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Risk Mitigation Strategies for Adverse Reactions Associated with the Disease-Modifying Drugs in Multiple Sclerosis

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Abstract

Over the past several years, the number of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has doubled in number. The 13 approved agents have shown a wide range of efficacy and safety in their clinical trials and post-marketing experience. While the availability of the newer agents allows for a wider selection of therapy for clinicians and patients, there is a need for careful understanding of the benefits and risks of each agent. Several factors such as the medication efficacy, side-effect profile, patient’s preference, and co-morbidities need to be considered. An individualized treatment approach is thus imperative. In this review, risk stratification and mitigation strategies of the various disease-modifying agents are discussed.

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References

  1. Dhib-Jalbut S, Marks S. Interferon-β mechanisms of action in multiple sclerosis. Neurology. 2010;74(1 Suppl. 1):S17–24.

    Article  CAS  PubMed  Google Scholar 

  2. Langer-Gould A, Moses HH, Murray TJ. Strategies for managing the side effects of treatments for multiple sclerosis. Neurology. 2004;63(11 Suppl. 5):S35–41.

    Article  PubMed  Google Scholar 

  3. Parfenov V, Schluep M, Du Pasquier R. Assessing risks of multiple sclerosis therapies. J Neurol Sci. 2013;332(1–2):59–65. doi:10.1016/j.jns.2013.06.013.

    Article  CAS  PubMed  Google Scholar 

  4. Reess J, Haas J, Gabriel K, Fuhlrott A, Fiola M. Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy. Mult Scler. 2002;8(1):15–8.

    Article  CAS  PubMed  Google Scholar 

  5. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta‐lb in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45(7):1277–85.

  6. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67(7):1242–9.

    Article  CAS  PubMed  Google Scholar 

  7. O’Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889–97. doi:10.1016/s1474-4422(09)70226-1.

    Article  PubMed  CAS  Google Scholar 

  8. Reder AT, Oger JF, Kappos L, O’Connor P, Rametta M. Short-term and long-term safety and tolerability of interferon beta-1b in multiple sclerosis. Mult Scler Relat Disord. 2014;3(3):294–302. doi:10.1016/j.msard.2013.11.005.

    Article  PubMed  Google Scholar 

  9. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology. 1999;53(8):1622–7.

    Article  CAS  PubMed  Google Scholar 

  10. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359(9316):1453–60.

    Article  CAS  PubMed  Google Scholar 

  11. Farrell RA, Giovannoni G. Measuring and management of anti-interferon beta antibodies in subjects with multiple sclerosis. Mult Scler. 2007;13(5):567–77. doi:10.1177/1352458506073522.

    Article  CAS  PubMed  Google Scholar 

  12. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(1 Suppl. 1):S25–30.

    Article  CAS  PubMed  Google Scholar 

  13. Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903–14.

    Article  CAS  PubMed  Google Scholar 

  14. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995;45(7):1268–76.

    Article  CAS  PubMed  Google Scholar 

  15. Korczyn AD, Nisipeanu P. Safety profile of copolymer 1: analysis of cumulative experience in the United States and Israel. J Neurol. 1996;243(4 Suppl. 1):S23–6.

    Article  CAS  PubMed  Google Scholar 

  16. Novantrone® (mitoxantrone) Prescribing Information. Rockland, MA, USA: Serono, Inc.

  17. Fidler JM, DeJoy SQ, Gibbons JJ Jr. Selective immunomodulation by the antineoplastic agent mitoxantrone. I. Suppression of B lymphocyte function. J Immunol. 1986;137(2):727–32.

    CAS  PubMed  Google Scholar 

  18. Kopadze T, Dehmel T, Hartung HP, Stuve O, Kieseier BC. Inhibition by mitoxantrone of in vitro migration of immunocompetent cells: a possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis. Arch Neurol. 2006;63(11):1572–8.

