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Thymectomy Plus Prednisone Is More Effective Than Prednisone Alone for Myasthenia Gravis

Talan, Jamie

doi: 10.1097/01.NT.0000554410.37651.af
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ARTICLE IN BRIEF:

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New findings from a study comparing thymectomy and prednisone combined with prednisone therapy alone finds that the combined therapy confers benefits that persist for five years in patients with generalized non-thymomatous myasthenia gravis.

Nearly three years ago, a landmark study published in The New England Journal of Medicine put to rest a half century-old controversy over whether to offer patients with non-thymomatous myasthenia gravis a surgical procedure to remove the thymus— thymectomy—to reduce symptoms of the disease.

The researchers found a significant benefit from the surgery from the standpoint of improved disease control and reduced corticosteroid requirements, especially in patients under 50, and they decided to follow some of the patients in a two-year extension study to see whether the improvements of the surgery persisted.

Now, findings from this extension study show that patients who were in the thymectomy plus corticosteroid arm of the study continued to do better over time than those receiving corticosteroids only. That means that the scientists now have five years of information on some of the patients in the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX).

In the current paper, the researchers reported that the patients who had the surgery continued to have better clinical outcomes on the Quantitative Myasthenia Gravis (QMG) score, a measure of strength and muscle function, and were able to maintain a lower corticosteroid dose. The findings were published online in The Lancet Neurology on January 25.

“The findings reinforce the positive impact of thymectomy we saw in the original three-year study,” said Gil I. Wolfe, MD, FAAN, the Irvin and Rosemary Smith professor and chair in the department of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, SUNY.

“The thymectomy benefit persisted, and even grew over the additional two years of follow-up. The separation between the two groups of patients increased further between 36 and 60 months. This dispels doubts about the procedure's benefits or the longevity of its effects.”

Despite the impressive 2016 study results in the NEJM, there doesn't seem to be a big push for thymectomy—at least not yet. Studies suggest that the number of hospital admissions for thymectomy in myasthenia gravis (MG) has fallen over the last 10 to 20 years and that less than 50 percent of patients opt for the surgical intervention.

“I think patients don't want to go under the knife in an environment of increasing medical options,” Dr. Wolfe added. But he said that medications can be quite expensive and carry an increased risk of infection.

He and his colleagues hope to update MG treatment guidelines to include the data on benefits of thymectomy. The investigators in the international, multi-center MGTX trial used a transsternal approach. Now, there are many other methods, including thoracoscopic thymectomy that reduce scarring and the time spent in a hospital.

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Study Design, Findings

The MGTX study was conducted at 36 centers in 15 countries and 111 adult patients (18- to 65 years old) with generalized non-thymomatous myasthenia gravis completed the three-year study. They had to have been diagnosed within five years of entering the study and have acetylcholine receptor antibody titers of 1.00 nmol/L or higher. They were on anticholinesterase therapy, with or without oral corticosteroids, and then were randomly assigned to thymectomy/prednisone or prednisone alone.

At the end of the study, they asked patients whether they would like to be part of a two-year extension follow-up. Fifty patients went on to complete the 60-month assessment, 24 in the prednisone only group and 26 in the prednisone plus thymectomy group. (The prednisone dosing protocol used in the study remained the same throughout the extension phase.)

The primary outcome measures were the QMG score and the doses of alternate-day oral prednisone from the start of the initial study to month 60. Many neurologists think that a two- to three-point reduction in the QMG score is a meaningful change.

In the extension study, the time-weighted mean QMG score was 3.87 points lower at five years in the thymectomy plus prednisone group than in the prednisone alone group, a larger estimated difference than that at year three in the MGTX trial, where there was a 2.85 reduction.

At five years, the proportion of patients in minimal manifestation status (MMS — meaning, the patient has no symptoms or functional limitations from MG but has some weakness on examination of some muscles — was also significantly higher in those who had thymectomy: 23 of 26 (88 percent) of patients in the surgical/medication group compared with 14 of 24 (58 percent) in the prednisone alone group. Again, the proportion of patients in MMS for both groups was higher at five years than in the three-year MGTX study: 39 of 58 (67 percent) in the thymectomy plus prednisone group and 24 of 51 (47 percent) in the prednisone alone group.

The thymectomy group continued to take less prednisone and had fewer hospitalizations for acute exacerbation of MG during the two-year extension period. The alternate-day prednisone dose in patients who had a thymectomy fell to 11.9 mg at month 60. That averages to just over 5 mg per day, the target dose for prednisone or prednisolone, according to Japanese national guidelines for managing MG. There were also fewer treatment-related complications in the thymectomy/prednisone group.

The study team spelled out the limitations of the extension study, including the small numbers in the study. Also, it could be that patients who agreed to be part of the extension study did better overall and this might lead to a more favorable outcome. Dr. Wolfe said that he believes that those who enrolled in the extension phase are representative of the original 111 MGTX cohort.

The MGTX study was the first to compare thymectomy plus prednisone to thymectomy alone. Its use was based on the observation that it worked to reduce clinical symptoms. “All of us who treat MG patients have used thymectomy,” said Dr. Wolfe. “There is comfort in knowing that what we have done for many years has been shown to really benefit our patients.”

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Expert Commentary

“The MGTX study, published in 2016, established the benefit of extended transsternal thymectomy plus prednisone over prednisone alone on muscle strength (measured by the time weighted QMG score) and prednisone requirement at three years,” said Pushpa Narayanaswami, MD, FAAN, associate professor of neurology at Harvard Medical School and director of quality assurance in the department of neurology at Beth Israel Deaconess Medical Center.

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“This trial reflects the dogged determination of the MGTX investigators, who screened almost 7,000 people to recruit 126 participants. The improvement in muscle strength in the thymectomy plus prednisone group was both statistically significant and clinically meaningful. The time-weighted average alternate day prednisone dose was lower by 22 mg (95% CI, 12-22 mg) in the thymectomy plus prednisone group. The ability to reduce steroid dose by 10-11 mg per day is also a clinically meaningful endpoint in terms of reducing short- and long-term side effects of corticosteroids.

“In clinical practice it is not unusual to start patients on corticosteroids and an alternative agent for steroid sparing simultaneously,” said Dr. Narayanaswami. “Where thymectomy falls in the treatment algorithm of these patients, and whether thymectomy should be considered standard of care in all patients with myasthenia gravis within five years of disease onset remains unclear. However, the bottom line is that these well-designed and robustly executed, long trials provide conclusive evidence about the benefit of thymectomy in myasthenia gravis with respect to improvements in muscle strength, reduced prednisone dose, and less frequent hospitalizations.”

“It was a definitive study that will strengthen the argument for recommending thymectomy for patients with the most common form of myasthenia gravis,” said Robert Ruff, MD, retired national director for neurology for the Veteran's Affairs Administration. “There was a clear separation between the two groups—those who had the thymectomy and those who didn't. The more evidence to support a treatment the more likely a patient will be approved by insurance to get it.”

He added that the reduction in the use of corticosteroids in the thymectomy group is also critically important. “There are many side effects to steroid use and the reduction in the use of steroids mean that patients are less susceptible to the risks of diabetes and bone weakness.”

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Link Up for More Information

•. Wolfe GI, Kaminski HJ, Aban IB, et al Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomized trial https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30392-2/fulltext. Lancet Neurol 2019; Epub 2019 Jan 25.
    •. Wolfe GI, Kaminski HJ, Aban IB, et alfor the MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis https://www.nejm.org/doi/full/10.1056/nejmoa1602489. N Engl J Med 2016; 375:511–522.
      © 2019 American Academy of Neurology