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Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients

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Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Several disease-modifying therapies have been shown to ameliorate the disease course; however, the individual treatment response and the occurrence of adverse events remain highly unpredictable. In the last 2 decades, a multitude of studies have aimed to identify biomarkers that enable treatment allocation in the individual patient or subgroup of patients with regard to treatment efficacy and safety profile. Following a PubMed database search, we provide an overview on what is presently known about body fluid markers for the prediction of response to the currently approved MS therapeutics. We also discuss the potential use of biomarkers with regard to drug-induced adverse events. To date, only a few molecules have been introduced in clinical routine: anti-drug antibodies against interferon (IFN)-β and natalizumab that are associated with abolished drug levels and treatment failure; anti-JC virus (JCV) antibody index that allows risk stratification for the development of progressive multifocal leukoencephalopathy (PML), a rare but severe adverse event during natalizumab treatment; and serostatus of varicella zoster virus as screening examination prior to fingolimod therapy to prevent the infection. A few candidate biomarkers still need closer examination, such as type I IFN signature and T-helper cell (Th)-17 reactivity for prediction of IFN-β treatment response, L-selectin expression for prediction of natalizumab-associated PML, interleukin (IL)-21 levels for prediction of secondary autoimmunity after exposure to alemtuzumab, lymphocyte count with regard to PML risk while receiving dimethyl fumarate or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) for monitoring of cardiac side effects during mitoxantrone therapy.

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References

  1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359(9313):1221–31. doi:10.1016/S0140-6736(02)08220-X.

    Article  PubMed  Google Scholar 

  2. PRISMS study group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352(9139):1498–504.

    Article  Google Scholar 

  3. The IFNb Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43(4):655–61.

    Article  Google Scholar 

  4. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–94. doi:10.1002/ana.410390304.

    Article  CAS  PubMed  Google Scholar 

  5. 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. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–76.

    Article  CAS  PubMed  Google Scholar 

  6. 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. doi:10.1056/NEJMoa044397.

    Article  CAS  PubMed  Google Scholar 

  7. 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. doi:10.1056/NEJMoa044396.

    Article  CAS  PubMed  Google Scholar 

  8. 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. doi:10.1056/NEJMoa0909494.

    Article  CAS  PubMed  Google Scholar 

  9. 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. doi:10.1056/NEJMoa0907839.

    Article  CAS  PubMed  Google Scholar 

  10. 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. doi:10.1056/NEJMoa1114287.

    Article  CAS  PubMed  Google Scholar 

  11. 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. doi:10.1056/NEJMoa1206328.

    Article  CAS  PubMed  Google Scholar 

  12. 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. doi:10.1056/NEJMoa1014656.

    Article  PubMed  Google Scholar 

  13. 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. doi:10.1016/S0140-6736(12)61769-3.

    Article  CAS  PubMed  Google Scholar 

  14. 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. doi:10.1016/S0140-6736(12)61768-1.

    Article  CAS  PubMed  Google Scholar 

  15. Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9884):2167–75. doi:10.1016/S0140-6736(12)62190-4.

    Article  CAS  PubMed  Google Scholar 

  16. Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015;373(15):1418–28. doi:10.1056/NEJMoa1501481.

    Article  CAS  PubMed  Google Scholar 

  17. Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25. doi:10.1016/S0140-6736(02)12023-X.

    Article  PubMed  Google Scholar 

  18. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907–11.

    Article  CAS  PubMed  Google Scholar 

  19. Bielekova B, Kadom N, Fisher E, Jeffries N, Ohayon J, Richert N, et al. MRI as a marker for disease heterogeneity in multiple sclerosis. Neurology. 2005;65(7):1071–6. doi:10.1212/01.wnl.0000178984.30534.f9.

    Article  CAS  PubMed  Google Scholar 

  20. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707–17.

    Article  CAS  PubMed  Google Scholar 

  21. Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. doi:10.1067/mcp.2001.113989.

    Article  Google Scholar 

  22. Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol. 2014;13(1):113–26. doi:10.1016/S1474-4422(13)70233-3.

    Article  PubMed  Google Scholar 

  23. Rio J, Nos C, Tintore M, Tellez N, Galan I, Pelayo R, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344–52. doi:10.1002/ana.20740.

    Article  CAS  PubMed  Google Scholar 

  24. Gneiss C, Tripp P, Reichartseder F, Egg R, Ehling R, Lutterotti A, et al. Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients. Mult Scler. 2006;12(6):731–7.

    Article  CAS  PubMed  Google Scholar 

  25. Perini P, Calabrese M, Biasi G, Gallo P. The clinical impact of interferon beta antibodies in relapsing-remitting MS. J Neurol. 2004;251(3):305–9. doi:10.1007/s00415-004-0312-8.

    Article  CAS  PubMed  Google Scholar 

  26. Deisenhammer F. Neutralizing antibodies to interferon-beta and other immunological treatments for multiple sclerosis: prevalence and impact on outcomes. CNS Drugs. 2009;23(5):379–96. doi:10.2165/00023210-200923050-00003.

