CNS Drugs

, Volume 25, Issue 6, pp 491–502 | Cite as

The Mechanism of Action of Interferon-β in Relapsing Multiple Sclerosis

  • Bernd C. KieseierEmail author
Review Article


Multiple sclerosis (MS) is characterized by autoimmune inflammation and subsequent neurodegeneration. It is believed that early in the disease course, proinflammatory T cells that are activated in the periphery by antigen presentation cross the blood-brain barrier (BBB) into the CNS directed by various chemotaxic agents. However, to date, there has been no formal demonstration of a specific precipitating antigen. Once inside the CNS, activated T cells including T helper-1 (Th1), Th17, γδ and CD8+ types are believed to secrete proinflammatory cytokines. Decreased levels of Th2 cells also correlate with relapses and disease progression in MS, since Th2-derived cytokines are predominantly anti-inflammatory. In healthy tissue, inflammatory effects are opposed by specific subsets of regulatory T cells (Tregs) including CD4+, CD25+ and FoxP3+ cells that have the ability to downregulate the activity of proinflammatory T cells, allowing repair and recovery to generally follow inflammatory insult. Given their function, the pathogenesis of MS most likely involves deficits of Treg function, which allow autoimmune inflammation and resultant neurodegeneration to proceed relatively unchecked.

Interferons (IFNs) are naturally occurring cytokines possessing a wide range of anti-inflammatory properties. Recombinant forms of IFNβ are widely used as first-line treatment in relapsing forms of MS. The mechanism of action of IFNb is complex, involving effects at multiple levels of cellular function. IFNβ appears to directly increase expression and concentration of anti-inflammatory agents while downregulating the expression of proinflammatory cytokines. IFNβ treatment may reduce the trafficking of inflammatory cells across the BBB and increase nerve growth factor production, leading to a potential increase in neuronal survival and repair. IFNβ can also increase the number of CD56bright natural killer cells in the peripheral blood. These cells are efficient producers of anti-inflammatory mediators, and may have the ability to curb neuron inflammation. The mechanistic effects of IFNβ manifest clinically as reduced MRI lesion activity, reduced brain atrophy, increased time to reach clinically definite MS after the onset of neurological symptoms, decreased relapse rate and reduced risk of sustained disability progression.

The mechanism of action of IFNβ in MS is multifactorial and incompletely understood. Ongoing and future studies will increase our understanding of the actions of IFNβ on the immune system and the CNS, which will in turn aid advances in the management of MS.


Multiple Sclerosis Nerve Growth Factor Expand Disability Status Scale Clinically Isolate Syndrome Multiple Sclerosis Pathogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Kieseier has received honoraria for lecturing, travel expenses for attending meetings and financial support for research from Bayer Health Care, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi and Teva. Editorial support for the writing of this manuscript was provided by Infusion Communications and was funded by Biogen Idec Inc. The author was not compensated and retained full editorial control.