    Article  PubMed  Google Scholar 

  19. Watson CM, Davison AN, Baker D, O’Neill JK, Turk JL. Suppression of demyelination by mitoxantrone. Int J Immunopharmacol. 1991;13(7):923–30.

    Article  CAS  PubMed  Google Scholar 

  20. Cocco E, Marrosu MG. The current role of mitoxantrone in the treatment of multiple sclerosis. Expert Rev Neurother. 2014;14(6):607–16.

    Article  CAS  PubMed  Google Scholar 

  21. Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegel BA, Abbey EE. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler. 2003;9(1):59–62.

    Article  CAS  PubMed  Google Scholar 

  22. Paul F, Dorr J, Wurfel J, Vogel HP, Zipp F. Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2007;78(2):198–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Rivera VM, Jeffery DR, Weinstock-Guttman B, Bock D, Dangond F. Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study. BMC Neurol. 2013;13:80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone. J Neurol. 2005;252(10):1217–22 (Epub 2005 Apr 18).

    Article  CAS  PubMed  Google Scholar 

  25. Ellis R, Brown S, Boggild M. Therapy-related acute leukaemia with mitoxantrone: Four years on, what is the risk and can it be limited? Mult Scler. 2014;21(5):642–5.

    Article  PubMed  CAS  Google Scholar 

  26. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356(6364):63–6.

    Article  CAS  PubMed  Google Scholar 

  27. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910.

    Article  CAS  PubMed  Google Scholar 

  28. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911–23.

    Article  CAS  PubMed  Google Scholar 

  29. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005;353(4):369–74.

    Article  CAS  PubMed  Google Scholar 

  30. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005;353:375–81. doi:10.1056/NEJMoa051847.

    Article  CAS  PubMed  Google Scholar 

  31. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353(4):362–8.

    Article  PubMed  Google Scholar 

  32. Tysabri® (natalizumab) prescribing information. Cambridge: Biogen Idec Inc.; 2013.

  33. Inc. BI. TYSABRI® (natalizumab) Update: PML incidence in patients receiving TYSABRI. Online accessed 30 June 2015.

  34. Carruthers RL, Chitnis T, Healy BC. Modeling probability of additional cases of natalizumab-associated JCV sero-negative progressive multifocal leukoencephalopathy. Mult Scler. 2014;20(6):757–60.

    Article  PubMed  Google Scholar 

  35. Bozic C, Richman S, Plavina T, Natarajan A, Scanlon JV, Subramanyam M, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742–50.

    Article  PubMed  Google Scholar 

  36. Gorelik L, Lerner M, Bixler S, Crossman M, Schlain B, Simon K, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68(3):295–303.

    Article  PubMed  Google Scholar 

  37. Bozic C, Subramanyam M, Richman S, Plavina T, Zhang A, Ticho B. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol. 2014;21(2):299–304.

    Article  CAS  PubMed  Google Scholar 

  38. Olsson T, Achiron A, Alfredsson L, Berger T, Brassat D, Chan A, et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Mult Scler. 2013;19(11):1533–8.

    Article  PubMed  Google Scholar 

  39. Inc. BI. TYSABRI® (natalizumab) Update: PML incidence in patients receiving TYSABRI. 2015.

  40. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802–12.

    Article  CAS  PubMed  Google Scholar 

  41. Cutter GR, Stuve O. Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Mult Scler. 2014;20(10):1304–5. doi:10.1177/1352458514531843.

    Article  PubMed  Google Scholar 

  42. Clifford DB, DeLuca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9(4):438–46.

    Article  CAS  PubMed  Google Scholar 

  43. Khatri BO, Man S, Giovannoni G, Koo AP, Lee JC, Tucky B, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Agnihotri SP, Dang X, Carter JL, Fife TD, Bord E, Batson S, et al. JCV GCN in a natalizumab-treated MS patient is associated with mutations of the VP1 capsid gene. Neurology. 2014;83(8):727–32. doi:10.1212/wnl.0000000000000713.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Schippling S, Kempf C, Buchele F, Jelcic I, Bozinov O, Bont A, et al. JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol. 2013;74(4):622–6. doi:10.1002/ana.23973.

