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Steroids and immunosuppressant drugs in myasthenia gravis

Abstract

In chronic autoimmune conditions such as myasthenia gravis (MG), immunosuppression—usually long-term—is often necessary. The mechanisms of action of immunosuppressant drugs in MG fall into three main categories: inhibition of the cell cycle (azathioprine, cyclophosphamide, methotrexate and mycophenolate mofetil), immunosuppression of T cells (steroids, ciclosporin and tacrolimus), and B-cell depletion (rituximab). Data on immunosuppressant drugs in MG derive mainly from clinical experience, observational studies and expert opinion. The main drawbacks of the randomized evidence are the small size of most drug trials, variations in study design, and a lack of head-to-head studies. It is therefore difficult to determine the relative efficacy of each immunosuppressant. Oral prednisolone, usually started at a low dose on an alternate-day regimen, and gradually increased, is the recommended first-choice short-term immunosuppressant. Long-term immunosuppression regimens vary between different countries and physicians. Azathioprine is often the first-choice drug for long-term immunosuppression, and it is usually started together with steroids to allow tapering of steroids to the lowest dose possible. Methotrexate, mycophenolate mofetil or tacrolimus should be considered in patients who are intolerant of or unresponsive to azathioprine. Ciclosporin and cyclophosphamide should only be considered as a last resort, as these drugs can cause serious adverse events. Data on rituximab use in MG are sparse, but the initial results are promising.

Key Points

  • Immunosuppressant regimes in generalized myasthenia gravis vary between different countries and physicians, owing to a lack of good randomized evidence

  • Oral prednisolone is the recommended first-choice short-term immunosuppressant; it is usually started at a low dose on an alternate-day regime, and the dose is gradually increased

  • Azathioprine is often the first-choice drug for long-term immunosuppression

  • Methotrexate, mycophenolate mofetil or tacrolimus should be considered in patients who are intolerant of or unresponsive to azathioprine

  • Ciclosporin and cyclophosphamide should only be considered if other immunosuppressants fail, as these drugs can cause serious adverse events

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Figure 1: Inhibition of the cell cycle by immunosuppressants.
Figure 2: Immunosuppression of T cells.

References

  1. Drachman DB (1994) Myasthenia gravis. N Engl J Med 330: 1797–1810

    CAS  Article  Google Scholar 

  2. Vincent A and Newsom-Davis J (1985) Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis. J Neurol Neurosurg Psychiatry 48: 1246–1252

    CAS  Article  Google Scholar 

  3. Chan KH et al. (2007) Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 36: 651–658

    CAS  Article  Google Scholar 

  4. Conti-Fine BM et al. (2006) Myasthenia gravis: past, present, and future. J Clin Invest 116: 2843–2854

    CAS  Article  Google Scholar 

  5. Dalakas MC (2006) B cells in the pathophysiology of autoimmune neurological disorders: a credible therapeutic target. Pharmacol Ther 112: 57–70

    CAS  Article  Google Scholar 

  6. Vincent A et al. (2001) Myasthenia gravis. Lancet 357: 2122–2128

    CAS  Article  Google Scholar 

  7. Grob D et al. (1981) The natural course of myasthenia gravis and effect of therapeutic measures. Ann NY Acad Sci 377: 652–669

    CAS  Article  Google Scholar 

  8. Oosterhuis HJ (1981) Observations of the natural history of myasthenia gravis and the effect of thymectomy. Ann NY Acad Sci 377: 678–690

    CAS  Article  Google Scholar 

  9. Oosterhuis HJ (1988) Long-term effects of treatment in 374 patients with myasthenia gravis. Monogr Allergy 25: 75–85

    CAS  PubMed  Google Scholar 

  10. Taylor AL et al. (2005) Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 56: 23–46

    Article  Google Scholar 

  11. Allison AC (2000) Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 47: 63–83

    CAS  Article  Google Scholar 

  12. Barnes PJ and Adcock IM (1998) Transcription factors and asthma. Eur Respir J 12: 221–234

    CAS  Article  Google Scholar 

  13. Pescovitz MD (2006) Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 6: 859–866

    CAS  Article  Google Scholar 

  14. Matell G et al. (1976) Effects of some immunosuppressive procedures in myasthenia gravis. Ann NY Acad Sci 274: 659–676

