NIHR Signal Surgery to remove the thymus gland improves weakness for people with myasthenia gravis

Published on 3 October 2016

Having a thymectomy (surgery to remove the thymus gland) improves various measures of weakness and reduces the need for other treatment in people with myasthenia gravis. When combined with standard steroid treatment, surgery gives a meaningful, but small, improvement compared with steroids alone. Importantly it also reduced the requirement for steroids or immune suppressing drugs and their side effects.

Myasthenia gravis is a rare condition where the body’s own immune system attacks the nerves carrying signals to the muscles. This causes the muscles to become tired and weak. The thymus gland in the chest is part of the immune system. Although thymectomy has been used for many years as part of the management of severe myasthenia gravis, there has been no good evidence about its effectiveness for people without growths on the thymus gland (thymoma).

This is the first randomised controlled trial for this treatment in those without a thymoma. The new evidence might strengthen current guidelines, which are largely based on expert opinion.

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Why was this study needed?

Myasthenia gravis affects up to 15 in every 100,000 people in the UK. There is no cure for it, but treatments are available to control the symptoms, such as droopy eyelids, slurred speech and impairments due to muscle weakness.

Drug treatment is usually the first choice, but removing the thymus gland (thymectomy) can be an option. However, the use of thymectomy has been based on weak evidence. A Cochrane review published in 2013 found no randomised trials that tested how well thymectomy works to treat myasthenia gravis, so this landmark trial was funded to provide higher quality evidence.

What did this study do?

The MGTX study was a randomised controlled trial involving 126 adults from 36 centres. Participants were generally young adults (average age 32 to 33), who had myasthenia gravis for less than five years and a disease severity of two to four on a five-class scale. Participants received standard steroid drug treatment alone, or in combination with thymectomy.

Follow-up was for three years. The main outcomes of interest were the average steroid (prednisone) dose needed, and average score on the Quantitative Myasthenia Gravis scale. This is a scale from 0 to 39 with higher scores indicating more severe weakness. Thirteen muscle groups including those controlling the eyes, face, swallowing, arms and legs are tested and scored from 0 to 3. The higher the score the worse the weakness. A reduction of 2.3 points is considered a meaningful improvement.

As participants were aware of their treatment, this could have affected their symptom reporting. Also 32 of the 36 sites were in the US where standard treatment practices could differ from the UK.

What did it find?

  • People who had a thymectomy had a better average Quantitative Myasthenia Gravis score over three years than those who only took prednisone (6.15 versus 8.99). The average score difference between groups was 2.85 points (95% confidence interval 0.47 to 5.22), and so this is a meaningful, though small, improvement in weakness.
  • People in the thymectomy group also took a significantly lower dose of prednisone over the three years (average 44 mg versus 60 mg).
  • Fewer people in the thymectomy group than in the prednisone-only group needed treatment with another drug to suppress the immune system (azathioprine: 17% versus 48%).
  • Fewer people in the thymectomy group needed to be admitted to hospital for worsening symptoms (9% versus 37%).
  • There were fewer adverse effects in the thymectomy group, with 38% experiencing at least one event compared with 55% of the prednisone-only group. Life-threatening adverse effects were also significantly lower (affecting 1 person versus 7).

What does current guidance say on this issue?

The Association of British Neurologists’ management guidelines for treatment of myasthenia gravis suggest that thymectomy may be considered for adults aged under 45 years who have antibodies for the chemical (acetylcholine) receptors at the nerve endings.

The authors state that there is little evidence for their recommendations and that the guidelines are based on the practice of experts in the field. They say that many experts consider thymectomy, particularly by minimally invasive techniques, in younger people who meet the criteria. Thymectomy is thought to be most effective if carried out early on, within a few years of symptom onset.

What are the implications?

This evidence might inform updates of the current guidance, with the possibility of a stronger recommendation. Participants in this trial were on average young adults (32-33 years) with a relatively recent disease onset.

