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Infection Risk in Patients on Multiple Sclerosis Therapeutics

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Abstract

The interface of multiple sclerosis (MS) and infection occurs on several levels. First, infectious disease has been postulated as a potential trigger, if not cause, of MS. Second, exacerbation of MS has been well-documented as a consequence of infection, and, lastly, infectious diseases have been recognized as a complication of the therapies currently employed in the treatment of MS. MS is a disease in which immune dysregulation is a key component. Examination of central nervous system (CNS) tissue of people affected by MS demonstrates immune cell infiltration, activation and inflammation. Therapies that alter the immune response have demonstrated efficacy in reducing relapse rates and evidence of brain inflammation on magnetic resonance imaging (MRI). Despite the altered immune response in MS, there is a lack of evidence that these patients are at increased risk of infectious disease in the absence of treatment or debility. Links between infections and disease-modifying therapies (DMTs) used in MS will be discussed in this review, as well as estimates of occurrence and ways to potentially minimize these risks. We address infection in MS in a comprehensive fashion, including (1) the impact of infections on relapse rates in patients with MS; (2) a review of available infection data from pivotal trials and postmarketing studies for the approved and experimental DMTs, including frequency, types and severity of infections; and (3) relevant risk minimization strategies, particularly as they pertain to progressive multifocal leukoencephalopathy (PML).

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References

  1. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. I: clinical course and disability. Brain. 1989;112:133–46.

    PubMed  Google Scholar 

  2. Polman CH, Reingold SC, Banwell B. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.

    PubMed Central  PubMed  Google Scholar 

  3. Murta V, Ferrari CC. Influence of peripheral inflammation on the progression of multiple sclerosis: evidence from the clinic and experimental animal models. Mol Cell Neurosci. 2013;53:6–13.

    CAS  PubMed  Google Scholar 

  4. Stadelmann C, Wegner C, Bruck W. Inflammation, demyelination, and degeneration: recent insights from MS pathology. Biochim Biophys Acta. 2011;1812:275–82.

    CAS  PubMed  Google Scholar 

  5. Sospedra M, Martin R. Immunology of multiple sclerosis. Ann Rev Immunol. 2005;23:683–747.

    CAS  Google Scholar 

  6. Finsten B, Owens T. Innate immune responses in central nervous system inflammation. FEBS Lett. 2011;585(23):3806–12.

    Google Scholar 

  7. Esiri MM. Multiple sclerosis: a quantitative and qualitative study of immunoglobulin-containing cells in the central nervous system. Neuropathol Appl Neurobiol. 1980;6:9–21.

    CAS  PubMed  Google Scholar 

  8. Wootla B, Denic A, Keegan BM, et al. Evidence for the role of B cells and immunoglobulins in the pathogenesis of multiple sclerosis. Neurol Res Int. 2011;2011:780712.

    PubMed Central  PubMed  Google Scholar 

  9. Cotran R, Kumar V, Tucker C. Robbins pathologic basis of disease. 6th ed. Philadelphia: WB Saunders; 1999. p. 1326.

    Google Scholar 

  10. Anthony DC, Couch Y, Losey P, Evans MC. The systemic response to brain injury and disease. Brain Behav Immun. 2012;26(4):534–40.

    CAS  PubMed  Google Scholar 

  11. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet. 1985;1:1313–5.

    CAS  PubMed  Google Scholar 

  12. Andersen O, Lygner PE, Bergstrom T, et al. Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol. 1993;240:417–22.

    CAS  PubMed  Google Scholar 

  13. Buljevac D, Flach HZ, Hop WCJ, et al. Prospective study on the relation between infections and multiple sclerosis exacerbations. Brain. 2002;125:952–60.

    CAS  PubMed  Google Scholar 

  14. Confavreux C. Infections and the risk of relapse in multiple sclerosis. Brain. 2002;125(5):933–4.

    PubMed  Google Scholar 

  15. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol. 1999;46:296–304.

    CAS  PubMed  Google Scholar 

  16. Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology. 2006;67(4):652–9.

