Randomized Trial of Thymectomy in Myasthenia Gravis. New England Journal of Medicine - August 11, 2016

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Estella Doris Shaw
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1 Randomized Trial of Thymectomy in Myasthenia Gravis New England Journal of Medicine - August 11, 2016

2 Disclosures None At all.

3 Example Case 38 year-old female with no pertinent PMH who presents with a 5-week history of fluctuating fatigue and weakness, and a 1 week history of blurry vision that is worst at the end of the day. She notes that she sees two of everything when she uses her ipad while lying in bed at night. She also notes that she has a particularly difficult time brushing her hair before bedtime, as her arms feel too heavy.

4 Physical Exam General, cardiovascular, pulmonary, gastrointestinal, and genitourinary exams were within normal limits. Neuro Exam PERRL, EOMI Bilateral ptosis and diplopia after prolonged upward gaze Visual fields full to confrontation Cranial nerves otherwise intact Notable weakness in bilateral upper extremities DTRs 2+ throughout Normal muscle bulk and tone Sensation to vibration, light touch, and pinprick intact throughout Speech, cognition, and cerebellar function all within normal limits

5 Workup? Edrophonium (tensilon) test Ice pack test AChR antibodies Repetitive nerve stimulation (RNS) Single-fiber EMG Others? MuSK antibodies in AChR-Ab-negative patients whose diagnosis is strongly suspected

6 Results Ptosis and diplopia improved with edrophonium administration AChR-Ab: POSITIVE Single-fiber EMG showed increased jitter consistent with neuromuscular junction disease Chest CT negative for mediastinal mass and otherwise unremarkable

7 Diagnosis? Myasthenia Gravis (shocking, right?)

8 Treatment Options Cholinesterase inhibitors Immunotherapy Pyridostigmine (Mestinon) Neostigmine (rarely used) Prednisone (most common) Azathioprine Mycophenolate mofetil Cyclosporine Big Guns IV immunoglobulin Can be used in acute setting or on a scheduled basis for refractory disease Plasmapheresis

9 Case Continued Despite the initiation of standard therapy and dose escalation, she continues to have persistent symptoms and has had two episodes requiring hospitalization. She is given the option of receiving monthly IVIG infusions, but she is worried that this approach may have a significant negative impact on her quality of life. She asks if she has any other options that might help improve her long-term outcome. Thoughts?

10 Thymectomy? Thymectomy is an obvious treatment option in patients with thymoma, but would it help our patient who has no evidence of thymoma?

11 Enter: MGTX

12 Trial Design Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) International randomized controlled trial (18 countries) Patients treated with prednisone alone or prednisone plus thymectomy Followed for 36 months after enrollment Rater-blinded (single-blind) Seen by non-blinded neurologist for 4 months as patients recovered from surgery All patients wore black high-collared shirts to cover sternotomy incisions (or lack thereof)

13 Inclusion Criteria Disease duration 3 years Age years old Serum ACh-R antibody level of 1.00 nmol/l Also included nmol/l if diagnosis confirmed by: Positive edrophonium test Abnormal repetitive nerve stimulation Abnormal single-fiber EMG Myasthenia Gravis Foundation of America clinical class II-IV Note: 2 years after enrollment began, age limit was increased to 65 and maximum disease duration was increased to 5 years to boost enrollment

14 Exclusion Criteria Thymoma on CT or MRI Immunotherapy other than prednisone Pregnancy or lactation Unwillingness to avoid pregnancy Contraindications to glucocorticoids Substantial medical illness Note: patients could be on appropriate anticholinesterase therapy with or without glucocorticoids

15 Outcome Measures Dual Primary Outcome Time-weighted average Quantitative Myasthenia Gravis score Time-weighted average required dose of prednisone over 3-year period Secondary Outcomes Days of hospitalization Survey addressing 36 treatment-associated complications and 29 symptoms a/w glucocorticoids Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Myasthenia Gravis Activities of Daily Living score Proportion of participants who achieved minimal manifestation status Use of nonglucocorticoid immunosuppressants, plasma exchange, and IV immunoglobulin.

16 Quantitative Myasthenia Gravis Scale (QMG)

17 Myasthenia Gravis Activities of Daily Living Scale (MG-ADL)

18 The Patients

19 Results

20 Estimated difference = 2.85 points (99.5% CI, 0.47 to 5.22) Estimated difference = 22 mg (99.5% CI, 12 to 32)

22 Other Notable Results Percentage of patients achieving minimal manifestation status at month 36 was greater in the thymectomy group (67% vs. 47%, p=0.03) Average time-weighted score on the MG-ADL scale was lower in the thymectomy group (2.24 vs 3.41, p=0.008) The percentage of patients requiring the use of azathioprine was lower in the thymectomy group (17% vs 48%, p<0.001)

24 Wait, there s more!

25 Stats Error The authors published a correction in NEJM stating that they had made a statistical error, but it did not change the outcomes of the study. In fact, the effects may have actually been a bit stronger.

26 Discussion

27 To put it simply, thymectomy seemed to... Improve overall clinical outcomes Reduce requirements for prednisone and azathioprine Reduce adverse effects associated with immunotherapy Decrease number of hospitalizations

28 Back to Our Case Does this apply to our patient? What should we tell her?

29 My Thoughts Study confirms that thymectomy in patients similar to the one in the case may be beneficial in terms of long-term outcomes Thymectomy is a HUGE procedure and and it s risks should be strongly weighted against the potential benefit Long, painful recovery What if it doesn t work? Would the patient look back and think it was worth a try?

30 Limitations

31 Design Limitations You can t cut open someone s chest for no good reason Sham thymectomy was unethical Therefore, the patients are always aware of their assignment group Pill count method is not the most reliable way of measuring administered dosage Only looked at outcomes over 3 year period What about at 10 years?

32 Thymus: Role in Pathogenesis? Patients discovered to have thymoma at time of thymectomy were treated based on intention-to-treat model (one patient) Thymomatous MG more likely to result in good outcome? Previous trial that served as the grounds for performing thymectomy in MG patients noted increased survival associated with severe thymic hyperplasia compared to atrophic or normal thymus glands2 Most patients in the current study had mild hyperplasia and significant atrophy

33 Thoughts, anyone?

34 Bibliography Wolfe, G. I., Kaminski, H. J., Aban, I. B., Minisman, G., Kuo, H.-C., Marx, A.,... Cutter, G. R. (2016). Randomized Trial of Thymectomy in Myasthenia Gravis. New England Journal of Medicine, 375(6), doi: /NEJMoa Buckingham, J. M., Howard, F. M., Bernatz, P. E., Payne, W. S., Harrison, E. G., O Brien, P. C., & Weiland, L. H. (1976). The value of thymectomy in myasthenia gravis: a computer-assisted matched study. Annals of Surgery, 184(4),

Myasthenia Gravis. Mike Gilchrist 10/30/06

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