  1. 1.
    Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9PubMedCrossRefGoogle Scholar
  2. 2.
    Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85PubMedCrossRefGoogle Scholar
  3. 3.
    Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202–12PubMedCrossRefGoogle Scholar
  4. 4.
    Haines JL, Ter-Minassian M, Bazyk A, et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex: the Multiple Sclerosis Genetics Group. Nat Genet 1996; 13: 469–71PubMedCrossRefGoogle Scholar
  5. 5.
    Olsson T, Hillert J. The genetics of multiple sclerosis and its experimental models. Curr Opin Neurol 2008; 21: 255–60PubMedCrossRefGoogle Scholar
  6. 6.
    Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple clerosis. N Engl J Med 2000; 343: 938–52PubMedCrossRefGoogle Scholar
  7. 7.
    Gilden DH. Infectious causes of multiple sclerosis. Lancet Neurol 2005; 4: 195–202PubMedGoogle Scholar
  8. 8.
    McCandless EE, Piccio L, Woerner BM, et al. Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 2008; 172: 799–808PubMedCrossRefGoogle Scholar
  9. 9.
    McCandless EE, Budde M, Lees JR, et al. IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol 2009; 183: 613–20PubMedCrossRefGoogle Scholar
  10. 10.
    Platten M, Steinman L. Multiple sclerosis: trapped in deadly glue. Nat Med 2005; 11: 252–3PubMedCrossRefGoogle Scholar
  11. 11.
    Fletcher JM, Lalor SJ, Sweeney CM, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 2010; 162: 1–11PubMedCrossRefGoogle Scholar
  12. 12.
    Venken K, Hellings N, Liblau R, et al. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med 2010; 16: 58–68PubMedCrossRefGoogle Scholar
  13. 13.
    Pettinelli CB, McFarlin DE. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2-T lymphocytes. J Immunol 1981; 127: 1420–3PubMedGoogle Scholar
  14. 14.
    Zamvil S, Nelson P, Trotter J, et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 1985; 317: 355–8PubMedCrossRefGoogle Scholar
  15. 15.
    Aranami T, Yamamura T. Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 2008; 57: 115–20PubMedCrossRefGoogle Scholar
  16. 16.
    Sun D, Whitaker JN, Huang Z, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 2001; 166: 7579–87PubMedGoogle Scholar
  17. 17.
    Huseby ES, Liggitt D, Brabb T, et al. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 2001; 194: 669–76PubMedCrossRefGoogle Scholar
  18. 18.
    Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from gamma delta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331–41PubMedCrossRefGoogle Scholar
  19. 19.
    Yong VW, Chabot S, Stuve O, et al. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998; 51: 682–9PubMedCrossRefGoogle Scholar
  20. 20.
    Dhib-Jabut. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 2007; 68(22 Suppl. 3): S13–21CrossRefGoogle Scholar
  21. 21.
    Arnason BG, Dayal A, Qu ZX, et al. Mechanisms of action of interferon-beta in multiple sclerosis. Springer Sem Immunopathol 1996; 18: 125–48CrossRefGoogle Scholar
  22. 22.
    Segal BM, Dwyer BK, Shevach EM. An interleukin (IL)-10/ IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 1998; 187: 537–46PubMedCrossRefGoogle Scholar
  23. 23.
    Renkl AC, Wussler J, Ahrens T, et al. Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype. Blood 2005; 106: 946–55PubMedCrossRefGoogle Scholar
  24. 24.
    van Boxel-Dezaire AH, Hoff SC, van Oosten BW, et al. Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Ann Neurol 1999; 45: 695–703PubMedCrossRefGoogle Scholar
  25. 25.
    Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta 2010; 1812: 252–64PubMedGoogle Scholar
  26. 26.
    Waubant E, Goodkin DE, Gee L, et al. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999; 53: 1397–401PubMedCrossRefGoogle Scholar
  27. 27.
    Leppert D, Ford J, Stabler G, et al. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 1998; 121: 2327–34PubMedCrossRefGoogle Scholar
  28. 28.
    Waubant E, Goodkin D, Bostrom A, et al. IFNX lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS. Neurology 2003; 60: 52–7PubMedCrossRefGoogle Scholar
  29. 29.
    Boz C, Ozmenoglu M, Velioglu S, et al. Matrix metallo-proteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta. Clin Neurol Neurosurg 2006; 108: 124–8PubMedCrossRefGoogle Scholar
  30. 30.