Future guidelines might consider the patient characteristics and surgical techniques associated with the best outcomes. Although meaningful, yet small, improvements were observed, the improvements in weakness and the ability to reduce doses of other drugs will be important for patients and their advisors.

Citation and Funding

Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med. 2016;375(6):511-22.

This project was funded by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, and by the Muscular Dystrophy Association and the Myasthenia Gravis Foundation of America.

Bibliography

Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10:46.

Cea G, Benatar M, Verdugo RJ, Salinas RA. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database of Syst Rev. 2013;(10):CD008111.

NHS Choices. Myasthenia Gravis. London: Department of Health; 2015.

Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis. Neurology. 2016;87:419-425.

Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists’ management guidelines. Pract Neurol. 2015;15:199-206.

Why was this study needed?

Myasthenia gravis affects up to 15 in every 100,000 people in the UK. There is no cure for it, but treatments are available to control the symptoms, such as droopy eyelids, slurred speech and impairments due to muscle weakness.

Drug treatment is usually the first choice, but removing the thymus gland (thymectomy) can be an option. However, the use of thymectomy has been based on weak evidence. A Cochrane review published in 2013 found no randomised trials that tested how well thymectomy works to treat myasthenia gravis, so this landmark trial was funded to provide higher quality evidence.

What did this study do?

The MGTX study was a randomised controlled trial involving 126 adults from 36 centres. Participants were generally young adults (average age 32 to 33), who had myasthenia gravis for less than five years and a disease severity of two to four on a five-class scale. Participants received standard steroid drug treatment alone, or in combination with thymectomy.

Follow-up was for three years. The main outcomes of interest were the average steroid (prednisone) dose needed, and average score on the Quantitative Myasthenia Gravis scale. This is a scale from 0 to 39 with higher scores indicating more severe weakness. Thirteen muscle groups including those controlling the eyes, face, swallowing, arms and legs are tested and scored from 0 to 3. The higher the score the worse the weakness. A reduction of 2.3 points is considered a meaningful improvement.

As participants were aware of their treatment, this could have affected their symptom reporting. Also 32 of the 36 sites were in the US where standard treatment practices could differ from the UK.

What did it find?

  • People who had a thymectomy had a better average Quantitative Myasthenia Gravis score over three years than those who only took prednisone (6.15 versus 8.99). The average score difference between groups was 2.85 points (95% confidence interval 0.47 to 5.22), and so this is a meaningful, though small, improvement in weakness.
  • People in the thymectomy group also took a significantly lower dose of prednisone over the three years (average 44 mg versus 60 mg).
  • Fewer people in the thymectomy group than in the prednisone-only group needed treatment with another drug to suppress the immune system (azathioprine: 17% versus 48%).
  • Fewer people in the thymectomy group needed to be admitted to hospital for worsening symptoms (9% versus 37%).
  • There were fewer adverse effects in the thymectomy group, with 38% experiencing at least one event compared with 55% of the prednisone-only group. Life-threatening adverse effects were also significantly lower (affecting 1 person versus 7).

What does current guidance say on this issue?

The Association of British Neurologists’ management guidelines for treatment of myasthenia gravis suggest that thymectomy may be considered for adults aged under 45 years who have antibodies for the chemical (acetylcholine) receptors at the nerve endings.

The authors state that there is little evidence for their recommendations and that the guidelines are based on the practice of experts in the field. They say that many experts consider thymectomy, particularly by minimally invasive techniques, in younger people who meet the criteria. Thymectomy is thought to be most effective if carried out early on, within a few years of symptom onset.

What are the implications?

This evidence might inform updates of the current guidance, with the possibility of a stronger recommendation. Participants in this trial were on average young adults (32-33 years) with a relatively recent disease onset.

Future guidelines might consider the patient characteristics and surgical techniques associated with the best outcomes. Although meaningful, yet small, improvements were observed, the improvements in weakness and the ability to reduce doses of other drugs will be important for patients and their advisors.

