Myasthenia gravis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The mainstays of medical therapy for myasthenia gravis are: Symptomatic treatments (An oral anticholinesterase like pyridostigmine), chronic immunomodulating treatments (glucocorticoids and immunosuppressive drugs), rapid immunomodulating treatments (plasmapheresis and intravenous immune globulin).

Medical Therapy

The mainstays of medical therapy for myasthenia gravis are:

Symptomatic treatments

Chronic immunomodulating treatments

  1. Azathioprine: Azathioprine, a purine analogue which inhibits the nucleic acids synthesis, can cause improvement in about 90 percent of myasthenia gravis patients but the onset of this effect takes at least 6 to 12 month.[16][17][18][19] Azathioprine can cause macrocytosis (increased MCV) and malignancies such as non-hodgkin lymphoma.[20][21]
  2. Mycophenolate: Mycophenolate mofetil, a purine synthesis blocker in lymphocytes, is proven to be effective in reducing the symptoms of MG patients and their need to glucocorticoids.[22][23]
  3. Cyclosporine: Cyclosporine, an immunomodulatory agent which blocks the production of interleukin-2 and inhibits the function of T helper cells, can cause improvement in about 90 percent of MG patients after 1 to 2 months of start but the maximum effect will appear after 7 months.[24][25][26] This drug can cause nephrotoxicity[27], tremor, nausea, myalgias, gingival hyperplasia, hypertrichosis and malignancies such as squamous cell skin cancer and lymphoma.[26]
  4. Tacrolimus: Tacrolimus, an immunosuppressive macrolid can significantly reduce the requirement to prednisolone and MG symptoms in almost 67 to 87 percent of patients with less nephrotoxicity than cyclosporine.[27][28][29] the side effects of this drug include hyperglycemia, hypomagnesemia, paresthesias and tremor.[30]
  5. Rituximab: Rituximab, a monoclonal antibody against B cell membrane marker CD20 can be used in refractory myasthenia gravis. This drug is also effective in patients with anti MuSK antibody.[31][32][33][34]
  6. Methotrexate: Methotrexate is an immunosuppressant agent which suggested to be effective as a second line immunosuppressant for MG patients.[35][36]
  7. Etanercept: Etanercept is made of TNF receptor linked to Fc portion of human IgG1. This drug can inhibit TNF-alpha which is a proinflammatory cytokine, and improve the symptoms of MG patients.[37]
  8. Cyclophosphamide: Cyclophosphamide is an alkylating agent which inhibits the proliferation of B and T cells. Monthly high dose intravenous administration of this drug is proved to be more effective than daily oral type.[38] the side effects of this drug include anorexia, nausea and vomiting, leukopenia, alopecia and hemorrhagic cystitis and it can also increase the risk of malignancies.[38][39]