    Neumann H. Molecular mechanisms of axonal damage in inflammatory central nervous systems diseases. Curr Opin Neurol 2003; 16: 247–52CrossRefGoogle Scholar
  31. 31.
    Trapp BD, Ransohoff R, Rudick R. Axonal pathology inmultiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999; 12: 295–302PubMedCrossRefGoogle Scholar
  32. 32.
    Trapp BD, Ransohoff RM, Fisher E, et al. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist 1999; 5: 48–57CrossRefGoogle Scholar
  33. 33.
    Liuzzi G, Trojano M, Fanelli M, et al. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis. Mult Scler 2002; 8: 222–8PubMedCrossRefGoogle Scholar
  34. 34.
    Bitsch A, da Costa C, Bunkowski S, et al. Identification of macrophage populations expressing tumor necrosis factor-alphamRNA in acute multiple sclerosis. Acta Neuro-pathol 1998; 95: 373–7CrossRefGoogle Scholar
  35. 35.
    Takeuchi M, Keino H, Suzuki J, et al. Possibility of inducing anterior chamber-associated immune deviation by TGF-beta2 treatment of monocytes isolated from Behçet’s patients. Exp Eye Res 2006; 83: 981–8PubMedCrossRefGoogle Scholar
  36. 36.
    Muzio L, Martino G, Furlan R. Multifaceted aspects of inflammation in multiple sclerosis: the role of microglia. J Neuroimmunol 2007; 191: 39–44PubMedCrossRefGoogle Scholar
  37. 37.
    Villoslada P, Hauser SL, Bartke I, et al. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 2000; 191: 1799–806PubMedCrossRefGoogle Scholar
  38. 38.
    Flügel A, Matsumuro K, Neumann H, et al. Antiin-flammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur J Immunol 2001; 31: 11–22PubMedCrossRefGoogle Scholar
  39. 39.
    Kohm AP, Carpentier PA, Anger HA, et al. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 2002; 169: 4712–6PubMedGoogle Scholar
  40. 40.
    Zhang X, Koldzic DN, Izikson L, et al. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+ CD4+ regulatory T cells. Int Immunol 2004; 16: 249–56PubMedCrossRefGoogle Scholar
  41. 41.
    Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the life-span of mice. Nat Immunol 2007; 8: 191–7PubMedCrossRefGoogle Scholar
  42. 42.
    Anderton SM, Liblau RS. Regulatory T cells in the control of inflammatory demyelinating diseases of the central nervous system. Curr Opin Neurol 2008; 21: 248–54PubMedCrossRefGoogle Scholar
  43. 43.
    Kozovska ME, Hong J, Zang YC, et al. Interferon beta induces T-helper 2 immune deviation in MS. Neurology 1999; 53: 1692–7PubMedCrossRefGoogle Scholar
  44. 44.
    Liu Z, Pelfrey CM, Cotleur A, et al. Immunomodulatory effects of interferon beta-1a in multiple sclerosis. J Neuroimmunol 2001; 112: 153–62PubMedCrossRefGoogle Scholar
  45. 45.
    Chen M, Chen G, Nie H, et al. Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T cells in MS. Eur J Immunol 2009; 39: 2525–36PubMedCrossRefGoogle Scholar
  46. 46.
    Guo B, Chang EY, Cheng G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest 2008; 118: 1680–90PubMedCrossRefGoogle Scholar
  47. 47.
    Shinohara ML, Kim JH, Garcia VA, et al. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 2008; 29: 68–78PubMedCrossRefGoogle Scholar
  48. 48.
    Prinz M, Schmidt H, Mildner A, et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 2008; 28: 675–86PubMedCrossRefGoogle Scholar
  49. 49.
    Krakauer M, Sorensen P, Khademi M, et al. Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-beta treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression. Mult Scler 2008; 14: 622–30PubMedCrossRefGoogle Scholar
  50. 50.
    Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008; 7: 796–804PubMedCrossRefGoogle Scholar
  51. 51.
    Mirandola SR, Hallal DE, Farias AS, et al. Interferon-beta modifies the peripheral blood cell cytokine secretion in patients with multiple sclerosis. Int Immunopharmacol 2009; 9: 824–30PubMedCrossRefGoogle Scholar
  52. 52.
    Carrieri PB, Ladogana P, Di Spigna G, et al. Interleukin-10 and interleukin-12 modulation in patients with relapsing-remitting multiple sclerosis on therapy with interferon-beta 1a: differences in responders and non responders. Immunopharmacol Immunotoxicol 2008; 30: 1–9PubMedCrossRefGoogle Scholar
  53. 53.
    Chabot S, Williams G, Yong VW. Microglial production of TNF-alpha is induced by activated T lymphocytes: involvement of VLA-4 and inhibition by interferonbeta-1b. J Clin Invest 1997; 100: 604–12PubMedCrossRefGoogle Scholar