    Article  CAS  PubMed  Google Scholar 

  46. Miller DH, Soon D, Fernando KT, MacManus DG, Barker GJ, Yousry TA, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390–401. doi:10.1212/01.wnl.0000260064.77700.fd.

    Article  CAS  PubMed  Google Scholar 

  47. O’Connor P, Goodman A, Kappos L, Lublin F, Polman C, Rudick RA, et al. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. Neurology. 2014;83(1):78–86. doi:10.1212/wnl.0000000000000541.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Bozic C, LaGuette J, Panzara MA, Sandrock AW. Natalizumab and central nervous system lymphoma: no clear association. Ann Neurol. 2009;66(3):261–2. doi:10.1002/ana.21835.

    Article  PubMed  Google Scholar 

  49. Matzke M, Schreiber S, Elolf E, Metz I, Mawrin C, Heinze HJ, et al. Natalizumab-associated central nervous system lymphoma?–another patient. Mult Scler. 2012;18(11):1653–4. doi:10.1177/1352458512439336.

    Article  PubMed  Google Scholar 

  50. Na A, Hall N, Kavar B, King J. Central nervous system lymphoma associated with natalizumab. J Clin Neurosci. 2014;21(6):1068–70. doi:10.1016/j.jocn.2013.10.018.

    Article  PubMed  Google Scholar 

  51. Phan-Ba R, Bisig B, Deprez M, De Prijck B, Delrue G, Herens C, et al. Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol. 2011;69(6):1060–1. doi:10.1002/ana.22296 (author reply 1–2).

  52. Schweikert A, Kremer M, Ringel F, Liebig T, Duyster J, Stuve O, et al. Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol. 2009;66(3):403–6. doi:10.1002/ana.21782.

    Article  CAS  PubMed  Google Scholar 

  53. Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31(9):1028–35. doi:10.1111/j.1365-2036.2010.04262.x.

    CAS  PubMed  Google Scholar 

  54. Lisotti A, Azzaroli F, Brillanti S, Mazzella G. Severe acute autoimmune hepatitis after natalizumab treatment. Dig Liver Dis. 2012;44(4):356–7. doi:10.1016/j.dld.2011.11.003.

    Article  PubMed  Google Scholar 

  55. Abbas M, Lalive PH, Chofflon M, Simon HU, Chizzolini C, Ribi C. Hypereosinophilia in patients with multiple sclerosis treated with natalizumab. Neurology. 2011;77(16):1561–4. doi:10.1212/WNL.0b013e318233b391.

    Article  CAS  PubMed  Google Scholar 

  56. Robier C, Amouzadeh-Ghadikolai O, Bregant C, Diez J, Melinz K, Neubauer M, et al. The anti-VLA-4 antibody natalizumab induces erythroblastaemia in the majority of the treated patients with multiple sclerosis. Mult Scler. 2014;20(9):1269–72. doi:10.1177/1352458514521307.

    Article  PubMed  CAS  Google Scholar 

  57. O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858–65. doi:10.1212/WNL.0b013e31821e7c8a.

    Article  PubMed  Google Scholar 

  58. Chiba K, Adachi K. Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis. Pharmaceuticals (Basel). 2012;5(5):514–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91–101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759–77.

    Article  CAS  PubMed  Google Scholar 

  61. GILENYA® (fingolimod) prescribing information. Basel: Novartis Pharmaceuticals; 2014.

  62. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    Article  CAS  PubMed  Google Scholar 

  63. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.

    Article  CAS  PubMed  Google Scholar 

  64. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–56.

    Article  CAS  PubMed  Google Scholar 

  65. Kappos L, O’Connor P, Radue EW, Polman C, Hohlfeld R, Selmaj K, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;20(10):1462.