Rapid immunomodulating treatments

References

  1. ↑ Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J, Narayanaswami P (July 2016). "International consensus guidance for management of myasthenia gravis: Executive summary". Neurology. 87 (4): 419–25. doi:10.1212/WNL.0000000000002790. PMC 4977114. PMID 27358333.
  2. ↑ Punga AR, Stålberg E (June 2009). "Acetylcholinesterase inhibitors in MG: to be or not to be?". Muscle Nerve. 39 (6): 724–8. doi:10.1002/mus.21319. PMID 19260048.
  3. ↑ Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR (April 2005). "Corticosteroids for myasthenia gravis". Cochrane Database Syst Rev (2): CD002828. doi:10.1002/14651858.CD002828.pub2. PMID 15846640.
  4. ↑ Mann JD, Johns TR, Campa JF (August 1976). "Long-term administration of corticosteroids in myasthenia gravis". Neurology. 26 (8): 729–40. PMID 821005.
  5. ↑ Pascuzzi RM, Coslett HB, Johns TR (March 1984). "Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients". Ann. Neurol. 15 (3): 291–8. doi:10.1002/ana.410150316. PMID 6721451.
  6. ↑ Arsura E, Brunner NG, Namba T, Grob D (December 1985). "High-dose intravenous methylprednisolone in myasthenia gravis". Arch. Neurol. 42 (12): 1149–53. PMID 4062612.
  7. ↑ Fardet L, Flahault A, Kettaneh A, Tiev KP, Généreau T, Tolédano C, Lebbé C, Cabane J (July 2007). "Corticosteroid-induced clinical adverse events: frequency, risk factors and patient's opinion". Br. J. Dermatol. 157 (1): 142–8. doi:10.1111/j.1365-2133.2007.07950.x. PMID 17501951.
  8. ↑ Huscher D, Thiele K, Gromnica-Ihle E, Hein G, Demary W, Dreher R, Zink A, Buttgereit F (July 2009). "Dose-related patterns of glucocorticoid-induced side effects". Ann. Rheum. Dis. 68 (7): 1119–24. doi:10.1136/ard.2008.092163. PMID 18684744.
  9. ↑ Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW (March 2006). "Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data". Ann. Rheum. Dis. 65 (3): 285–93. doi:10.1136/ard.2005.038638. PMC 1798053. PMID 16107513.
  10. ↑ Wei L, MacDonald TM, Walker BR (November 2004). "Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease". Ann. Intern. Med. 141 (10): 764–70. PMID 15545676.
  11. ↑ Messer J, Reitman D, Sacks HS, Smith H, Chalmers TC (July 1983). "Association of adrenocorticosteroid therapy and peptic-ulcer disease". N. Engl. J. Med. 309 (1): 21–4. doi:10.1056/NEJM198307073090105. PMID 6343871.
  12. ↑ Piper JM, Ray WA, Daugherty JR, Griffin MR (May 1991). "Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs". Ann. Intern. Med. 114 (9): 735–40. PMID 2012355.
  13. ↑ MacAdams MR, White RH, Chipps BE (May 1986). "Reduction of serum testosterone levels during chronic glucocorticoid therapy". Ann. Intern. Med. 104 (5): 648–51. PMID 3083749.
  14. ↑ Crilly R, Cawood M, Marshall DH, Nordin BE (October 1978). "Hormonal status in normal, osteoporotic and corticosteroid-treated postmenopausal women". J R Soc Med. 71 (10): 733–6. PMC 1436218. PMID 712726.
  15. ↑ Wolkowitz OM, Burke H, Epel ES, Reus VI (October 2009). "Glucocorticoids. Mood, memory, and mechanisms". Ann. N. Y. Acad. Sci. 1179: 19–40. doi:10.1111/j.1749-6632.2009.04980.x. PMID 19906230.
  16. ↑ Saperstein DS, Barohn RJ (March 2004). "Management of myasthenia gravis". Semin Neurol. 24 (1): 41–8. doi:10.1055/s-2004-829586. PMID 15229791.
  17. ↑ Matell G (1987). "Immunosuppressive drugs: azathioprine in the treatment of myasthenia gravis". Ann. N. Y. Acad. Sci. 505: 589–94. PMID 3479940.
  18. ↑ Mertens HG, Hertel G, Reuther P, Ricker K (1981). "Effect of immunosuppressive drugs (azathioprine)". Ann. N. Y. Acad. Sci. 377: 691–9. PMID 6951493.
  19. ↑ Mantegazza R, Antozzi C, Peluchetti D, Sghirlanzoni A, Cornelio F (November 1988). "Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis". J. Neurol. 235 (8): 449–53. PMID 3062134.
  20. ↑ Witte AS, Cornblath DR, Schatz NJ, Lisak RP (November 1986). "Monitoring azathioprine therapy in myasthenia gravis". Neurology. 36 (11): 1533–4. PMID 3762975.
  21. ↑ Herrlinger U, Weller M, Dichgans J, Melms A (May 2000). "Association of primary central nervous system lymphoma with long-term azathioprine therapy for myasthenia gravis?". Ann. Neurol. 47 (5): 682–3. PMID 10805346.
  22. ↑ Chaudhry V, Cornblath DR, Griffin JW, O'Brien R, Drachman DB (January 2001). "Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases". Neurology. 56 (1): 94–6. PMID 11148242.
  23. ↑ Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB (January 2001). "Mycophenolate mofetil for myasthenia gravis: an open-label pilot study". Neurology. 56 (1): 97–9. PMID 11148243.
  24. ↑ Tindall RS, Rollins JA, Phillips JT, Greenlee RG, Wells L, Belendiuk G (March 1987). "Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis". N. Engl. J. Med. 316 (12): 719–24. doi:10.1056/NEJM198703193161205. PMID 3547126.
  25. ↑ Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K (June 1993). "A clinical therapeutic trial of cyclosporine in myasthenia gravis". Ann. N. Y. Acad. Sci. 681: 539–51. PMID 8357194.