  54. 54.
    Muraro PA, Leist T, Bielekova B, et al. VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis. J Neuroimmunol 2000; 111: 186–94PubMedCrossRefGoogle Scholar
  55. 55.
    Muraro PA, Liberati L, Bonanni L, et al. Decreased integrin gene expression in patients with MS responding to interferon-beta treatment. J Neuroimmunol 2004; 150: 123–31PubMedCrossRefGoogle Scholar
  56. 56.
    Avolio C, Filippi M, Tortorella C, et al. Serum MMP-9/ TIMP-1 and MMP-2/TIMP-2 ratios in multiple sclerosis: relationships with different magnetic resonance imaging measures of disease activity during IFN-beta-1a treatment. Mult Scler 2005; 11: 441–6PubMedCrossRefGoogle Scholar
  57. 57.
    Corsini E, Gelati M, Dufour A, et al. Effects of beta-IFN-1b treatment in MS patients on adhesion between PBMCs, HUVECs and MS-HBECs: an in vivo and in vitro study. J Neuroimmunol 1997; 79: 76–83PubMedCrossRefGoogle Scholar
  58. 58.
    Gelati M, Corsini E, Dufour A, et al. Immunological effects of in vivo interferon-beta1b treatment in ten patients with multiple sclerosis: a 1-year follow-up. J Neurol 1999; 246: 569–73PubMedCrossRefGoogle Scholar
  59. 59.
    Defazio G, Gelati M, Corsini E, et al. In vitro modulation of adhesion molecules, adhesion phenomena, and fluid phase endocytosis on human umbilical vein endothelial cells and brain-derived microvascular endothelium by IFN-beta 1a. J Interferon Cytokine Res 2001; 21: 267–72PubMedCrossRefGoogle Scholar
  60. 60.
    Defazio G, Livrea P, Giorelli M, et al. Interferon beta-1a downregulates TNFalpha-induced intercellular adhesion molecule 1 expression on brain microvascular endothelial cells through a tyrosine kinase-dependent pathway. Brain Res 2000; 881: 227–30PubMedCrossRefGoogle Scholar
  61. 61.
    Defazio G, Trojano M, Ribatti D, et al. ICAM 1 expression and fluid phase endocytosis of cultured brain microvascular endothelial cells following exposure to interferon beta-1a and TNFalpha. J Neuroimmunol 1998; 88: 13–20PubMedCrossRefGoogle Scholar
  62. 62.
    Salama HH, Kolar OJ, Zang YC, et al. Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis. Mult Scler 2003; 9: 28–31PubMedCrossRefGoogle Scholar
  63. 63.
    Leppert D, Waubant E, Bürk MR, et al. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996; 40: 846–52PubMedCrossRefGoogle Scholar
  64. 64.
    Stüve O, Dooley NP, Uhm JH, et al. Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996; 40: 853–63PubMedCrossRefGoogle Scholar
  65. 65.
    Jin S, Kawanokuchi J, Mizuno T, et al. Interferon-beta is neuroprotective against the toxicity induced by activated microglia. Brain Res 2007; 1179: 140–6PubMedCrossRefGoogle Scholar
  66. 66.
    Biernacki K, Antel JP, Blain M, et al. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol 2005; 62: 563–8PubMedCrossRefGoogle Scholar
  67. 67.
    Boutros T, Croze E, Yong VW. Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 1997; 69: 939–46PubMedCrossRefGoogle Scholar
  68. 68.
    Saraste M, Irjala H, Airas L. Expansion of CD56bright natural killer cells in the peripheral blood of multiple sclerosis patients treated with interferon-beta. Neurol Sci 2007; 28: 121–6PubMedCrossRefGoogle Scholar
  69. 69.
    Vandenbark AA, Huan J, Agotsch M, et al. Interferon-beta-1a treatment increases CD56(bright) natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis. J Neuroimmunol 2009; 215(1–2): 125–8PubMedCrossRefGoogle Scholar
  70. 70.
    Sellebjerg F, Datta P, Larsen J, et al. Gene expression analysis of interferon-beta treatment in multiple sclerosis. Mult Scler 2008; 14: 615–21PubMedCrossRefGoogle Scholar
  71. 71.
    Weinstock-Guttman B, Bhasi K, Badgett D, et al. Genomic effects of once-weekly, intramuscular interferon-beta1a treatment after the first dose and on chronic dosing: relationships to 5-year clinical outcomes in multiple sclerosis patients. J Neuroimmunol 2008; 205: 113–25PubMedCrossRefGoogle Scholar
  72. 72.
    Kauffman MA, Yankilevich P, Barrero P, et al. Whole genome analysis of the action of interferon-beta. Int J Clin Pharmacol Ther 2009; 47: 328–57PubMedGoogle Scholar
  73. 73.
    Balashov KE, Aung LL, Vaknin-Dembinsky A, et al. Interferon-β inhibits toll-like receptor 9 processing inmultiple sclerosis. Ann Neurol 2010; 68: 899–906PubMedCrossRefGoogle Scholar
  74. 74.