    CAS  PubMed  Google Scholar 

  17. Edwards LJ, Sharrack B, Ismail A, et al. Central inflammation versus peripheral regulation in multiple sclerosis. J Neurol. 2011;258:1518–27.

    CAS  PubMed  Google Scholar 

  18. Mikulkova Z, Praksova P, Stourac P, et al. Imbalance in T-cell and cytokine profiles in patients with relapsing-remitting multiple sclerosis. J Neurol Sci. 2011;300:135–41.

    CAS  PubMed  Google Scholar 

  19. Trenova AG, Manova MG, Kostadinova II, et al. Clinical and laboratory study of pro-inflammatory and anti-inflammatory cytokines in women with multiple sclerosis. Folia Med (Plovdiv). 2011;53:29–35.

    PubMed  Google Scholar 

  20. Ysrraelit MC, Gaitan MI, Lopez AS, Correale J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology. 2008;71:1948–54.

    CAS  PubMed  Google Scholar 

  21. Hauser SL, Doolittle TH, Lincoln R, et al. Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurology. 1990;40:1735–9.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011;9:409–16.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011;(10):CD007621.

  25. Saidha S, Eckstein C, Calabresi PA. New and emerging disease modifying therapies for multiple sclerosis. Ann N Y Acad Sci. 2012;1247:117–37.

    CAS  PubMed  Google Scholar 

  26. Brinkmann V, Pinschewer D, Chiba K, Feng L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci. 2000;21(2):49–52.

    CAS  PubMed  Google Scholar 

  27. Chun J, Brinkmann V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med. 2011;12(64):213–28.

    PubMed Central  PubMed  Google Scholar 

  28. Gasperini C, Ruggieri S. New oral drugs for multiple sclerosis. Neurol Sci. 2009;30(Suppl 2):S179–83.

    PubMed  Google Scholar 

  29. Gasperini C, Ruggieri S. Emerging oral drugs for relapsing-remitting multiple sclerosis. Expert Opin Emerg Drugs. 2011;16:697–712.

    CAS  PubMed  Google Scholar 

  30. Gold R, Kappos L, Bar-Or A. Clinical efficacy of BG-12, an oral therapy, in relapsing remitting multiple sclerosis: data from the phase 3 DEFINE trial. Mult Scler J. 2011;17:S34.

    Google Scholar 

  31. Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurol. 2011;10:1026–34.

    CAS  PubMed  Google Scholar 

  32. Perry VH, Newman TA, Cunningham C. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003;4:103–12.

    CAS  PubMed  Google Scholar 

  33. Ransohoff R. Natalizumab and PML. Nat Neurosci. 2005;8:1275.

    CAS  PubMed  Google Scholar 

  34. Berger JR. Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf. 2010;33:969–83.

    CAS  PubMed  Google Scholar 

  35. Doerck S, Gobel K, Weise G, et al. Temporal pattern of ICAM-I mediated regulatory T cell recruitment to sites of inflammation in adoptive transfer model of multiple sclerosis. PLoS One. 2010;5:e15478.

    PubMed Central  PubMed  Google Scholar 

  36. Schweingruber N, Reichardt SD, Luhder F, Reichardt HM. Mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol. 2007;24:174–82.

    Google Scholar 

  37. Cutolo MB, Seriolo C, Pizzorni ME, et al. Use of glucocorticoids and risk of infections. Autoimmun Rev. 2008;8(2):153–5.

    CAS  PubMed  Google Scholar 

  38. Van Delden C. Infectious risks of immunomodulating therapies in rheumatology [in French]. Rev Med Suisse. 2006;2(57):738–40 (743–5).

    PubMed  Google Scholar 

  39. Klein NC, Go CH, Cunha BA. Infections associated with steroid use. Infect Dis Clin North Am. 2001;15(2):423–32 (viii).