Citation and Funding

Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med. 2016;375(6):511-22.

This project was funded by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, and by the Muscular Dystrophy Association and the Myasthenia Gravis Foundation of America.

Bibliography

Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10:46.

Cea G, Benatar M, Verdugo RJ, Salinas RA. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database of Syst Rev. 2013;(10):CD008111.

NHS Choices. Myasthenia Gravis. London: Department of Health; 2015.

Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis. Neurology. 2016;87:419-425.

Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists’ management guidelines. Pract Neurol. 2015;15:199-206.

Randomized Trial of Thymectomy in Myasthenia Gravis

Published on 11 August 2016

Wolfe, G. I.,Kaminski, H. J.,Aban, I. B.,Minisman, G.,Kuo, H. C.,Marx, A.,Strobel, P.,Mazia, C.,Oger, J.,Cea, J. G.,Heckmann, J. M.,Evoli, A.,Nix, W.,Ciafaloni, E.,Antonini, G.,Witoonpanich, R.,King, J. O.,Beydoun, S. R.,Chalk, C. H.,Barboi, A. C.,Amato, A. A.,Shaibani, A. I.,Katirji, B.,Lecky, B. R.,Buckley, C.,Vincent, A.,Dias-Tosta, E.,Yoshikawa, H.,Waddington-Cruz, M.,Pulley, M. T.,Rivner, M. H.,Kostera-Pruszczyk, A.,Pascuzzi, R. M.,Jackson, C. E.,Garcia Ramos, G. S.,Verschuuren, J. J.,Massey, J. M.,Kissel, J. T.,Werneck, L. C.,Benatar, M.,Barohn, R. J.,Tandan, R.,Mozaffar, T.,Conwit, R.,Odenkirchen, J.,Sonett, J. R.,Jaretzki, A., 3rd,Newsom-Davis, J.,Cutter, G. R.

N Engl J Med Volume 375 Issue 6 , 2016

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.).

Myasthenia gravis is a long-term autoimmune condition in which muscles become tired and weak. It’s due to the body’s own immune system targeting the chemical receptors at the end of nerves that stimulate the muscles to contract. It affects muscles that are controlled voluntarily – commonly those controlling the eyes and eyelids, facial expression, chewing, swallowing and speaking.  The muscle weakness is usually worse after physical activity or at the end of the day, and gets better with rest.

Medical treatments for myasthenia gravis include pyridostigmine, an acetylcholinesterase inhibitor. This prevents the breakdown of acetylcholine, an important chemical that helps the muscles contract (tighten). This works best in mild myasthenia gravis. Steroid tablets, such as prednisolone, or other immunosupressants, are used for more severe cases. The dose can be increased gradually over time and is usually kept at a high dose for several months until remission is achieved.

Thymectomy is surgery to remove the thymus – a small gland in the upper chest, just behind the breastbone. This gland is part of the immune system, and is often abnormal in people with myasthenia gravis – although the exact role it plays is not clear. A non-cancerous tumour called a thymoma is found in about 1 in 10 people. Thymectomy is always recommended if a thymoma is found. The people in this trial didn’t have thymoma.

Expert commentary

This blinded study of trans-sternal thymectomy in the treatment of myasthenia gravis, demonstrated reduced prednisone requirements and symptoms following thymectomy. Three years following thymectomy, more patients (67% vs. 47%) had ‘minimal manifestations’ and less required immunosuppression with azathioprine (17% vs. 48%). Thymectomy reduced average alternate day steroid requirements from 60 mg to 44 mg, which is greater than expected from clinical practice. The moderate benefit of thymectomy justifies consideration of early thymectomy in appropriate patients, though which subgroup is most likely to benefit is unclear. Important questions remain, including whether video assisted endoscopic thymectomy is as effective, and the role of thymectomy in the era of immunotherapy.

Dr Jon Sussman, Consultant Neurologist, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust