As a third-year medical student in my neurology clerkship, I went to the emergency room to evaluate Ms. B, who presented with eyelid weakness and fatigue. She was a 45-year-old woman who was diagnosed 2 years earlier with myasthenia gravis (MG). This was her third hospitalization for exacerbation of the disease. At the time of diagnosis, the CT scan showed no evidence of thymoma. She had been taking pyridostigmine and prednisone, but had steroid-related side effects, including weight gain and irritability. Because of the severity of her symptoms, we treated Ms. B with IVIG and discharged her from the hospital several days later. I knew this wouldn’t be the last exacerbation for Ms. B. In the 10% of patients with MG who have a thymoma, thymectomy is the standard of care. But would this patient benefit from surgery? Six years later, we now have more information to help answer this question.
Many patients with non-thymomatous MG have hyperplastic thymic changes that are not seen in otherwise healthy individuals, leading to speculation about the role of thymectomy, even in the absence of thymoma. Several retrospective observational trials have yielded mixed results on rates of improvement and duration of response associated with thymectomy as a treatment for non-thymomatous MG. Based on these limited data, thymectomy is often performed in some patients with non-thymomatous MG with generalized disease and positive acetylcholine receptor antibodies. However, the benefit of thymectomy for such patients had never been examined in a randomized trial.
A multi-center, international, randomized-controlled trial, conducted by the MGTX Study Group and published in NEJM this week, aims to answer this question. The trial enrolled 126 patients, from 67 centers, with recently diagnosed myasthenia gravis and at least mild generalized disease. Patients were randomized to undergo transsternal thymectomy plus prednisone or prednisone alone. The investigators developed an alternate-day prednisone dosing protocol with specific thresholds to adjust doses based on symptoms. If patients did not achieve minimum manifestation status (defined as no symptoms or functional limitations from myasthenia gravis) or had intolerable prednisone-related side effects, they could receive azathioprine. The dual primary outcome included a validated quantitative myasthenia gravis score and total prednisone exposure to ensure that any differences in outcomes were attributable to thymectomy and not to higher doses of glucocorticoids.
Analysis of the primary outcome revealed that during the 36-month follow-up, patients who underwent thymectomy had improvement in quantitative myasthenia gravis scores, compared with patients who did not (6.15 vs. 8.99; P<0.001), and received a significantly lower prednisone dose (average alternate-day dosage, 44 mg vs. 60 mg; 95% CI, 7-25 mg, P<0.001). The thymectomy group also had lower hospitalization rates (9% vs. 37%, P<0.001), a smaller percentage of patients who received azathioprine (17% vs. 48%, P<0.001), and a higher proportion of patients who achieved minimal manifestation status (67% vs. 47%, P=0.03). Treatment-associated complications did not differ significantly between the two groups. Study limitations include the unblinded design (due to the unethical nature of performing sham surgery) and the necessary, but imperfect ,metric of pill counts to calculate prednisone exposure.
In an accompanying editorial, Dr. Allan Ropper, Deputy Editor of NEJM observed that the absolute difference between the two groups in the primary outcome was modest, but reported secondary outcomes were of high importance to patients. Dr. Roper notes that “[t]he data from the trial will be useful in counseling patients but they offer no further clarity regarding selection of patients for thymectomy because subgroup analyses did not allow conclusions regarding the effects of surgery for men vs. women or age under vs. over 55 years.”
Overall, this trial used the rigor of a randomized-controlled trial to answer an important, decades-old question: Do patients with myasthenia gravis without thymoma benefit from thymectomy? The trial demonstrates that thymectomy can lead to improved outcomes without significant side effects, and adds important data to this field for clinicians, investigators, and most importantly for patients with myasthenia gravis.
Browse more From Pages to Practice »
Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.