    CAS  PubMed  Google Scholar 

  40. Stahn C, Lowenberg M, Homes DW, Buttgereit F. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol. 2007;275:71–8.

    CAS  PubMed  Google Scholar 

  41. Spies CM, Biflsma JW, Burmester GR, Buttgereit F. Pharmacology of glucocorticoids in rheumatoid arthritis. Curr Opin Pharmacol. 2010;10:302–7.

    CAS  PubMed  Google Scholar 

  42. Wiendl H, Toyka KV, Rieckmann P, Multiple Sclerosis Therapy Consensus Group. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008;255:1449–63.

    CAS  PubMed  Google Scholar 

  43. Johnson KP. Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2012;12:371–84.

    CAS  PubMed  Google Scholar 

  44. Karussis D. Immunotherapy of multiple sclerosis: the state of the art. Bio Drugs. 2013;27:113–48.

    CAS  Google Scholar 

  45. Winkelman A, Loebermann M, Reisinger EC, Zettl UK. Multiple sclerosis treatment and infectious issues: update. Clin Exp Immunol. 2014;175:425–38.

    Google Scholar 

  46. Fridkis-Hareli M, Strominger JL. Promiscuous binding of synthetic copolymer-1 to purified HLA-DR molecules. J Immunol. 1998;160:4386–97.

    CAS  PubMed  Google Scholar 

  47. Ziemsen T, Kumpfel T, Klinkert WE, et al. Glatiramer acetate-specific T-helper 1-and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain. 2002;125:2381–91.

    Google Scholar 

  48. Hong J, Li N, Zhang X, et al. Induction of CD4+CD25+ regulatory T cells by copolymer-1 through activation of transcription factor Foxp3. Proc Natl Acad Sci. 2005;102:6449–54.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Johnson KP, Brooks BR, Cohen JA, 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. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268–76.

    CAS  PubMed  Google Scholar 

  50. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone®) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1998;50:701–8.

    CAS  PubMed  Google Scholar 

  51. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW, Therapeutics, Technology Assessment Subcommittee of the American Academy of Neurology. Evidence report: the efficacy and safety of mitoxantrone (Novantrone®) in the treatment of multiple sclerosis. Neurology. 2010;74:1463–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Martinelli V, Radaelli M, Straffi L, et al. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol Sci. 2009;30(Suppl 2):S167–70.

    PubMed  Google Scholar 

  53. Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997;244(3):153–9.

    CAS  PubMed  Google Scholar 

  54. Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62:112–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Hartung H, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25.

    PubMed  Google Scholar 

  56. Leger OJ, Yednock TA, Tanner L, et al. Humanization of a mouse antibody against human alpha-4- integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum Antibodies. 1997;8:3–16.

    CAS  PubMed  Google Scholar 

  57. Biogen Idec. Tysabri® prescribing information and safety update. Available at: https://medinfo.biogenidec.com/. Accessed 2 Mar 2015.

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

    CAS  PubMed  Google Scholar 

  59. Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005;353:375–81.

    CAS  PubMed  Google Scholar 

  60. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353:362–8.

    PubMed  Google Scholar 

  61. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin. 1984;2(2):299–313.

    CAS  PubMed  Google Scholar 

  62. Berger J, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol. 1998;4(1):59–66.

    CAS  PubMed  Google Scholar 

  63. Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain. 1958;81:93–111.

    CAS  PubMed  Google Scholar 

  64. Berger J, Aksamit MD, Clifford D, et al. PML diagnostic criteria consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80:1430–8.

    PubMed Central  PubMed  Google Scholar 

  65. Berger J, Khalili K. The pathogenesis of progressive multifocal leukoencephalopathy. Discov Med. 2011;12(67):495–503.

    PubMed  Google Scholar 

  66. Bechtel M, Sanders C, Bechtel A. Neurological complications of biologic therapy in psoriasis: a review. J Clin Aesthet Dermatol. 2009;2(11):27–32.

    PubMed Central  PubMed  Google Scholar 

  67. Grinyo J, Charpentier B, Medina J, et al. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation. 2010;90(12):1521–7.