    CAS  Article  Google Scholar 

  15. Mertens HG et al. (1981) Effect of immunosuppressive drugs (azathioprine). Ann NY Acad Sci 377: 691–698

    CAS  Article  Google Scholar 

  16. Witte AS et al. (1984) Azathioprine in the treatment of myasthenia gravis. Ann Neurol 15: 602–605

    CAS  Article  Google Scholar 

  17. Kuks JBM et al. (1991) Azathioprine in myasthenia gravis: observations in 41 patients and a review of literature. Neuromuscul Disord 1: 423–431

    CAS  Article  Google Scholar 

  18. Mantegazza R et al. (1988) Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis. J Neurol 235: 449–453

    CAS  Article  Google Scholar 

  19. Heckmann JM et al. (2001) High-dose immunosuppressive therapy in generalised myasthenia gravis—a 2-year follow-up study. S Afr Med J 91: 765–770

    CAS  PubMed  Google Scholar 

  20. Myasthenia Gravis Clinical Study Group (1993) A randomised clinical trial comparing prednisolone and azathioprine in myasthenia gravis. Results of a second interim analysis. J Neurol Neurosurg Psychiatry 56: 1157–1163

  21. Palace J et al. (1998) A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 50: 1778–1783

    CAS  Article  Google Scholar 

  22. Schalke BCG et al. (1990) Immunosuppressive treatment of myasthenia gravis. Results of a double-blind trial—ciclosporin A (CSA) versus azathioprine (AZA). Jikeikai Med J 37 (Suppl): 165–169

    Google Scholar 

  23. Bromberg MB et al. (1997) Randomized trial of azathioprine or prednisolone for initial immunosuppressive treatment of myasthenia gravis. J Neurol Sci 150: 59–62

    CAS  Article  Google Scholar 

  24. Perez MC et al. (1981) Stable remissions in myasthenia gravis. Neurology 31: 32–37

    CAS  Article  Google Scholar 

  25. De Feo LG et al. (2002) Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve 26: 31–36

    Article  Google Scholar 

  26. Skeie GO et al. (2006) Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 13: 691–699

    CAS  Article  Google Scholar 

  27. Cos L et al. (2000) Mycophenolate mofetil (MyM) is safe and well tolerated in myasthenia gravis (MG). Neurology 54 (Suppl 3): A137

    Google Scholar 

  28. Ciafaloni E et al. (2001) Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 56: 97–99

    CAS  Article  Google Scholar 

  29. Chaudhry V et al. (2001) Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 56: 94–96

    CAS  Article  Google Scholar 

  30. Meriggioli MN et al. (2003) Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology 61: 1438–1440

    CAS  Article  Google Scholar 

  31. Meriggioli MN et al. (2003) Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann NY Acad Sci 998: 494–499

    CAS  Article  Google Scholar 

  32. Aspreva Pharmaceuticals Corporation [http://www.aspreva.com]

  33. Goulon M et al. (1988) Results of a one-year open trial of cyclosporine in ten patients with severe myasthenia gravis. Transplant Proc 20 (3 Suppl 4): 211–217

    CAS  PubMed  Google Scholar 

  34. Bonifati DM and Angelini C (1997) Long-term cyclosporine treatment in a group of severe myasthenia gravis patients. J Neurol 244: 542–547

    CAS  Article  Google Scholar 

  35. Lavrnic D et al. (2005) Cyclosporine in the treatment of myasthenia gravis. Acta Neurol Scand 111: 247–252

    CAS  Article  Google Scholar 

  36. Tindall RSA et al. (1987) Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 316: 719–724

    CAS  Article  Google Scholar 

  37. Tindall RS et al. (1993) A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci 681: 539–551

    CAS  Article  Google Scholar 

  38. Hart IK et al. (2007) Immunosuppressive agents for myasthenia gravis. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD005224. doi:10.1002/14651858.CD005224.pub2

