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

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 2 placebo: 2488.0 mg, 95% confidence interval 22,443.4 to 1,467.3, p 5 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.

The placebo response in myasthenia gravis assessed by quantitative myasthenia gravis score: A meta‐analysis

“…Beside the total QMG score, a group of single reliable clinical parameters was also identified: disease duration at entry: number of thymectomized patients, number of patients who had a thymoma, bilateral handgrip, and forced vital capacity. The authors of selected studies were contacted in case of missing data . Unfortunately, none of the requested information was provided, because no longer accessible, unretrievable, or protected as intellectual property of the study sponsors and investigators.…”

“…The authors of selected studies were contacted in case of missing data. [35][36][37][38][39][40][41][42][43][44] Unfortunately, none of the requested information was provided, because no longer accessible, unretrievable, or protected as intellectual property of the study sponsors and investigators.…”

Immunosuppressive and monoclonal antibody treatment for myasthenia gravis: A network meta‐analysis

“…The data from the two studies by Sanders 21,22 were not pooled for different participant cohorts, neither were the data from the four studies by Howard 23,24 or Tindall 25,26 for different time points. Finally, 14 studies [21][22][23][24][25][26][27][28][29][30][31][32][33][34] were included in the NMA of our study.…”

Comparative effectiveness clinical trials to advance treatment of myasthenia gravis

“…However, placebo‐controlled trials are generally unethical in MG. The failure of prior RCTs of mycophenolate mofetil and methotrexate in MG is likely the result of factors including short duration, lack of precision, and the unpredictable effect of concomitant IS therapies . For further details on study design challenges in trials for MG, the reader is referred to Benatar et al …”

“…However, placebo-controlled trials are generally unethical in MG. The failure of prior RCTs of mycophenolate mofetil 17,18 and methotrexate 19 in MG is likely the result of factors including short duration, lack of precision, and the unpredictable effect of concomitant IS therapies. 13,20 For further details on study design challenges in trials for MG, the reader is referred to Benatar et al 21 Despite the paucity of RCT evidence to inform the treatment of MG, treatment decisions continue to be made, patients have questions about the best option for their condition, and payers make coverage decisions.…”