    PubMed  Google Scholar 

  68. Nived O, Bengtsson AA, Jonsen A, Sturfelt G. Progressive multifocal leukoencephalopathy: the importance of early diagnosis illustrated in four cases. Lupus. 2008;17(11):1036–41.

    CAS  PubMed  Google Scholar 

  69. Kothary N, Diak I, Brinker A, et al. Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. J Am Acad Dermatol. 2011;65:546–51.

    CAS  PubMed  Google Scholar 

  70. Waggoner J, Martinu T, Palmer S. Progressive multifocal leukoencephalopathy following heightened immunosuppression after lung transplant. J Heart Lung Transplant. 2009;28:395–8.

    PubMed Central  PubMed  Google Scholar 

  71. Neff RT, Hurst FP, Falta EM, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation. 2008;86(10):1474–8.

    PubMed  Google Scholar 

  72. Gonzalez H, Bolgert F, Camporo P, Leblond V. Progressive multifocal leukoencephalitis (PML) in three patients treated with standard-dose fludarabine (FAMP). Hematol Cell Ther. 1999;41:183–6.

    CAS  PubMed  Google Scholar 

  73. Leonard S, Hulin C, Anxionnat R, et al. Multifocal progressive leukoencephalitis in a patient given fludarabine for chronic lymphoid leukemia [in French]. Rev Neurol (Paris). 2002;158:1121–3.

    CAS  PubMed  Google Scholar 

  74. Saumoy M, Castells G, Escoda L, et al. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma. 2002;43:433–6.

    PubMed  Google Scholar 

  75. Lejniece S, Murovska M, Chapenko S, et al. Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient. Exp Oncol. 2011;33:239–41.

    CAS  PubMed  Google Scholar 

  76. Warnatz K, Peter HH, Schumacher M, et al. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis. 2003;62(1):50–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Rahmlow M, Shuster E, Domnik J, et al. Leflunomide-associated progressive multifocal leukoencephalopathy. Arch Neurol. 2008;65(11):1538–9.

    PubMed  Google Scholar 

  78. Ermis U, Wiesmann M, Nolte K, et al. Fumaric acid-associated progressive multifocal leukencephalopathy (PML), treatment and survival in a patient with psoriasis [abstract no. 84]. In: Presented at Kongress der Deutschen Gesellschaft fur Neurologie mit Fortbidlunsakademie. Nurnberg; 2011.

  79. Van Oosten B, Killestein J, Barkhof F, et al. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368:17.

    Google Scholar 

  80. Biogen Idec. Tecfidera® package insert. http://www.tecfidera.com/pdfs/full-prescribing-information.pdf. Accessed 25 Jan 2015.

  81. Zaheer F, Berger J. Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps. Ther Adv Drug Saf. 2012;3(5):227–39.

    PubMed Central  PubMed  Google Scholar 

  82. Kappos L, Bates D, Hartung H, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol. 2007;6:431–41.

    PubMed  Google Scholar 

  83. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2013;366:1870.

    Google Scholar 

  84. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis. 2013;57(6):849–52.

    CAS  PubMed  Google Scholar 

  85. Bourdette D, Gilden D. Fingolimod and multiple sclerosis: four cautionary tales. Neurology. 2012;79(19):1942–3.

    PubMed  Google Scholar 

  86. Yeung J, Cauquil C, Saliou G, et al. Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab. Neurology. 2013;80(19):1812–3.

    PubMed Central  PubMed  Google Scholar 

  87. Bourre B, Lefaucheur R, Ahtoy P, et al. Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab. Neurology. 2013;81(22):1966–7.

    PubMed  Google Scholar 

  88. Kwiatkowski A, Gallois J, Bilbault N, et al. Herpes encephalitis during natalizumab treatment in multiple sclerosis. Mult Scler. 2012;18(6):909–11.

    CAS  PubMed  Google Scholar 

  89. Shenoy ES, Mylonakis E, Hurtado RM, Venna N. Natalizumab and HSV meningitis. J Neurovirol. 2011;17(3):288–90.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Fragoso YD, Brooks JB, Gomes S, de Oliveira FT, da Gama PD. Report of three cases of herpes zoster during treatment with natalizumab. CNS Neurosci Ther. 2013;19(4):280–1.