    Google Scholar 

  66. DiMarco JP, O’Connor P, Cohen JA, Francis G, Collins W, Zhang-Auberson L, et al. First-dose effect of fingolimod: pooled safety data from two phase-3 studies (TRANSFORMS and FREEDOMS). Mult Scler. 2010;16(10 Suppl.):S290.

    Google Scholar 

  67. Collins W, Cohen J, O’Connor P, de Vera A, Zhang-Auberson L, Jin FJ, et al. Long-term safety of oral fingolimod (FTY720) in relapsing multiple sclerosis: integrated analyses of phase 2 and 3 studies. Mult Scler. 2010;16(10 Suppl.):S295.

    Google Scholar 

  68. Zarbin MA, Jampol LM, Jager RD, Reder AT, Francis G, Collins W, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120(7):1432–9.

    Article  PubMed  Google Scholar 

  69. Brown JC, Solomon SD, Bressler SB, Schachat AP, DiBernardo C, Bressler NM. Detection of diabetic foveal edema: contact lens biomicroscopy compared with optical coherence tomography. Arch Ophthalmol. 2004;122(3):330–5.

    Article  PubMed  Google Scholar 

  70. VARIVAX® (varicella virus vaccine) prescribing information. Merck & Co., Inc.; 2014.

  71. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355(11):1124–40.

    Article  CAS  PubMed  Google Scholar 

  72. Conzett KB, Kolm I, Jelcic I, Kamarachev J, Dummer R, Braun R, et al. Melanoma occurring during treatment with fingolimod for multiple sclerosis: a case report. Arch Dermatol. 2011;147(8):991–2. doi:10.1001/archdermatol.2011.212.

    Article  PubMed  Google Scholar 

  73. Kappos L, Cohen J, Collins W, de Vera A, Zhang-Auberson L, Ritter S, et al. Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord. 2014;3(4):494–504. doi:10.1016/j.msard.2014.03.002.

    Article  PubMed  Google Scholar 

  74. Lorvik KB, Bogen B, Corthay A. Fingolimod blocks immunosurveillance of myeloma and B-cell lymphoma resulting in cancer development in mice. Blood. 2012;119(9):2176–7. doi:10.1182/blood-2011-10-388892.

    Article  CAS  PubMed  Google Scholar 

  75. Samaraweera AP, Cohen SN, Akay EM, Evangelou N. Lymphomatoid papulosis: a cutaneous lymphoproliferative disorder in a patient on fingolimod for multiple sclerosis. Mult Scler. 2015;. doi:10.1177/1352458515597568.

    PubMed  Google Scholar 

  76. Tully T, Barkley A, Silber E. Kaposi sarcoma in a patient with relapsing-remitting multiple sclerosis receiving fingolimod. Neurology. 2015;84(19):1999–2001. doi:10.1212/wnl.0000000000001556.

    Article  PubMed  Google Scholar 

  77. Ward MD, Jones DE, Goldman MD. Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis. Expert Opin Drug Saf. 2014;13(7):989–98. doi:10.1517/14740338.2014.920820.

    Article  CAS  PubMed  Google Scholar 

  78. Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology. 2014;82(8):674–80. doi:10.1212/wnl.0000000000000137.

    Article  PubMed Central  PubMed  Google Scholar 

  79. Gilenya. Risk of progressive multifocal leukoencephalopathy (PML). In: Subei A, editor. Novartis Pharmaceuticals; 2015. p. 12.

  80. Gilenya Safety Update. Novartis Pharmaceuticals. 2015. http://www.novartis.com/newsroom/product-related-info-center/gilenya-safety-update.shtml. Accessed 16 Feb 2015.

  81. Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999;93(3):198–208.

    Article  CAS  PubMed  Google Scholar 

  82. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Ruckemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF, Kirschbaum B, et al. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem. 1998;273(34):21682–91.

    Article  CAS  PubMed  Google Scholar 

  84. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–56.

    Article  CAS  PubMed  Google Scholar 

  85. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–303.

    Article  PubMed  Google Scholar 

  86. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10):977–86.

