Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial.

BACKGROUND: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. METHODS: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. FINDINGS: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. INTERPRETATION: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke.

The MGTX experience: challenges in planning and executing an international, multicenter clinical trial.

We present our experience planning and launching a multinational, NIH/NINDS funded study of thymectomy in myasthenia gravis. We highlight the additional steps required for international sites and analyze and contrast the time investment required to bring U.S. and non-U.S. sites into full regulatory compliance. Results show the mean time for non-U.S. centers to achieve regulatory approval was significantly longer (mean 13.4+/0.96 [corrected] months) than for U.S. sites (9.67+/0.74 [corrected] months; p=0.003, [corrected] t-test). The delay for non-U.S. sites was mainly attributable to Federalwide Assurance certification and State Department clearance.

Thymectomy for nonthymomatous myasthenia gravis: a critical analysis.

There continues to be debate concerning which thymectomy technique is the procedure of choice in the treatment of nonthymomatous myasthenia gravis (MG). The debate persists primarily because of the lack of controlled prospective studies but also because of the varying presentations and clinical courses of MG patients. Analysis has been complicated by the absence, until very recently, of accepted objective definitions of severity of the illness and response to therapy as well as variable patient selection, timing of surgery, type of surgery, and methods of analysis of results. Without resolution of these issues by properly designed prospective studies, there can be no unequivocally valid comparison of the various thymectomy techniques. In this review, attempts have been made to clarify some of the controversial issues concerning the selection of a thymectomy technique in the treatment of nonthymomatous MG and to make limited recommendations based on the best available evidence.

Status of the thymectomy trial for nonthymomatous myasthenia gravis patients receiving prednisone.

The primary study [MGTX] aims to answer three questions: does extended transsternal thymectomy combined with the prednisone protocol, when compared with the prednisone protocol alone: (1) result in a greater improvement in myasthenic weakness, (2) result in a lower total dose of prednisone, thus decreasing the likelihood of concurrent and long-term toxic effects, (3) enhance the quality of life by reducing adverse events and symptoms associated with the therapies? Inclusion criteria are MGFA Class 2, 3, or 4; acetylcholine receptor antibody positive; age at least 18.0 years and <60.0 years; MG history of <3 years. Patients can be prednisone naïve or not. The National Institute for Neurological Disorders and Stroke awarded funding for MGTX in September 2005, and NIH awarded funding for the ancillary Biomarkers study (BioMG) in February 2006. Diverse regulatory obstacles have been encountered in this international study, but we now have a total of over 70 centers in 22 countries (North America, South America, Europe, Australasia, South Africa) either actively recruiting or at various levels of readiness.

Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy.

Thymectomy has been regularly used in the management of nonthymomatous autoimmune myasthenia gravis (MG), but its benefits have not been established in a randomized, controlled trial. The widespread use of thymectomy in MG patients without thymoma is largely based on retrospective, nonrandomized case series that have produced a consensus that the procedure is sometimes beneficial. Still, the benefits and utilization of thymectomy are actively debated among MG experts. In this paper, we describe the development of a multicenter, international trial to determine whether extended transsternal thymectomy reduces corticosteroid requirements for patients with generalized AChR antibody-positive nonthymomatous MG.

Thymectomy for myasthenia gravis: analysis of controversies--patient management.

BACKGROUND: Debate continues regarding the effectiveness of thymectomy in the treatment of nonthymomatous autoimmune myasthenia gravis primarily because there have been no controlled prospective studies. The debate is compounded by the lack of recognition that all thymectomies are not equal in extent or effectiveness and by the fact that all the studies are retrospective without common definitions of myasthenia gravis manifestations or response to therapy. In addition, the analysis of data is often inappropriate. REVIEW SUMMARY: Evidence is presented demonstrating that the extent of the various thymic resectional techniques is very variable and often incomplete and that the more complete the thymic resection the better the results. The indications for thymectomy, the selection of the technique of the resection, the reoperations issue, the perioperative management of the myasthenia gravis patient, morbidity and mortality, and appropriate methods of outcome research are also reviewed. CONCLUSION: In view of the impressive results associated with a complete thymic resection in the treatment of myasthenia gravis, patients should not be denied this operation because of lack of prospective proof to-date, and when a thymectomy is performed a total resection is indicated.

Thymectomy in the management of myasthenia gravis.

There continues to be a debate regarding the effectiveness of thymectomy in the treatment of nonthymomatous myasthenia gravis (MG) and, when undertaken, which thymectomy technique is the procedure of choice. The debate persists primarily because of the lack of controlled prospective studies. Analysis has been complicated by the absence, until very recently, of accepted objective definitions of severity of the illness and response to therapy as well as variable patient selection, timing of surgery, type of surgery, and methods of analysis of results. Without resolution of these issues by properly controlled prospective studies, there can be no unequivocal determination of the effectiveness of thymectomy or valid comparison of the various thymectomy techniques. In this review, based on previous analyses, attempts will be made to clarify some of the controversial issues concerning thymectomy for nonthymomatous MG and make limited recommendations based on the best available evidence.