    PubMed  Google Scholar 

  91. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–8.

    CAS  PubMed  Google Scholar 

  92. Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66:460–71.

    CAS  PubMed  Google Scholar 

  93. Lanini S, Molloy AC, Fine PE, et al. Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis. BMC Med. 2011;9:36.

    PubMed Central  PubMed  Google Scholar 

  94. Carbone J, del Pozo N, Gallego A, Sarmiento E. Immunological risk factors for infection after immunosuppressive and biologic therapies. Expert Rev Anti Infect Ther. 2011;9:405–13.

    CAS  PubMed  Google Scholar 

  95. Molloy E, Calabrese L. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun Rev. 2008;8:144–6.

    CAS  PubMed  Google Scholar 

  96. Carson K, Evens A, Richey E, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Genentech Personal Communication. San Francisco: July 18, 2014.

  98. Fox EJ. Alemtuzumab in the treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2010;10(12):1789–97.

    CAS  PubMed  Google Scholar 

  99. Klotz L, Meuth S, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis: a focus on alemtuzumab. Clin Immunol. 2012;142:25–30.

    CAS  PubMed  Google Scholar 

  100. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomized controlled phase 3 trial. Lancet. 2012;380:1819–28.

    CAS  PubMed  Google Scholar 

  101. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. Lancet. 2012;380:1829–39.

    CAS  PubMed  Google Scholar 

  102. Genzyme. Lemtrada® package insert. http://www.tecfidera.com/pdfs/full-prescribing-information.pdf. Accessed 6 Feb 2015.

  103. Martin S, Mart F, Fiumara K, et al. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006;43:16–24.

    CAS  PubMed  Google Scholar 

  104. O’Sullivan C, Dev KK. The structure and function of the S1P1 receptor. Trends Pharmaco Sci. 2013;34(7):401–12.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

    CAS  PubMed  Google Scholar 

  107. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    CAS  PubMed  Google Scholar 

  108. Uccelli A, Ginocchio F, Mancardi GL, Bassetti M. Primary varicella zoster infection associated with fingolimod treatment. Neurology. 2011;76(11):1023–4.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  110. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–40.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  112. Francis G, Kappos L, O’Connor P, et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2014;20(4):471–80.

    CAS  PubMed  Google Scholar 

  113. Berger JR. Varicella vaccination after fingolimod: a case report. Mult Scler Related Dis. 2013;2:391–4.

    Google Scholar 

  114. Ferraro D, De Biasi S, Vitetta F, et al. Recurrent varicella following steroids and fingolimod in a multiple sclerosis patient. J Neuroimmune Pharmacol. 2014;8(5):1059–61.

    Google Scholar 

  115. Ratchford JN, Costello K, Reich DS, Calabresi PA. Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod. Neurology. 2013;81(3):306.

    PubMed  Google Scholar 

  116. Kern RZ. Dear healthcare Provider. East hanover, NJ: Novartis (E-mail 17 Feb 2015).

  117. Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999;93:198–208.

    CAS  PubMed  Google Scholar 

  118. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293–303.

    PubMed  Google Scholar 

  119. Jenks KA, Stamp LK, O’Donnell JL, et al. Leflunomide-associated infections in rheumatoid arthritis. J Rheumatol. 2007;34(11):2201–3.

    CAS  PubMed  Google Scholar 

  120. O’Connor PW, Li D, Freedman MS, et al. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894–900.

    PubMed  Google Scholar 

  121. Confavreux C, Li DK, Freedman MS, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012;18:1278–89.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Treumer F, Zhu K, Glaser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol. 2003;121:1383–8.

    CAS  PubMed  Google Scholar 

  123. Stoof T, Flier J, Sampat S, et al. The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol. 2001;144:1114–20.

    CAS  PubMed  Google Scholar 

  124. Gold R, Linker RA, Stangel M. Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action. Clin Immunol. 2012;142:44–8.