    Article  CAS  PubMed  Google Scholar 

  27. The IFNB Multiple Sclerosis Study Group. The University of British Columbia MS/MRI Analysis Group. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology. 1996;47(4):889–94.

    Article  Google Scholar 

  28. Francis GS, Rice GP, Alsop JC, Group PS. Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology. 2005;65(1):48–55. doi:10.1212/01.wnl.0000171748.48188.5b.

    Article  CAS  PubMed  Google Scholar 

  29. Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW, Hartung HP, Hohlfeld R, et al. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study. Neurology. 2005;65(1):40–7. doi:10.1212/01.wnl.0000171747.59767.5c.

    Article  CAS  PubMed  Google Scholar 

  30. Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, et al. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology. 2004;62(11):2031–7.

    Article  CAS  PubMed  Google Scholar 

  31. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet. 2003;362(9391):1184–91. doi:10.1016/S0140-6736(03)14541-2.

    Article  CAS  PubMed  Google Scholar 

  32. Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung HP, Hemmer B, et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010;9(7):740–50. doi:10.1016/S1474-4422(10)70103-4.

    Article  CAS  PubMed  Google Scholar 

  33. Hegen H, Schleiser M, Gneiss C, Di Pauli F, Ehling R, Kuenz B, et al. Persistency of neutralizing antibodies depends on titer and interferon-beta preparation. Mult Scler. 2012;18(5):610–5. doi:10.1177/1352458511426738.

    Article  CAS  PubMed  Google Scholar 

  34. Khan OA, Dhib-Jalbut SS. Neutralizing antibodies to interferon beta-1a and interferon beta-1b in MS patients are cross-reactive. Neurology. 1998;51(6):1698–702.

    Article  CAS  PubMed  Google Scholar 

  35. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13(7):657–65. doi:10.1016/S1474-4422(14)70068-7.

    Article  CAS  PubMed  Google Scholar 

  36. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermuller J, Stadler PF, et al. HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet. 2008;83(2):219–27. doi:10.1016/j.ajhg.2008.07.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Buck D, Cepok S, Hoffmann S, Grummel V, Jochim A, Berthele A, et al. Influence of the HLA-DRB1 genotype on antibody development to interferon beta in multiple sclerosis. Arch Neurol. 2011;68(4):480–7. doi:10.1001/archneurol.2011.65.

    Article  PubMed  Google Scholar 

  38. Weber F, Cepok S, Wolf C, Berthele A, Uhr M, Bettecken T, et al. Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-beta therapy in multiple sclerosis patients. Pharmacogenomics J. 2012;12(3):238–45. doi:10.1038/tpj.2011.14.

    Article  CAS  PubMed  Google Scholar 

  39. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M, et al. Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Mult Scler. 2014;20(5):577–87. doi:10.1177/1352458513503597.

    Article  CAS  PubMed  Google Scholar 

  40. Giovannoni G, Barbarash O, Casset-Semanaz F, King J, Metz L, Pardo G, et al. Safety and immunogenicity of a new formulation of interferon beta-1a (Rebif New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results. Mult Scler. 2009;15(2):219–28. doi:10.1177/1352458508097299.

    Article  CAS  PubMed  Google Scholar 

  41. Clanet M, Radue EW, Kappos L, Hartung HP, Hohlfeld R, Sandberg-Wollheim M, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002;59(10):1507–17.

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Sominanda A, Rot U, Suoniemi M, Deisenhammer F, Hillert J, Fogdell-Hahn A. Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity. Mult Scler. 2007;13(2):208–14. doi:10.1177/1352458506070762.

    Article  CAS  PubMed  Google Scholar 

  44. Farrell R, Kapoor R, Leary S, Rudge P, Thompson A, Miller D, et al. Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta. Mult Scler. 2008;14(2):212–8. doi:10.1177/1352458507082066.

    Article  CAS  PubMed  Google Scholar 

  45. Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study G. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005;65(1):33–9. doi:10.1212/01.WNL.0000166049.51502.6A.

    Article  CAS  PubMed  Google Scholar 

  46. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MSSG. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: clinical results. Neurology. 2001;56(11):1496–504.

    Article  Google Scholar 

  47. Petkau AJ, White RA, Ebers GC, Reder AT, Sibley WA, Lublin FD, et al. Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler. 2004;10(2):126–38.

    Article  CAS  PubMed  Google Scholar 

  48. Frank JA, Richert N, Bash C, Stone L, Calabresi PA, Lewis B, et al. Interferon-beta-1b slows progression of atrophy in RRMS: three-year follow-up in NAb- and NAb + patients. Neurology. 2004;62(5):719–25.

    Article  CAS  PubMed  Google Scholar 

  49. Polman C, Kappos L, White R, Dahlke F, Beckmann K, Pozzilli C, et al. Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology. 2003;60(1):37–43.

    Article  CAS  PubMed  Google Scholar 

  50. Panitch H, Miller A, Paty D, Weinshenker B, North American Study Group on Interferon beta-1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63(10):1788–95.

    Article  PubMed  CAS  Google Scholar 

  51. 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. doi:10.1016/S0140-6736(07)61194-5.

    Article  CAS  PubMed  Google Scholar 

  52. Sbardella E, Tomassini V, Gasperini C, Bellomi F, Cefaro LA, Morra VB, et al. Neutralizing antibodies explain the poor clinical response to interferon beta in a small proportion of patients with multiple sclerosis: a retrospective study. BMC Neurol. 2009;9:54. doi:10.1186/1471-2377-9-54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Gonzalez-Navajas JM, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012;12(2):125–35. doi:10.1038/nri3133.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. van Baarsen LG, van der Pouw Kraan TC, Kragt JJ, Baggen JM, Rustenburg F, Hooper T, et al. A subtype of multiple sclerosis defined by an activated immune defense program. Genes Immun. 2006;7(6):522–31. doi:10.1038/sj.gene.6364324.

    Article  PubMed  CAS  Google Scholar 

  55. van Baarsen LG, Vosslamber S, Tijssen M, Baggen JM, van der Voort LF, Killestein J, et al. Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients. PLoS One. 2008;3(4):e1927. doi:10.1371/journal.pone.0001927.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Bustamante MF, Fissolo N, Rio J, Espejo C, Costa C, Mansilla MJ, et al. Implication of the Toll-like receptor 4 pathway in the response to interferon-beta in multiple sclerosis. Ann Neurol. 2011;70(4):634–45. doi:10.1002/ana.22511.

    Article  CAS  PubMed  Google Scholar 

  57. Comabella M, Lunemann JD, Rio J, Sanchez A, Lopez C, Julia E, et al. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain. 2009;132(Pt 12):3353–65. doi:10.1093/brain/awp228.

    Article  CAS  PubMed  Google Scholar 

  58. von Wussow P, Jakschies D, Hochkeppel HK, Fibich C, Penner L, Deicher H. The human intracellular Mx-homologous protein is specifically induced by type I interferons. Eur J Immunol. 1990;20(9):2015–9. doi:10.1002/eji.1830200920.

    Article  Google Scholar 

  59. Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res. 2011;31(1):79–87. doi:10.1089/jir.2010.0076.

    Article  CAS  PubMed  Google Scholar 

  60. Deisenhammer F, Reindl M, Harvey J, Gasse T, Dilitz E, Berger T. Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology. 1999;52(6):1239–43.

    Article  CAS  PubMed  Google Scholar 

  61. Sominanda A, Hillert J, Fogdell-Hahn A. In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent. J Neurol Neurosurg Psychiatry. 2008;79(1):57–62. doi:10.1136/jnnp.2007.122549.

    Article  CAS  PubMed  Google Scholar 

  62. Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, et al. Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology. 2008;70(13 Pt 2):1119–27. doi:10.1212/01.wnl.0000304040.29080.7b.

    Article  CAS  PubMed  Google Scholar 

  63. van der Voort LF, Vennegoor A, Visser A, Knol DL, Uitdehaag BM, Barkhof F, et al. Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurology. 2010;75(14):1228–33. doi:10.1212/WNL.0b013e3181f6c556.

    Article  PubMed  CAS  Google Scholar 

  64. Matas E, Bau L, Martinez-Iniesta M, Romero-Pinel L, Mane MA, Cobo-Calvo A, et al. Baseline MxA mRNA expression predicts interferon beta response in multiple sclerosis patients. PLoS One. 2014;9(11):e112758. doi:10.1371/journal.pone.0112758.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Matas E, Bau L, Martinez-Iniesta M, Romero-Pinel L, Mane-Martinez MA, Martinez-Yelamos S. Absence of MxA induction is related to a poor clinical response to interferon beta treatment in multiple sclerosis patients. J Neurol. 2016;263(4):722–9. doi:10.1007/s00415-016-8053-z.

    Article  CAS  PubMed  Google Scholar 

  66. van der Voort LF, Visser A, Knol DL, Oudejans CB, Polman CH, Killestein J. Lack of interferon-beta bioactivity is associated with the occurrence of relapses in multiple sclerosis. Eur J Neurol. 2009;16(9):1049–52. doi:10.1111/j.1468-1331.2009.02649.x.

    Article  PubMed  Google Scholar 

  67. Matas E, Bau L, Martinez-Iniesta M, Romero-Pinel L, Mane-Martinez MA, Cobo-Calvo A, et al. MxA mRNA expression as a biomarker of interferon beta response in multiple sclerosis patients. J Neuroimmunol. 2016;291:73–7. doi:10.1016/j.jneuroim.2015.12.015.

    Article  CAS  PubMed  Google Scholar 

  68. Hegen H, Adrianto I, Lessard CJ, Millonig A, Bertolotto A, Comabella M, et al. Cytokine profiles show heterogeneity of interferon-beta response in multiple sclerosis patients. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e202. doi:10.1212/NXI.0000000000000202.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Malhotra S, Rio J, Urcelay E, Nurtdinov R, Bustamante MF, Fernandez O, et al. NLRP3 inflammasome is associated with the response to IFN-beta in patients with multiple sclerosis. Brain. 2015;138(Pt 3):644–52. doi:10.1093/brain/awu388.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8(9):942–9. doi:10.1038/ni1496.

    Article  CAS  PubMed  Google Scholar 

  71. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950–7. doi:10.1038/ni1497.

    Article  CAS  PubMed  Google Scholar 

  72. Watanabe H, Kawaguchi M, Fujishima S, Ogura M, Matsukura S, Takeuchi H, et al. Functional characterization of IL-17F as a selective neutrophil attractant in psoriasis. J Invest Dermatol. 2009;129(3):650–6. doi:10.1038/jid.2008.294.

    Article  CAS  PubMed  Google Scholar 

  73. Shahrara S, Pickens SR, Mandelin AM 2nd, Karpus WJ, Huang Q, Kolls JK, et al. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. J Immunol. 2010;184(8):4479–87. doi:10.4049/jimmunol.0901942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee LF, Axtell R, Tu GH, Logronio K, Dilley J, Yu J, et al. IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-beta in multiple sclerosis. Sci Transl Med. 2011;3(93):93ra68. doi:10.1126/scitranslmed.3002400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16(4):406–12. doi:10.1038/nm.2110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hartung HP, Steinman L, Goodin DS, Comi G, Cook S, Filippi M, et al. Interleukin 17F level and interferon beta response in patients with multiple sclerosis. JAMA Neurol. 2013;70(8):1017–21. doi:10.1001/jamaneurol.2013.192.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bushnell SE, Zhao Z, Stebbins CC, Cadavid D, Buko AM, Whalley ET, et al. Serum IL-17F does not predict poor response to IM IFNbeta-1a in relapsing-remitting MS. Neurology. 2012;79(6):531–7. doi:10.1212/WNL.0b013e318259e123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Palace J, Leite MI, Nairne A, Vincent A. Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol. 2010;67(8):1016–7. doi:10.1001/archneurol.2010.188.

    Article  PubMed  Google Scholar 

  79. Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Mult Scler. 2012;18(10):1480–3. doi:10.1177/1352458512439439.

    Article  PubMed  CAS  Google Scholar 

  80. Shimizu Y, Yokoyama K, Misu T, Takahashi T, Fujihara K, Kikuchi S, et al. Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J Neurol. 2008;255(2):305–7. doi:10.1007/s00415-007-0730-5.

    Article  PubMed  Google Scholar 

  81. Feng X, Reder NP, Yanamandala M, Hill A, Franek BS, Niewold TB, et al. Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis. J Neurol Sci. 2012;313(1–2):48–53. doi:10.1016/j.jns.2011.09.032.

    Article  CAS  PubMed  Google Scholar 

  82. Liu Y, Carlsson R, Comabella M, Wang J, Kosicki M, Carrion B, et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat Med. 2014;20(3):272–82. doi:10.1038/nm.3485.

    Article  CAS  PubMed  Google Scholar 

  83. Serana F, Imberti L, Amato MP, Comi G, Gasperini C, Ghezzi A, et al. MxA mRNA quantification and disability progression in interferon beta-treated multiple sclerosis patients. PLoS ONE. 2014;9(4):e94794. doi:10.1371/journal.pone.0094794.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Batocchi AP, Rotondi M, Caggiula M, Frisullo G, Odoardi F, Nociti V, et al. Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta. J Neuroimmunol. 2003;139(1–2):150–4.

    Article  CAS  PubMed  Google Scholar 

  85. Kvarnstrom M, Ydrefors J, Ekerfelt C, Vrethem M, Ernerudh J. Longitudinal interferon-beta effects in multiple sclerosis: differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-gamma, IL-4 or IL-13. J Neurol Sci. 2013;325(1–2):79–85. doi:10.1016/j.jns.2012.12.001.

    Article  CAS  PubMed  Google Scholar 

  86. Dhib-Jalbut S, Sumandeep S, Valenzuela R, Ito K, Patel P, Rametta M. Immune response during interferon beta-1b treatment in patients with multiple sclerosis who experienced relapses and those who were relapse-free in the START study. J Neuroimmunol. 2013;254(1–2):131–40. doi:10.1016/j.jneuroim.2012.08.012.

    Article  CAS  PubMed  Google Scholar 

  87. Sellebjerg F, Krakauer M, Limborg S, Hesse D, Lund H, Langkilde A, et al. Endogenous and recombinant type I interferons and disease activity in multiple sclerosis. PLoS ONE. 2012;7(6):e35927. doi:10.1371/journal.pone.0035927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Martinez-Rodriguez JE, Lopez-Botet M, Munteis E, Rio J, Roquer J, Montalban X, et al. Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis. Clin Immunol. 2011;141(3):348–56. doi:10.1016/j.clim.2011.09.006.

    Article  CAS  PubMed  Google Scholar 

  89. Bosca I, Villar LM, Coret F, Magraner MJ, Simo-Castello M, Alvarez-Cermeno JC, et al. Response to interferon in multiple sclerosis is related to lipid-specific oligoclonal IgM bands. Mult Scler. 2010;16(7):810–5. doi:10.1177/1352458510371961.

    Article  CAS  PubMed  Google Scholar 

  90. Comabella M, Rio J, Espejo C, Ruiz de Villa M, Al-Zayat H, Nos C, et al. Changes in matrix metalloproteinases and their inhibitors during interferon-beta treatment in multiple sclerosis. Clin Immunol. 2009;130(2):145–50. doi:10.1016/j.clim.2008.09.010.

    Article  CAS  PubMed  Google Scholar 

  91. Reuss R, Pohle S, Retzlaff K, Hemberger J, Oschmann P. Interferon beta-1a induces tumor necrosis factor receptor 1 but decreases tumor necrosis factor receptor 2 leukocyte mRNA levels in relapsing-remitting multiple sclerosis. NeuroImmunoModulation. 2009;16(3):171–6. doi:10.1159/000204230.

    Article  CAS  PubMed  Google Scholar 

  92. Wiesemann E, Deb M, Trebst C, Hemmer B, Stangel M, Windhagen A. Effects of interferon-beta on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-beta treatment in patients with multiple sclerosis. Mult Scler. 2008;14(2):166–76. doi:10.1177/1352458507081342.

    Article  CAS  PubMed  Google Scholar 

  93. Buttmann M, Merzyn C, Hofstetter HH, Rieckmann P. TRAIL, CXCL10 and CCL2 plasma levels during long-term Interferon-beta treatment of patients with multiple sclerosis correlate with flu-like adverse effects but do not predict therapeutic response. J Neuroimmunol. 2007;190(1–2):170–6. doi:10.1016/j.jneuroim.2007.08.009.

    Article  CAS  PubMed  Google Scholar 

  94. Sellebjerg F, Kristiansen TB, Wittenhagen P, Garred P, Eugen-Olsen J, Frederiksen JL, et al. Chemokine receptor CCR5 in interferon-treated multiple sclerosis. Acta Neurol Scand. 2007;115(6):413–8. doi:10.1111/j.1600-0404.2007.00826.x.

    Article  CAS  PubMed  Google Scholar 

  95. Bartosik-Psujek H, Stelmasiak Z. The interleukin-10 levels as a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients. Clin Neurol Neurosurg. 2006;108(7):644–7. doi:10.1016/j.clineuro.2005.10.011.

    Article  PubMed  Google Scholar 

  96. Sellebjerg F, Ross C, Koch-Henriksen N, Sorensen PS, Frederiksen JL, Bendtzen K, et al. CD26 + CD4 + T cell counts and attack risk in interferon-treated multiple sclerosis. Mult Scler. 2005;11(6):641–5.

    Article  CAS  PubMed  Google Scholar 

  97. Soilu-Hanninen M, Laaksonen M, Hanninen A, Eralinna JP, Panelius M. Downregulation of VLA-4 on T cells as a marker of long term treatment response to interferon beta-1a in MS. J Neuroimmunol. 2005;167(1–2):175–82. doi:10.1016/j.jneuroim.2005.06.022

  98. Muraro PA, Liberati L, Bonanni L, Pantalone A, Caporale CM, Iarlori C, et al. Decreased integrin gene expression in patients with MS responding to interferon-beta treatment. J Neuroimmunol. 2004;150(1–2):123–31. doi:10.1016/j.jneuroim.2004.01.002.

    Article  CAS  PubMed  Google Scholar 

  99. Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet. 2003;361(9374):2036–43. doi:10.1016/S0140-6736(03)13641-0.

    Article  CAS  PubMed  Google Scholar 

  100. Sharief MK, Semra YK, Seidi OA, Zoukos Y. Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis. J Neuroimmunol. 2001;120(1–2):199–207.

    Article  CAS  PubMed  Google Scholar 

  101. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, Group GS. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73(6):705–13. doi:10.1002/ana.23938.

    Article  CAS  PubMed  Google Scholar 

  102. Kruszewski AM, Rao G, Tatomir A, Hewes D, Tegla CA, Cudrici CD, et al. RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp Mol Pathol. 2015;99(3):498–505. doi:10.1016/j.yexmp.2015.09.007.

    Article  CAS  PubMed  Google Scholar 

  103. Tumani H, Kassubek J, Hijazi M, Lehmensiek V, Unrath A, Sussmuth S, et al. Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate. Eur Neurol. 2011;65(3):164–9. doi:10.1159/000324035.

    Article  CAS  PubMed  Google Scholar 

  104. Valenzuela RM, Costello K, Chen M, Said A, Johnson KP, Dhib-Jalbut S. Clinical response to glatiramer acetate correlates with modulation of IFN-gamma and IL-4 expression in multiple sclerosis. Mult Scler. 2007;13(6):754–62. doi:10.1177/1352458506074510.

    Article  CAS  PubMed  Google Scholar 

  105. Wiesemann E, Klatt J, Wenzel C, Heidenreich F, Windhagen A. Correlation of serum IL-13 and IL-5 levels with clinical response to Glatiramer acetate in patients with multiple sclerosis. Clin Exp Immunol. 2003;133(3):454–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Farina C, Wagenpfeil S, Hohlfeld R. Immunological assay for assessing the efficacy of glatiramer acetate (Copaxone) in multiple sclerosis. A pilot study. J Neurol. 2002;249(11):1587–92. doi:10.1007/s00415-002-0904-0.

    Article  CAS  PubMed  Google Scholar 

  107. Mindur JE, Valenzuela RM, Yadav SK, Boppana S, Dhib-Jalbut S, Ito K. IL-27: a potential biomarker for responders to glatiramer acetate therapy. J Neuroimmunol. 2016;. doi:10.1016/j.jneuroim.2016.07.004.

    PubMed  Google Scholar 

  108. Valenzuela RM, Kaufman M, Balashov KE, Ito K, Buyske S, Dhib-Jalbut S. Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis. J Neuroimmunol. 2016;. doi:10.1016/j.jneuroim.2016.06.005.

    Google Scholar 

  109. Sellebjerg F, Hesse D, Limborg S, Lund H, Sondergaard HB, Krakauer M, et al. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis. Mult Scler. 2013;19(2):179–87. doi:10.1177/1352458512450353.

    Article  CAS  PubMed  Google Scholar 

  110. Stuve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev. 2007;13(1):79–95. doi:10.1111/j.1527-3458.2007.00003.x.

    Article  PubMed  Google Scholar 

  111. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007;69(14):1391–403. doi:10.1212/01.wnl.0000277457.17420.b5.

    Article  CAS  PubMed  Google Scholar 

  112. Oliver B, Fernandez O, Orpez T, Alvarenga MP, Pinto-Medel MJ, Guerrero M, et al. Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months. Mult Scler. 2011;17(3):368–71. doi:10.1177/1352458510385508.

    Article  CAS  PubMed  Google Scholar 

  113. Vennegoor A, Rispens T, Strijbis EM, Seewann A, Uitdehaag BM, Balk LJ, et al. Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis. Mult Scler. 2013;19(5):593–600. doi:10.1177/1352458512460604.

    Article  CAS  PubMed  Google Scholar 

  114. Jensen PE, Koch-Henriksen N, Sellebjerg F, Sorensen PS. Prediction of antibody persistency from antibody titres to natalizumab. Mult Scler. 2012;18(10):1493–9. doi:10.1177/1352458512441688.

    Article  PubMed  CAS  Google Scholar 

  115. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9(4):425–37. doi:10.1016/S1474-4422(10)70040-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–80. doi:10.1056/NEJMoa1107829.

    Article  CAS  PubMed  Google Scholar 

  117. 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. doi:10.1177/1352458513477925.

    Article  PubMed  Google Scholar 

  118. Trampe AK, Hemmelmann C, Stroet A, Haghikia A, Hellwig K, Wiendl H, et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology. 2012;78(22):1736–42. doi:10.1212/WNL.0b013e3182583022.

    Article  CAS  PubMed  Google Scholar 

  119. 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. doi:10.1002/ana.22606.

    Article  PubMed  Google Scholar 

  120. Outteryck O, Zephir H, Salleron J, Ongagna JC, Etxeberria A, Collongues N, et al. JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. Mult Scler. 2013;. doi:10.1177/1352458513505353.

    Google Scholar 

  121. 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. doi:10.1002/ana.24286.

    Article  CAS  PubMed  Google Scholar 

  122. Schwab N, Schneider-Hohendorf T, Posevitz V, Breuer J, Gobel K, Windhagen S, et al. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology. 2013;81(10):865–71. doi:10.1212/WNL.0b013e3182a351fb.

    Article  CAS  PubMed  Google Scholar 

  123. Schwab N, Schneider-Hohendorf T, Pignolet B, Spadaro M, Gorlich D, Meinl I, et al. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler. 2016;22(8):1048–60. doi:10.1177/1352458515607651.

    Article  PubMed  Google Scholar 

  124. Lieberman LA, Zeng W, Singh C, Wang W, Otipoby KL, Loh C, et al. CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients. Neurology. 2016;86(4):375–81. doi:10.1212/WNL.0000000000002314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Millonig A, Hegen H, Di Pauli F, Ehling R, Gneiss C, Hoelzl M, et al. Natalizumab treatment reduces endothelial activity in MS patients. J Neuroimmunol. 2010;227(1–2):190–4. doi:10.1016/j.jneuroim.2010.07.012.