    Article  CAS  PubMed  Google Scholar 

  87. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–16.

    Article  CAS  PubMed  Google Scholar 

  88. Aubagio® (teriflunomide) prescribing information. Genzyme Co.; 2014.

  89. Jung Henson L, Benamor M, Truffinet P, Kieseier B. Updated pregnancy outcomes in patients and partners of patients in the teriflunomide clinical trial program (P4.161). Neurology. 2014;82(10 Suppl.):P4.161.

  90. Miller A, Turpault S, Menguy-Vacheron F. Rapid elimination procedure of teriflunomide with cholestyramine or activated charcoal. In: 4th Cooperative Meeting of CMSC and ACTRIMS; 30 May–2 June 2012: San Diego; 2012.

  91. Freedman MS, Confavreux C, Comi G, et al. Hair thinning associated with teriflunomide therapy is manageable. In: 4th Cooperative Meeting of CMSC and ACTRIMS; 30 May–2 June 2012: San Diego; 2012.

  92. Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study. Br J Dermatol. 1998;138(3):456–60.

    Article  CAS  PubMed  Google Scholar 

  93. Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994;30(6):977–81.

    Article  CAS  PubMed  Google Scholar 

  94. de Jong R, Bezemer AC, Zomerdijk TP, van de Pouw-Kraan T, Ottenhoff TH, Nibbering PH. Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. Eur J Immunol. 1996;26(9):2067–74.

    Article  PubMed  Google Scholar 

  95. Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J Dermatol. 1998;139(3):390–5.

    Article  CAS  PubMed  Google Scholar 

  96. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun. 1997;234(1):19–23.

    Article  CAS  PubMed  Google Scholar 

  97. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006;13(6):604–10.

    Article  CAS  PubMed  Google Scholar 

  98. Linker RA, Lee D-H, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(3):678–92.

    Article  PubMed  Google Scholar 

  99. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97.

    Article  CAS  PubMed  Google Scholar 

  100. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107.

    Article  CAS  PubMed  Google Scholar 

  101. Sheikh SI, Nestorov I, Russell H, O’Gorman J, Huang R, Milne GL, et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013;35(10):1582–94 e9.

  102. Tecfidera® (dimethyl fumarate) Prescribing Information. Cambridge: Biogen Inc.; 2015.

  103. Mellen Center Approaches: use of DMF in MS (Tecfidera, BG12). 2014. http://my.clevelandclinic.org/services/neurological_institute/mellen-center-multiple-sclerosis/medical-professionals. Accessed 2 Aug 2015.

  104. O’Gorman J, Russell HK, Li J, Phillips G, Kurukulasuriya NC, Viglietta V. Effect of aspirin pretreatment or slow dose titration on flushing and gastrointestinal events in healthy volunteers receiving delayed-release dimethyl fumarate. Clin Ther. 2015;37(7):1402–19 e5. doi:10.1016/j.clinthera.2015.03.028.

  105. Nieuwkamp DJ, Murk JL, van Oosten BW, Cremers CH, Killestein J, Viveen MC, et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med. 2015;372(15):1474–6.

    Article  CAS  PubMed  Google Scholar 

  106. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368(17):1657–8.

    Article  CAS  PubMed  Google Scholar 

  107. Sweetser MT, Dawson KT, Bozic C. Manufacturer’s response to case reports of PML. N Engl J Med. 2013;368(17):1659–61.

    Article  CAS  PubMed  Google Scholar 

  108. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368(17):1658–9.

    Article  PubMed  CAS  Google Scholar 

  109. Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med. 2015;372(15):1476–8.

    Article  CAS  PubMed  Google Scholar 

  110. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.

    Article  PubMed  Google Scholar 

  111. Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005;35(11):3332–42.

    Article  CAS  PubMed  Google Scholar 

  112. Investigators TCT. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786–801.

  113. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819–28.

    Article  CAS  PubMed  Google Scholar 

  114. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–39.

