hill), Michael Pulley(University of North Carolina at Chapel Hill), Mara L. Becker(University of North Carolina at Chapel Hill), Tahseen Mozaffar(University of North Carolina at Chapel Hill), Michael Benatar(University of North Carolina at Chapel Hill), Robert Pazcuzzi(University of North Carolina at Chapel Hill), Ericka Simpson(University of North Carolina at Chapel Hill), Jeffrey Rosenfeld(University of North Carolina at Chapel Hill), Mazen M. Dimachkie(University of North Carolina at Chapel Hill), Jeffrey Statland(University of North Carolina at Chapel Hill), Richard J. Barohn(University of North Carolina at Chapel Hill), The Methotrexate in MG Investigators of the Muscle Study Group(University of North Carolina at Chapel Hill), The Methotrexate in MG Investigators of the Muscle Study Group(University of North Carolina at Chapel Hill), Richard J. Barohn(University of North Carolina at Chapel Hill), Mamatha Pasnoor(University of North Carolina at Chapel Hill), Mazen M. Dimachkie(University of North Carolina at Chapel Hill), L McVey(University of North Carolina at Chapel Hill), Jeffrey Statland(University of North Carolina at Chapel Hill), Laura Herbelin(University of North Carolina at Chapel Hill), Jennifer Miller, Sharon Nations(The University of Texas Southwestern Medical Center), Nina Gorham(University of North Carolina at Chapel Hill), Rhonda McLin, Carlayne E. Jackson(The University of Texas Southwestern Medical Center), Pam Kittrell(University of North Carolina at Chapel Hill), Deborah L. Myers, Ted M. Burns(The University of Texas Southwestern Medical Center), Kristen Keller(University of North Carolina at Chapel Hill), Amruta Joshi, Michael Benatar(University of North Carolina at Chapel Hill), Alexandra Waltz(University of North Carolina at Chapel Hill), Bakri Elsheikh(The University of Texas Southwestern Medical Center), John T. Kissel(The University of Texas Southwestern Medical Center), Amy Bartlett, Colleen Pineda(University of North Carolina at Chapel Hill), Wendy King(University of North Carolina at Chapel Hill), Annabel K. Wang(The University of Texas Southwestern Medical Center), Tahseen Mozaffar(The University of Texas Southwestern Medical Center), Verónica Puertas‐Martín(University of North Carolina at Chapel Hill), Brian Minton, Jeffrey Rosenfeld(The University of Texas Southwestern Medical Center), Christine Banda(University of North Carolina at Chapel Hill), Kim Voelz, Robert M. Pascuzzi(University of North Carolina at Chapel Hill), Sandra Guingrich, James F. Howard(University of North Carolina at Chapel Hill), Manisha Chopra(University of North Carolina at Chapel Hill), Namita Goyal(The University of Texas Southwestern Medical Center), William David(University of North Carolina at Chapel Hill), Owen A. O’Connor, Andrea Swenson(University of North Carolina at Chapel Hill), Jeri Sieren, Aziz Shaibani(University of North Carolina at Chapel Hill), Chia Arif(University of North Carolina at Chapel Hill), Ericka Simpson(University of North Carolina at Chapel Hill), Sharon Halton(University of North Carolina at Chapel Hill), Luis Lay, Matthew Wicklund(University of North Carolina at Chapel Hill), Heidi M. Runk, David Saperstein(University of North Carolina at Chapel Hill), Nicole Hank, Michael Pulley(University of North Carolina at Chapel Hill), Lisa Smith, Vera Bril(The University of Texas Southwestern Medical Center), P. Nwe(University of North Carolina at Chapel Hill), Mehran Soltani, Eduardo Ng, Angela Genge, Austin Zaloum(University of North Carolina at Chapel Hill), Kristiana Salmon(University of North Carolina at Chapel Hill), Mara L. Becker(University of North Carolina at Chapel Hill), Annabel K. Wang(University of North Carolina at Chapel Hill), Ted M. Burns(University of North Carolina at Chapel Hill), Richard J. Barohn(University of North Carolina at Chapel Hill), Mamatha Pasnoor(University of North Carolina at Chapel Hill), Laura Herbelin(The University of Texas Southwestern Medical Center), Jianghua He(The University of Texas Southwestern Medical Center), Kevin Latinis, Anthony Amato, Erik Ensrud, Jonathan Goldstein
Neurology
June 16, 2016
10.1212/wnl.0000000000002795
Cited by 130Open Access
Full Text

Abstract

OBJECTIVE: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). METHODS: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. RESULTS: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). CONCLUSIONS: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

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