    Article  CAS  PubMed  Google Scholar 

  126. Defer G, Mariotte D, Derache N, Toutirais O, Legros H, Cauquelin B, et al. CD49d expression as a promising biomarker to monitor natalizumab efficacy. J Neurolog Sci. 2012;314(1–2):138–42. doi:10.1016/j.jns.2011.10.005.

    Article  CAS  Google Scholar 

  127. Signoriello E, Lanzillo R, Brescia Morra V, Di Iorio G, Fratta M, Carotenuto A, et al. Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis. Mult Scler. 2016;22(7):921–5. doi:10.1177/1352458515604381.

    Article  CAS  PubMed  Google Scholar 

  128. Kuhle J, Malmestrom C, Axelsson M, Plattner K, Yaldizli O, Derfuss T, et al. Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis. Acta Neurolog Scand. 2013;128(6):e33–6. doi:10.1111/ane.12151.

    Article  CAS  Google Scholar 

  129. Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, et al. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Neurology. 2014;82(24):2158–64. doi:10.1212/WNL.0000000000000520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cossburn MD, Harding K, Ingram G, El-Shanawany T, Heaps A, Pickersgill TP, et al. Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Neurology. 2013;80(1):55–61. doi:10.1212/WNL.0b013e31827b5927.

    Article  CAS  PubMed  Google Scholar 

  131. Sanford M. Fingolimod: a review of its use in relapsing-remitting multiple sclerosis. Drugs. 2014;74(12):1411–33. doi:10.1007/s40265-014-0264-y.

    Article  CAS  PubMed  Google Scholar 

  132. Arvin AM, Wolinsky JS, Kappos L, Morris MI, Reder AT, Tornatore C, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72(1):31–9. doi:10.1001/jamaneurol.2014.3065.

    Article  PubMed  Google Scholar 

  133. Gilenya. Product information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf. Accessed 25 Aug 2016.

  134. Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics. 2013;10(1):29–33. doi:10.1007/s13311-012-0159-0.

    Article  CAS  PubMed  Google Scholar 

  135. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14):1069–78. doi:10.1212/WNL.0b013e31824e8ee7.

    Article  CAS  PubMed  Google Scholar 

  136. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol. 2005;175(12):7867–79.

    Article  CAS  PubMed  Google Scholar 

  137. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408(6808):57–63. doi:10.1038/35040504.

    Article  CAS  PubMed  Google Scholar 

  138. Parrish-Novak J, Foster DC, Holly RD, Clegg CH. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukocyte Biol. 2002;72(5):856–63.

    CAS  PubMed  Google Scholar 

  139. Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009;119(7):2052–61. doi:10.1172/JCI37878.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Azzopardi L, Thompson SA, Harding KE, Cossburn M, Robertson N, Compston A, et al. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(7):795–8. doi:10.1136/jnnp-2013-307042.

    Article  PubMed  Google Scholar 

  141. Cossburn M, Baker KE, Ingram G, Pickersgill TP, Robertson NP. Serum IL-21 as a biomarker in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:e1.

    Article  Google Scholar 

  142. Bomprezzi R. Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord. 2015;8(1):20–30. doi:10.1177/1756285614564152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Khatri BO, Garland J, Berger J, Kramer J, Sershon L, Olapo T, et al. The effect of dimethyl fumarate (Tecfidera) on lymphocyte counts: a potential contributor to progressive multifocal leukoencephalopathy risk. Mult Scler Rel Disord. 2015;4(4):377–9. doi:10.1016/j.msard.2015.05.003.

    Article  Google Scholar 

  144. Longbrake EE, Naismith RT, Parks BJ, Wu GF, Cross AH. Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015;. doi:10.1177/2055217315596994.

    PubMed  PubMed Central  Google Scholar 

  145. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthr Rheum. 2012;64(9):3043–51. doi:10.1002/art.34468.

    Article  CAS  Google Scholar 

  146. 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. doi:10.1056/NEJMc1415408.

    Article  CAS  PubMed  Google Scholar 

  147. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368(17):1657–8. doi:10.1056/NEJMc1211805.

    Article  CAS  PubMed  Google Scholar 

  148. 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. doi:10.1056/NEJMc1215357.

    Article  PubMed  CAS  Google Scholar 

  149. 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. doi:10.1056/NEJMc1413724.

    Article  CAS  PubMed  Google Scholar 

  150. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BA, Zamvil SS. Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e76. doi:10.1212/NXI.0000000000000076.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Wiendl H, Gross CC. Modulation of IL-2Ralpha with daclizumab for treatment of multiple sclerosis. Nat Rev Neurol. 2013;9(7):394–404. doi:10.1038/nrneurol.2013.95.