    Google Scholar 

  39. Konishi T et al. (2003) Clinical study of FK506 in patients with myasthenia gravis. Muscle Nerve 28: 570–574

    CAS  Article  Google Scholar 

  40. Konishi T et al. (2005) Long-term treatment of generalised myasthenia gravis with FK506 (tacrolimus). J Neurol Neurosurg Psychiatry 76: 448–450

    CAS  Article  Google Scholar 

  41. Kawaguchi N et al. (2004) Low-dose tacrolimus treatment in thymectomised and steroid-dependent myasthenia gravis. Curr Med Res Opin 20: 1269–1273

    CAS  Article  Google Scholar 

  42. Ponseti JM et al. (2005) Long-term results of tacrolimus in cyclosporine- and prednisolone-dependent myasthenia gravis. Neurology 64: 1641–1643

    CAS  Article  Google Scholar 

  43. Ponseti JM et al. (2007) Tacrolimus for myasthenia gravis: a clinical study of 212 patients. Ann NY Acad Sci [doi:10.1196/annals.1405.000]

  44. Nagane Y et al. (2005) Efficacy of low-dose FK506 in the treatment of myasthenia gravis—a randomized pilot study. Eur Neurol 53: 146–150

    CAS  Article  Google Scholar 

  45. Simon HE (1935) Myasthenia gravis: effect of treatment with anterior pituitary extract. JAMA 104: 2065–2066

    Article  Google Scholar 

  46. Genkins G et al. (1971) The use of ACTH and corticosteroids in myasthenia gravis. Ann NY Acad Sci 183: 369–374

    CAS  Article  Google Scholar 

  47. Brunner NG et al. (1972) Corticosteroids in the management of severe generalized myasthenia gravis. Effectiveness and comparison with corticotropin therapy. Neurology 22: 603–610

    CAS  Article  Google Scholar 

  48. Arsura EL et al. (1985) High-dose intravenous methylprednisolone in myasthenia gravis. Arch Neurol 42: 1149–1153

    CAS  Article  Google Scholar 

  49. Pascuzzi RM et al. (1984) Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 15: 291–298

    CAS  Article  Google Scholar 

  50. Sghirlanzoni A et al. (1984) Myasthenia gravis: prolonged treatment with steroids. Neurology 34: 170–174

    CAS  Article  Google Scholar 

  51. Cosi V et al. (1991) Effectiveness of steroid treatment in myasthenia gravis: a retrospective study. Acta Neurol Scand 84: 33–39

    CAS  Article  Google Scholar 

  52. Evoli A et al. (1992) Long-term results of corticosteroid therapy in patients with myasthenia gravis. Eur Neurol 32: 37–43

    CAS  Article  Google Scholar 

  53. Bu B et al. (2000) A prospective study of effectiveness and safety of long-term prednisone therapy in patients with myasthenia gravis [Chinese]. Zhonghua Shen Jing Ge Za Zhi 33: 28–31

    Google Scholar 

  54. Howard FM Jr et al. (1976) Alternate-day prednisone: preliminary report of a double-blind controlled study. Ann NY Acad Sci 274: 596–607

    Article  Google Scholar 

  55. Lindberg C et al. (1998) Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand 97: 370–373

    CAS  Article  Google Scholar 

  56. Zhang J et al. (1998). Effectiveness of steroid treatment in juvenile myasthenia gravis [Chinese]. Zhonghua Er Ke Za Zhi 36: 612–614

    Google Scholar 

  57. Warmolts JR and Engel WK (1971) Benefit from alternate-day prednisone in myasthenis gravis. Neurology 21: 412–417

    Google Scholar 

  58. Thakre M et al. (2007) Rituximab in refractory MuSK antibody myasthenia gravis. J Neurol 254: 968–969

    Article  Google Scholar 

  59. Baek WS et al. (2007) Complete remission induced by rituximab in refractory, seronegative, muscle-specific, kinase-positive myasthenia gravis. J Neurol Neurosurg Psychiatry 78: 771

    Article  Google Scholar 

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Acknowledgements

CN Ng helped in the translation of two papers published in Chinese.

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Sathasivam, S. Steroids and immunosuppressant drugs in myasthenia gravis. Nat Rev Neurol 4, 317–327 (2008). https://doi.org/10.1038/ncpneuro0810

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