    Article  CAS  PubMed  Google Scholar 

  115. Genzyme’s Lemtrada™ approved in canada for treatment of multiple sclerosis. Genzyme Co.; 2013.

  116. Genzyme’s Lemtrada Approved by the FDA. Cambridge: Genzyme; 2014. http://news.genzyme.com/press-release/genzymes-lemtrada-approved-fda. Accessed 27 Apr 2015.

  117. Lemtrada® (alemtuzumab) Prescribing Information. Cambridge: Genzyme; 2014.

  118. Mellen Center Approaches: use of alemtuzumab in MS (Lemtrada). 2015. http://my.clevelandclinic.org/services/neurological_institute/mellen-center-multiple-sclerosis/medical-professionals. Accessed 27 Apr 2015.

  119. Cossburn M, Pace AA, Jones J, Ali R, Ingram G, Baker K, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology. 2011;77(6):573–9.

    Article  CAS  PubMed  Google Scholar 

  120. Lycke J, Arnold DL, Cohen JA, Coles AJ, Confavreux C, Fox EJ, et al. Lymphocyte subset dynamics following alemtuzumab administration in the CARE-MS I trial. In: European Federation of Neurological Societies; September 8–11; Stockholm, Sweden; 2012.

  121. Miller T, Habek M, Margolin DH, Palmer J, Oyuela P. Analysis of data from RRMS alemtuzumab-treated patients in the clinical program to evaluate incidence rates of malignancy. Mult Scler. 2014;20(1 Suppl.):447.

    Google Scholar 

  122. Freedman MS, Selchen D, Arnold DL, Prat A, Banwell B, Yeung M, et al. Treatment optimization in MS: Canadian MS Working Group updated recommendations. Can J Neurol Sci. 2013;40(3):307–23.

    Article  PubMed  Google Scholar 

  123. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59(10):1496–506.

    Article  CAS  PubMed  Google Scholar 

  124. Vartanian T. An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther. 2003;25(1):105–18.

    Article  CAS  PubMed  Google Scholar 

  125. Klawiter EC, Cross AH, Naismith RT. The present efficacy of multiple sclerosis therapeutics: is the new 66 % just the old 33 %? Neurology. 2009;73(12):984–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430–8.

    Article  CAS  PubMed  Google Scholar 

  127. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61(11):1528–32.

    Article  PubMed  Google Scholar 

  128. Young PJ, Lederer C, Eder K, Daumer M, Neiss A, Polman C, et al. Relapses and subsequent worsening of disability in relapsing-remitting multiple sclerosis. Neurology. 2006;67(5):804–8.

    Article  CAS  PubMed  Google Scholar 

  129. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007;370(9585):389–97.

    Article  CAS  PubMed  Google Scholar 

  130. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001;56(12):1628–36.

  131. Johnson KP, Brooks BR, Ford CC, Goodman AD, Lisak RP, Myers LW, et al. Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial. Mult Scler. 2003;9(6):585–91.

    Article  CAS  PubMed  Google Scholar 

  132. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–23.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Avenue/U10, Cleveland, OH, 44195, USA

    Adnan M. Subei & Daniel Ontaneda

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  1. Adnan M. Subei
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Correspondence to Daniel Ontaneda.

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Funding

A. Subei is supported by Clinician Care Physician Fellowship Award CF 00104N-1 from the National Multiple Sclerosis Society. Dr Ontaneda is supported by NIH CTSC KL2TR0000440 award. No funding was directly received by either author in the preparation of this manuscript.

Conflict of interest

A Subei has received speaking fees from Genzyme. D. Ontaneda has received consulting fees from Acorda Therapeutics, Alkermes, Biogen Idec, Genzyme, Mallinckrodt, Novartis, and Teva.

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Subei, A.M., Ontaneda, D. Risk Mitigation Strategies for Adverse Reactions Associated with the Disease-Modifying Drugs in Multiple Sclerosis. CNS Drugs 29, 759–771 (2015). https://doi.org/10.1007/s40263-015-0277-4

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