    Paolillo A, Piattella MC, Pantano P, et al. The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA. J Neurol 2004; 251: 432–9PubMedCrossRefGoogle Scholar
  75. 75.
    Brex PA, Ciccarelli O, O’Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346: 158–64PubMedCrossRefGoogle Scholar
  76. 76.
    Tintoré M, Rovira A, Río J, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006; 67: 968–72PubMedCrossRefGoogle Scholar
  77. 77.
    Rudick R, Lee JC, Simon J, et al. Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol 2006; 60: 236–42PubMedCrossRefGoogle Scholar
  78. 78.
    Tomassini V, Paolillo A, Russo P, et al. Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol 2006; 253: 287–93PubMedCrossRefGoogle Scholar
  79. 79.
    Zivadinov R, Sepcic J, Nasuelli D, et al. A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 70: 773–80PubMedCrossRefGoogle Scholar
  80. 80.
    Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002; 59: 1412–20PubMedCrossRefGoogle Scholar
  81. 81.
    Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–82PubMedCrossRefGoogle Scholar
  82. 82.
    Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 1989; 112: 1419–28Google Scholar
  83. 83.
    Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demye-linating event in multiple sclerosis: CHAMPS Study Group. N Engl J Med 2000; 343: 898–904PubMedCrossRefGoogle Scholar
  84. 84.
    Simon JH, Lull J, Jacobs LD, et al. A longitudinal study of T1 hypointense lesions in relapsing MS: MSCRG trial of interferon beta-1a. Multiple Sclerosis Collaborative Research Group. Neurology 2000; 55: 185–92Google Scholar
  85. 85.
    Radue EW, Saharaian MA, Pace A, et al. The evaluation of black hole volume evolution as it relates to lesion load, extent of enhancement, and treatment with intramuscular interferon-beta-1a in two relapsing-remitting multiple sclerosis studies. Poster P608 presented at 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 2006 Sep 27–30; MadridGoogle Scholar
  86. 86.
    Paty DW, Li DKB; UBC MS/MRI Study Group and IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 662–7PubMedCrossRefGoogle Scholar
  87. 87.
    PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498–504CrossRefGoogle Scholar
  88. 88.
    Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS: Multiple Sclerosis Collaborative Research Group. Neurology 1999; 53: 1698–704PubMedCrossRefGoogle Scholar
  89. 89.
    Zivadinov R, Locatelli L, Cookfair D, et al. Interferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy. Mult Scler 2007; 13: 490–501PubMedGoogle Scholar
  90. 90.
    Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5: 256–66PubMedCrossRefGoogle Scholar
  91. 91.
    Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis: the Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39: 285–94PubMedCrossRefGoogle Scholar
  92. 92.
    Rudick R, Lee JC, Zhang H, et al. Progression of disability at 2 years predicts disability at 8 years: analysis from the phase 3 clinical trial of intramuscular interferon beta-1a. Poster P195 presented at 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 2007 Oct 11–14; PragueGoogle Scholar
  93. 93.
    IFNβ 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: 655–61Google Scholar
  94. 94.
    CHAMPIONS Study Group. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66: 678–84CrossRefGoogle Scholar
  95. 95.
    Kinkel RP, Dontchev M, Tanner JP, et al. CHAMPIONS: 10-year follow-up after a clinically isolated syndrome in patients at high risk for developing multiple sclerosis. Mult Scler 2009; 15: S5–277, poster P446Google Scholar
  96. 96.
    Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357: 1576–82PubMedCrossRefGoogle Scholar
  97. 97.
    Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242–9PubMedCrossRefGoogle Scholar
  98. 98.
    Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology 2002; 59: 1496–506PubMedCrossRefGoogle Scholar
  99. 99.
    Durelli L, Verdun E, Barbero P, 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: 1453–60PubMedCrossRefGoogle Scholar
  100. 100.
    Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 2001; 40: 539–51PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Department of NeurologyHeinrich-Heine UniversityDüsseldorfGermany

Personalised recommendations