    CAS  PubMed  Google Scholar 

  125. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–107.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. Bundesinstitut Fur Arzneimittel Und Medizinprodukte (BfArM) [Federal Institute for Drugs and Medical Devices]. Adverse events database 2013. http://www.bfarm.de/DE/Pharmakovigilanz/uaw-db-node.html. Accessed 8 Aug 2013.

  130. Keating M, Kantarjian H, Talpaz M, et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989;74:19–25.

    CAS  PubMed  Google Scholar 

  131. Sipe J. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother. 2005;5(6):721–7.

    CAS  PubMed  Google Scholar 

  132. Sipe J. Cladribine tablets: a potential new short-course annual treatment for relapsing multiple sclerosis. Expert Rev Neurother. 2010;10(3):365–75.

    CAS  PubMed  Google Scholar 

  133. Giacomini PS, Bar-Or A. Laquinimod in multiple sclerosis. Clin Immunol. 2012;142(1):38–43.

    CAS  PubMed  Google Scholar 

  134. Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306:173–9.

    CAS  PubMed  Google Scholar 

  135. Brunmark C, Runstrom A, Ohlsson L, et al. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;130:163–72.

    CAS  PubMed  Google Scholar 

  136. Gurevich M, Gritzman T, Orbach R, et al. Laquinimod suppress antigen presentation in relapsing- remitting multiple sclerosis: in-vitro high-throughput gene expression study. J Neuroimmunol. 2010;221(1–2):87–94.

    CAS  PubMed  Google Scholar 

  137. Polman C, Barkhof F, Sandberg-Wollheim M, et al. Laquinimod in relapsing MS. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology. 2005;64:987–91.

    CAS  PubMed  Google Scholar 

  138. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomized, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:2085–92.

    CAS  PubMed  Google Scholar 

  139. Comi G, Abramsky O, Arbizu T, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel group placebo-controlled study. Mult Scler. 2010;16:1360–6.

    CAS  PubMed  Google Scholar 

  140. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000–9.

    CAS  PubMed  Google Scholar 

  141. Tony HP, Burmester G, Schulze-Koops H, et al. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res Ther. 2011;13:R75.

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Bielekova B, Howard T, Packer AN, et al. Effect of Anti-CD25 Antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol. 2009;66(4):483–9.

    PubMed Central  PubMed  Google Scholar 

  143. Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics. 2013;10:55–67.

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Rose JW, Burns JB, Bjorklund J, et al. Daclizumab phase II trial in relapsing and remitting multiple sclerosis. Neurology. 2007;69(8):785–9.

    CAS  PubMed  Google Scholar 

  145. Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomized double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010;9:381–90.

    CAS  PubMed  Google Scholar 

  146. Liu J, Wang L, Zhan SY, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2012; (4): CD008127.

  147. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomized, double-blind, placebo-controlled trial. Lancet. 2013;381:2167–75.

    CAS  PubMed  Google Scholar 

  148. Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68:384–91.

    PubMed Central  PubMed  Google Scholar 

  149. Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76:802–12.

    CAS  PubMed  Google Scholar 

  150. Winkelman A, Loebermann M, Reisinger EC, et al. Fingolimod treatment for multiple sclerosis patients. What do we do with varicella? Ann Neurol. 2011;70:673–4 (author reply 4).

    Google Scholar 

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Acknowledgments

Eric M. Williamson reports no current financial relationships or disclosures in relation to the material herein. Joseph R. Berger reports grants from the PML Consortium and Biogen Idec, as well as personal fees from Millennium, Genentech, Amgen, Genzyme, Eisai, and Novartis outside the submitted work. No funding was received for the preparation of this review.

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  1. Division of Multiple Sclerosis, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 3 Gates Building, Philadelphia, PA, 19104, USA

    Eric M. Williamson & Joseph R. Berger

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Williamson, E.M., Berger, J.R. Infection Risk in Patients on Multiple Sclerosis Therapeutics. CNS Drugs 29, 229–244 (2015). https://doi.org/10.1007/s40263-015-0226-2

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