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

Mamatha Pasnoor, Jianghua He, Laura Herbelin, Ted M. Burns, Sharon Nations, Vera Bril, Annabel K. Wang, Bakri H. Elsheikh, John T. Kissel, David Saperstein, J. Aziz Shaibani, Carlayne E Jackson, Andrea Swenson, James F. Howard, Namita Goyal, William David, Matthew Wicklund, Michael Pulley, Mara Becker, Tahseen MozaffarMichael Benatar, Robert Pazcuzzi, Ericka Simpson, Jeffrey Rosenfeld, Mazen M. Dimachkie, Jeffrey M. Statland, Richard J. Barohn

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)57-64
Number of pages8
JournalNeurology
Volume87
Issue number1
DOIs
StatePublished - Jul 5 2016

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Myasthenia Gravis
Methotrexate
Randomized Controlled Trials
Prednisone
Placebos
Outcome Assessment (Health Care)
Steroids
Clinical Trials
Cholinergic Receptors
Activities of Daily Living
Quality of Life
Confidence Intervals
Pain
Muscles
Antibodies

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pasnoor, M., He, J., Herbelin, L., Burns, T. M., Nations, S., Bril, V., ... Barohn, R. J. (2016). A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology, 87(1), 57-64. https://doi.org/10.1212/WNL.0000000000002795

A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. / Pasnoor, Mamatha; He, Jianghua; Herbelin, Laura; Burns, Ted M.; Nations, Sharon; Bril, Vera; Wang, Annabel K.; Elsheikh, Bakri H.; Kissel, John T.; Saperstein, David; Shaibani, J. Aziz; Jackson, Carlayne E; Swenson, Andrea; Howard, James F.; Goyal, Namita; David, William; Wicklund, Matthew; Pulley, Michael; Becker, Mara; Mozaffar, Tahseen; Benatar, Michael; Pazcuzzi, Robert; Simpson, Ericka; Rosenfeld, Jeffrey; Dimachkie, Mazen M.; Statland, Jeffrey M.; Barohn, Richard J.

In: Neurology, Vol. 87, No. 1, 05.07.2016, p. 57-64.

Research output: Contribution to journalArticle

Pasnoor, M, He, J, Herbelin, L, Burns, TM, Nations, S, Bril, V, Wang, AK, Elsheikh, BH, Kissel, JT, Saperstein, D, Shaibani, JA, Jackson, CE, Swenson, A, Howard, JF, Goyal, N, David, W, Wicklund, M, Pulley, M, Becker, M, Mozaffar, T, Benatar, M, Pazcuzzi, R, Simpson, E, Rosenfeld, J, Dimachkie, MM, Statland, JM & Barohn, RJ 2016, 'A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis', Neurology, vol. 87, no. 1, pp. 57-64. https://doi.org/10.1212/WNL.0000000000002795
Pasnoor, Mamatha ; He, Jianghua ; Herbelin, Laura ; Burns, Ted M. ; Nations, Sharon ; Bril, Vera ; Wang, Annabel K. ; Elsheikh, Bakri H. ; Kissel, John T. ; Saperstein, David ; Shaibani, J. Aziz ; Jackson, Carlayne E ; Swenson, Andrea ; Howard, James F. ; Goyal, Namita ; David, William ; Wicklund, Matthew ; Pulley, Michael ; Becker, Mara ; Mozaffar, Tahseen ; Benatar, Michael ; Pazcuzzi, Robert ; Simpson, Ericka ; Rosenfeld, Jeffrey ; Dimachkie, Mazen M. ; Statland, Jeffrey M. ; Barohn, Richard J. / A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. In: Neurology. 2016 ; Vol. 87, No. 1. pp. 57-64.
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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.",
author = "Mamatha Pasnoor and Jianghua He and Laura Herbelin and Burns, {Ted M.} and Sharon Nations and Vera Bril and Wang, {Annabel K.} and Elsheikh, {Bakri H.} and Kissel, {John T.} and David Saperstein and Shaibani, {J. Aziz} and Jackson, {Carlayne E} and Andrea Swenson and Howard, {James F.} and Namita Goyal and William David and Matthew Wicklund and Michael Pulley and Mara Becker and Tahseen Mozaffar and Michael Benatar and Robert Pazcuzzi and Ericka Simpson and Jeffrey Rosenfeld and Dimachkie, {Mazen M.} and Statland, {Jeffrey M.} and Barohn, {Richard J.}",
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T1 - A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis

AU - Pasnoor, Mamatha

AU - He, Jianghua

AU - Herbelin, Laura

AU - Burns, Ted M.

AU - Nations, Sharon

AU - Bril, Vera

AU - Wang, Annabel K.

AU - Elsheikh, Bakri H.

AU - Kissel, John T.

AU - Saperstein, David

AU - Shaibani, J. Aziz

AU - Jackson, Carlayne E

AU - Swenson, Andrea

AU - Howard, James F.

AU - Goyal, Namita

AU - David, William

AU - Wicklund, Matthew

AU - Pulley, Michael

AU - Becker, Mara

AU - Mozaffar, Tahseen

AU - Benatar, Michael

AU - Pazcuzzi, Robert

AU - Simpson, Ericka

AU - Rosenfeld, Jeffrey

AU - Dimachkie, Mazen M.

AU - Statland, Jeffrey M.

AU - Barohn, Richard J.

PY - 2016/7/5

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N2 - 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.

AB - 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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