    Article  CAS  PubMed  Google Scholar 

  152. Diao L, Hang Y, Othman AA, Mehta D, Amaravadi L, Nestorov I, et al. Population PK- PD analyses of CD25 occupancy, CD56bright NK cell expansion, and regulatory T cell reduction by daclizumab HYP in subjects with multiple sclerosis. Br J Clin Pharmacol. 2016;. doi:10.1111/bcp.13051.

    PubMed  Google Scholar 

  153. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010;9(4):381–90. doi:10.1016/S1474-4422(10)70033-8.

    Article  CAS  PubMed  Google Scholar 

  154. Sheridan JP, Zhang Y, Riester K, Tang MT, Efros L, Shi J, et al. Intermediate-affinity interleukin-2 receptor expression predicts CD56(bright) natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis. Mult Scler. 2011;17(12):1441–8. doi:10.1177/1352458511414755.

    Article  CAS  PubMed  Google Scholar 

  155. O’Connor PW, Oh J. Disease-modifying agents in multiple sclerosis. Handb Clin Neurol. 2014;122:465–501. doi:10.1016/B978-0-444-52001-2.00021-2.

    Article  PubMed  Google Scholar 

  156. Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013;5:CD002127. doi:10.1002/14651858.CD002127.pub3.

  157. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW. Therapeutics, Technology Assessment Subcommittee of the American Academy of N. Evidence Report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74(18):1463–70. doi:10.1212/WNL.0b013e3181dc1ae0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Battaglia M, Pewsner D, Juni P, Egger M, Bucher HC, Bachmann LM. Accuracy of B-type natriuretic peptide tests to exclude congestive heart failure: systematic review of test accuracy studies. Arch Int Med. 2006;166(10):1073–80. doi:10.1001/archinte.166.10.1073.

    Article  Google Scholar 

  159. Luchowski P, Mitosek-Szewczyk K, Bartosik-Psujek H, Rubaj A, Jankiewicz M, Wojczal J, et al. B-type natriuretic peptide as a marker of subclinical heart injury during mitoxantrone therapy in MS patients–preliminary study. Clin Neurol Neurosurg. 2009;111(8):676–8. doi:10.1016/j.clineuro.2009.06.007.

    Article  PubMed  Google Scholar 

  160. Bertora P, Torzillo D, Baldi G, Vago T, Mariani C. Brain natriuretic peptide as a marker of cardiac toxicity in patients with multiple sclerosis treated with mitoxantrone. J Neurol. 2008;255(1):140–1. doi:10.1007/s00415-007-0689-2.

    Article  CAS  PubMed  Google Scholar 

  161. Podlecka-Pietowska A, Kochanowski J, Zakrzewska-Pniewska B, Opolski G, Kwiecinski H, Kaminska AM. The N-terminal pro-brain natriuretic peptide as a marker of mitoxantrone-induced cardiotoxicity in multiple sclerosis patients. Neurol Neurochir Pol. 2014;48(2):111–5. doi:10.1016/j.pjnns.2013.12.005.

    PubMed  Google Scholar 

  162. Buttmann M, Merzyn C, Rieckmann P. Interferon-beta induces transient systemic IP-10/CXCL10 chemokine release in patients with multiple sclerosis. J Neuroimmunol. 2004;156(1–2):195–203. doi:10.1016/j.jneuroim.2004.07.016.

    Article  CAS  PubMed  Google Scholar 

  163. Millonig A, Rudzki D, Holzl M, Ehling R, Gneiss C, Kunz B, et al. High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study. Mult Scler. 2009;15(8):977–83. doi:10.1177/1352458509105384.

    Article  CAS  PubMed  Google Scholar 

  164. Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, et al. Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1. Mult Scler. 2006;12(1):47–57.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Susan Goelz for significant contribution to the creation of Fig. 1.

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Authors and Affiliations

  1. Department of Neurology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria

    Harald Hegen, Michael Auer & Florian Deisenhammer

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  1. Harald Hegen
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  2. Michael Auer
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  3. Florian Deisenhammer
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Correspondence to Florian Deisenhammer.

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No sources of funding were used to conduct this study or prepare this manuscript.

Conflicts of interest

H Hegen has participated in meetings sponsored by and received speaker honoraria or travel funding from Bayer Schering, Biogen, Merck Serono and Novartis and has received honoraria for acting as consultant for Teva Pharmaceuticals Europe. M. Auer has no conflicts of interest. F. Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer Healthcare, Biogen Idec, Genzyme-Sanofi, Merck, Novartis Pharma and Teva-Ratiopharm. His institution has received financial support for participation in randomized controlled trials of IFN-β-1b (Betaferon, Bayer Schering Pharma), IFN-β-1a (Avonex, Biogen Idec; Rebif, Merck Serono), glatiramer acetate (Copaxone, Teva Pharmaceuticals) and natalizumab (Tysabri, Biogen Idec) in MS. He is section editor of the journal Multiple Sclerosis and Related Disorders.

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Hegen, H., Auer, M. & Deisenhammer, F. Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients. Drugs 76, 1421–1445 (2016). https://doi.org/10.1007/s40265-016-0639-3

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