Myasthenia Gravis: Finally, Clinical-Trial Evidence That Thymectomy Works

By Charles Meyer
Reviewed by Aaron Miller, MD, Professor of Neurology, Icahn School of Medicine at Mount Sinai and Medical Director at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, NY

Adult patients with generalized nonthymomatous myasthenia gravis (MG) who underwent thymectomy and received alternate-day prednisone had significantly improved disease severity and significantly reduced prednisone use compared with patients receiving prednisone alone.

Significantly fewer patients assigned to thymectomy required treatment with azathioprine and their hospitalization rates were significantly lower than those of patients assigned to prednisone alone.
These trial results should help dispel uncertainty among clinicians as to the benefits of the procedure in appropriately selected patients with MG.

Surgical removal of the thymus as a treatment for myasthenia gravis (MG) was first performed 75 years ago.1 For decades, it has remained an option, albeit a controversial one, for management of the disease, despite a lack of controlled clinical trial evidence supporting the procedure and uncertainty about which patients may benefit. Now an international randomized trial comparing thymectomy plus prednisone with prednisone alone has demonstrated that the procedure can decrease MG severity, reduce use of prednisone, help patients avoid treatment with more-powerful immunosuppressants, and prevent hospitalization.1

The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) was conducted at 67 centers in 18 countries on 6 continents, with patient evaluations spanning 9 years.1 The trial enrolled adults who had generalized nonthymomatous MG with disease duration of less than 5 years, Myasthenia Gravis Foundation of America classification of II to IV (on a scale from I to V; class V denotes a crisis requiring intubation), and elevated concentrations of acetylcholine (AChR)-receptor antibody.1 Patients were randomly assigned to alternate-day prednisone alone or prednisone plus extended trans-sternal thymectomy, with prednisone dose titrated, maintained, and tapered according to the same protocol in each treatment arm.1

Patient evaluations, which included clinical assessments, Quantitative Myasthenia Gravis (QMG) scoring (the QMG comprises 13 items, with a total score of 0 to 39 and higher score denoting greater severity), and pill counts to assess prednisone use, were done monthly by blinded examiners.1 Each patient was followed for at least 3 years. Because improved clinical status could correlate with greater prednisone dose and a lower dose with poorer clinical status, the trial employed a dual primary outcome comprising average QMG score and average required dose of prednisone over 3 years.

A total of 126 patients were assigned to thymectomy plus prednisone (n=66) or prednisone alone (n=60), of whom 118 (62 receiving thymectomy, 52 only prednisone) were evaluable for efficacy.1 Patients who underwent thymectomy had a significantly lower average QMS score over the 3 years than those who received prednisone alone (6.15 vs. 8.99). The estimated difference between the treatment groups (2.85; 99.5% confidence interval [CI], 0.47-5.22) exceeded the change in QMS score previously found to correspond with clinical improvement as judged by neurologists. Patients undergoing thymectomy also had a lower average requirement for alternate-day prednisone: 44 mg versus 60 mg, a difference of 16 mg (95% CI, 7-25; P<001).

Minimal-manifestation status (no symptoms or functional limitations, even if some weakness could be found on examination) at 36 weeks, a secondary endpoint, was attained by significantly more patients in the thymectomy arm than in the prednisone-only arm (67% vs 47%; P =.03).1 The thymectomy group also fared better in number of patients with treatment-related symptoms, total number of symptoms, and distress level related to symptoms over the 3-year period. The groups did not differ significantly in treatment-associated complications. Significantly fewer patients assigned to thymectomy than to prednisone alone required azathioprine for immunosupression (17% vs 48%). Finally, patients receiving thymectomy had significantly lower hospitalization rates (23% vs 52% for prednisone-only patients) and lower rates of hospitalization for MG exacerbations (9% vs 37%).

In prespecified subgroup analyses, prednisone treatment history, gender, and age individually did not significantly predict outcomes. However, only in women was thymectomy associated with significantly better QMG scores than was prednisone alone, and only in patients who had been previously treated with prednisone was thymectomy associated with reduced prednisone dose.1

Nicholas J. Silvestri, MD, clinical associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, explains “The impetus for performing this trial was the desire on the part of the MG community–particularly the physicians treating patients with MG–to make sure that we were doing right by our patients in recommending this procedure. Although many of us who treat myasthenia have seen a benefit with thymectomy in selected patients, this study now clearly demonstrates that it is an effective treatment.”

Are the results of MGTX “practice changing,” as the authors of the study have concluded?2 Dr Silvestri says, “I believe that any reservations that physicians or patients may have had about the procedure in the past should be dispelled by these data, and more patients are likely to be referred for thymectomy.”

Publication of the MGTX results followed the recent release of an international consensus guideline on management of MG from an expert panel convened by the Myasthenia Gravis Foundation.3 The guideline cited thymectomy as an option “to potentially avoid or minimize the dose or duration of immunotherapy, or if patients fail to respond to an initial trial of immunotherapy or have intolerable side effects from that therapy.” The guideline adds that the procedure may be considered in some children and patients without AChR antibodies who have not responded to or could not tolerate other therapies–patient populations not included in MGTX.3

Dr Silvestri says, “Most physicians such as myself who are treating patients with MG are more apt to refer for thymectomy those who are younger than 50 years of age, those who have generalized disease, and those who are acetylcholine-receptor positive.”

References:
Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med. 2016;375:511-522.
Cutter G, Kaminski H, Wolfe G, et al; MGTX Trial Research Group. Thymectomy in non-thymomatous myasthenia gravis: results from MGTX, a randomized, controlled trial. Presented at the American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada.
Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87:419-425.

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