  26. ↑ 26.0 26.1 Ciafaloni E, Nikhar NK, Massey JM, Sanders DB (August 2000). "Retrospective analysis of the use of cyclosporine in myasthenia gravis". Neurology. 55 (3): 448–50. PMID 10932288.
  27. ↑ 27.0 27.1 de Mattos AM, Olyaei AJ, Bennett WM (February 2000). "Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future". Am. J. Kidney Dis. 35 (2): 333–46. PMID 10676738.
  28. ↑ Nagane Y, Utsugisawa K, Obara D, Kondoh R, Terayama Y (2005). "Efficacy of low-dose FK506 in the treatment of Myasthenia gravis--a randomized pilot study". Eur. Neurol. 53 (3): 146–50. doi:10.1159/000085833. PMID 15900097.
  29. ↑ Evoli A, Di Schino C, Marsili F, Punzi C (January 2002). "Successful treatment of myasthenia gravis with tacrolimus". Muscle Nerve. 25 (1): 111–4. PMID 11754194.
  30. ↑ Ponseti JM, Azem J, Fort JM, López-Cano M, Vilallonga R, Buera M, Cervera C, Armengol M (May 2005). "Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis". Neurology. 64 (9): 1641–3. doi:10.1212/01.WNL.0000160392.32894.6D. PMID 15883336.
  31. ↑ Tandan R, Hehir MK, Waheed W, Howard DB (August 2017). "Rituximab treatment of myasthenia gravis: A systematic review". Muscle Nerve. 56 (2): 185–196. doi:10.1002/mus.25597. PMID 28164324.
  32. ↑ Stieglbauer K, Pichler R, Topakian R (April 2017). "10-year-outcomes after rituximab for myasthenia gravis: Efficacy, safety, costs of inhospital care, and impact on childbearing potential". J. Neurol. Sci. 375: 241–244. doi:10.1016/j.jns.2017.02.009. PMID 28320139.
  33. ↑ Stein B, Bird SJ (March 2011). "Rituximab in the treatment of MuSK antibody-positive myasthenia gravis". J Clin Neuromuscul Dis. 12 (3): 163–4. doi:10.1097/CND.0b013e3181df2b3e. PMID 21321497.
  34. ↑ Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, Juarez C, Gallardo E (September 2008). "Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients". J. Neuroimmunol. 201-202: 90–4. doi:10.1016/j.jneuroim.2008.04.039. PMID 18653247.
  35. ↑ Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M (August 2011). "A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis". BMC Neurol. 11: 97. doi:10.1186/1471-2377-11-97. PMC 3170595. PMID 21819556.
  36. ↑ Pasnoor M, He J, Herbelin L, Burns TM, Nations S, Bril V, Wang AK, Elsheikh BH, Kissel JT, Saperstein D, Shaibani JA, Jackson C, Swenson A, Howard JF, Goyal N, David W, Wicklund M, Pulley M, Becker M, Mozaffar T, Benatar M, Pazcuzzi R, Simpson E, Rosenfeld J, Dimachkie MM, Statland JM, Barohn RJ (July 2016). "A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis". Neurology. 87 (1): 57–64. doi:10.1212/WNL.0000000000002795. PMC 4932232. PMID 27306628.
  37. ↑ Rowin J, Meriggioli MN, Tüzün E, Leurgans S, Christadoss P (December 2004). "Etanercept treatment in corticosteroid-dependent myasthenia gravis". Neurology. 63 (12): 2390–2. PMID 15623708.
  38. ↑ 38.0 38.1 McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA (June 1988). "Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus". N. Engl. J. Med. 318 (22): 1423–31. doi:10.1056/NEJM198806023182203. PMID 3259286.
  39. ↑ De Feo LG, Schottlender J, Martelli NA, Molfino NA (July 2002). "Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis". Muscle Nerve. 26 (1): 31–6. doi:10.1002/mus.10133. PMID 12115946.
  40. ↑ Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE (November 1977). "Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis". N. Engl. J. Med. 297 (21): 1134–40. doi:10.1056/NEJM197711242972102. PMID 917042.
  41. ↑ Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG (March 1978). "Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange". Neurology. 28 (3): 266–72. PMID 564482.
  42. ↑ Gajdos P, Chevret S, Toyka K (2002). "Plasma exchange for myasthenia gravis". Cochrane Database Syst Rev (4): CD002275. doi:10.1002/14651858.CD002275. PMID 12519572.
  43. ↑ Rodnitzky RL, Goeken JA (June 1982). "Complications of plasma exchange in neurological patients". Arch. Neurol. 39 (6): 350–4. PMID 7092611.
  44. ↑ Pérez Nellar J, Domínguez AM, Llorens-Figueroa JA, Ferrá-Betancourt A, Pardo A, Quiala M, Gali Z (2001). "[A comparative study of intravenous immunoglobulin and plasmapheresis preoperatively in myasthenia]". Rev Neurol (in Spanish; Castilian). 33 (5): 413–6. PMID 11727205.
  45. ↑ Illa I (May 2005). "IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status". J. Neurol. 252 Suppl 1: I14–8. doi:10.1007/s00415-005-1104-5. PMID 15959667.
  46. ↑ Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, Attarian S, Chevret S (November 2005). "Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial". Arch. Neurol. 62 (11): 1689–93. doi:10.1001/archneur.62.11.1689. PMID 16286541.
  47. ↑ Dalakas MC (November 1999). "Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines". Muscle Nerve. 22 (11): 1479–97. PMID 10514226.
  48. ↑ Dalakas MC (June 2004). "The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile". Pharmacol. Ther. 102 (3): 177–93. doi:10.1016/j.pharmthera.2004.04.002. PMID 15246245.

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