Thymectomy Bests Medical Therapy in Myasthenia Gravis

Marlene Busko

August 11, 2016

The first global randomized controlled trial of patients with major myasthenia gravis without a thymus tumor (thymoma) has shown that thymectomy surgery plus immunosuppression with alternate-day prednisone resulted in better 3-year clinical outcomes than medical therapy alone.

Specifically, patients who underwent surgery had less muscle weakness, a reduced need for immunosuppressive drugs, and fewer symptoms associated with immunosuppressive treatment.

The findings, from the 126-patient, randomized, controlled Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX), were published online August 11 in the New England Journal of Medicine.

"We've been able to confirm the suspicion that's persisted for half a century — that thymectomy does confer benefits for patients with myasthenia gravis, even if they do not have a tumor of the thymus gland," Gil I. Wolfe, MD, from the Department of Neurology, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, New York, told Medscape Medical News.

In an accompanying editorial, Allan H. Ropper, MD, from the Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, agrees that "the data from the trial will be useful in counseling patients," but he cautions that "subgroup analyses did not allow conclusions regarding the effects of surgery in men versus women or in younger versus older patients."

Moreover, the difference in the rate of remission between the surgery and medical therapy groups appears to be shrinking over time, he writes.

Dr Wolfe agreed that the study outcomes were not as convincing for patients older than age 40 years and for men, but this was largely due to the small number of patients in these subgroups.

The team is analyzing longer follow-up data to see whether the findings persist. However, even if these advantages last only 3 years, the fact that patients had half as many hospitalizations, fewer adverse effect symptoms, and less exposure to immunosuppressants are all "meaningful benefits" of thymectomy, he argued.

Inconsistent Observational Studies

In myasthenia gravis, antibodies block, alter, or destroy the acetylcholine receptors at neuromuscular junctions, which prevents muscle contractions, the National Institutes of Health (NIH) notes. Scientists believe that the thymus gland, which is involved with immune development in childhood, may give incorrect instructions to developing immune cells to produce acetylcholine receptor antibodies.

Seventy-five years ago, Alfred Blalock, MD, and colleagues reported that a patient with nonthymomatous myasthenia gravis responded well to removal of the thymus, and this surgery has become a mainstay treatment, the authors write, but retrospective, observational studies have shown inconsistent results.

To look further at outcomes with this procedure, they conducted the MGTX trial, which randomly assigned 126 patients who were recruited from 67 centers in 18 countries on 6 continents, from 2006 to 2012.

The patients were 18 to 65 years old, had major myasthenia gravis (Myasthenia Gravis Foundation of America clinical class II to IV disease, on a scale of I to IV where IV is most severe) for a relatively short time (less than 5 years), as well as elevated acetylcholine receptor antibody levels.

The two co-primary trial outcomes were the average Quantitative Myasthenia Gravis score (from 0 to 39, with higher scores indicating more severe disease) and the average dose of prednisone required to attain minimal manifestation status (no myasthenia gravis symptoms), over a 3-year period.

All patients received alternate-day prednisone therapy, and half also underwent extended transsternal thymectomy. Patients who did not have minimal manifestation of myasthenia gravis symptoms at 12 months or had unacceptable side effects with prednisone could receive azathioprine (or another immunosuppressant if azathioprine caused unacceptable side effects).

Compared with patients in the medical therapy group, patients in the thymectomy group had better primary outcomes and better or similar secondary outcomes.

Table. Outcomes With Prednisone Alone vs Thymectomy Plus Prednisone

Outcome Prednisolone Alone Thymectomy Plus Prednisolone P Value
Average Quantitative Myasthenia Gravis scorea 8.99b 6.15b <.001
Average alternate-day prednisone dosea, mg 60 44 <.001
Azathioprine use, % 48 17 <.001
Hospitalized for exacerbations, % 37 9 <.001

aOver 3-year study.

b3.2-point reduction correlates with improved clinical status.

 

The most important benefit to patients was "fewer symptoms related to glucocorticosteroids and less distress caused by these symptoms," Dr Ropper notes. "The hope of complete remission—[absence of disabling diplopia, dysphagia, ptosis, or weakness in limb muscles and respiration]—was perhaps not realistic," he writes, noting that patients who had thymectomy still required 44 mg of prednisone on alternate days.

"The trial ends an 80-year controversy and contributes to the decline of the denominative term 'gravis,' but it emphasizes the fickleness of myasthenia," Dr Ropper summarizes.

"A Strong Case" to Discuss Thymectomy

"One could argue that if a patient [with myasthenia gravis] is doing really well on a first attempt at immunotherapy, and they can be brought down to low doses, that patient does not need a thymectomy," said Dr Wolfe, "but…where there is some struggle with medical immunotherapy alone, I think our trial makes a strong case that thymectomy should be discussed with the patient."

The procedure can cost $80,000 in the United States but insurance companies cover it, and patients who receive medical therapy likely have even higher costs when the costs of drugs and hospitalizations for severe exacerbations over a 3-year period are considered, he added.

The 2000 American Academy of Neurology practice parameter on thymectomy for autoimmune myasthenia gravis reviewed 21 clinical trials and classified thymectomy as a "treatment option" for patients with myasthenia gravis and no thymoma, he noted. "We think the language could be changed to 'recommended therapy,'" said Dr Wolfe.

The investigators are grateful, he concluded, to the more than 100 patients who waived their right to decide whether to have surgery or not when they agreed to be randomly assigned; the NIH for funding this study, which took 15 years; and two instrumental trial leaders who have since died: John Newsom-Davis, MD, from Oxford University, United Kingdom, and Dr Alfred Jaretzki III, from the Columbia University College of Physicians and Surgeons, New York.

The trial was supported by a grant from the National Institute of Neurological Disorders and Stroke, the NIH, and the Muscular Dystrophy Association and the Myasthenia Gravis Foundation of America. Dr Wolfe reports receiving lecture fees and fees for serving on advisory boards from Grifols and Baxalta, consulting fees from Alpha Cancer Technologies, argenx, and UCB, and grant support from CSL Behring and Alexion Pharmaceuticals. The disclosures of the other authors are listed with the article.

N Engl J Med. Published online August 11, 2016. Abstract Editorial

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