Top

Published in:

01-06-2011 | Review Article

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

Author: Prof. Bernd C. Kieseier

Published in: CNS Drugs | Issue 6/2011

Abstract

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 (T_h1), T_h17, γδ and CD8+ types are believed to secrete proinflammatory cytokines. Decreased levels of T_h2 cells also correlate with relapses and disease progression in MS, since T_h2-derived cytokines are predominantly anti-inflammatory. In healthy tissue, inflammatory effects are opposed by specific subsets of regulatory T cells (T_regs) 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 T_reg 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 CD56^bright 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.

Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9PubMedCrossRef

Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85PubMedCrossRef

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: 2202–12PubMedCrossRef

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: 469–71PubMedCrossRef

Olsson T, Hillert J. The genetics of multiple sclerosis and its experimental models. Curr Opin Neurol 2008; 21: 255–60PubMedCrossRef

Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple clerosis. N Engl J Med 2000; 343: 938–52PubMedCrossRef

Gilden DH. Infectious causes of multiple sclerosis. Lancet Neurol 2005; 4: 195–202PubMed

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: 799–808PubMedCrossRef

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: 613–20PubMedCrossRef

10.

Platten M, Steinman L. Multiple sclerosis: trapped in deadly glue. Nat Med 2005; 11: 252–3PubMedCrossRef

11.

Fletcher JM, Lalor SJ, Sweeney CM, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 2010; 162: 1–11PubMedCrossRef

12.

Venken K, Hellings N, Liblau R, et al. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med 2010; 16: 58–68PubMedCrossRef

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: 1420–3PubMed

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: 355–8PubMedCrossRef

15.

Aranami T, Yamamura T. Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 2008; 57: 115–20PubMedCrossRef

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: 7579–87PubMed

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: 669–76PubMedCrossRef

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: 331–41PubMedCrossRef

19.

Yong VW, Chabot S, Stuve O, et al. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998; 51: 682–9PubMedCrossRef

20.

Dhib-Jabut. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 2007; 68(22 Suppl. 3): S13–21CrossRef

21.

Arnason BG, Dayal A, Qu ZX, et al. Mechanisms of action of interferon-beta in multiple sclerosis. Springer Sem Immunopathol 1996; 18: 125–48CrossRef

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: 537–46PubMedCrossRef

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: 946–55PubMedCrossRef

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: 695–703PubMedCrossRef

25.

Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta 2010; 1812: 252–64PubMed

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: 1397–401PubMedCrossRef

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: 2327–34PubMedCrossRef

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: 52–7PubMedCrossRef

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: 124–8PubMedCrossRef

30.

Neumann H. Molecular mechanisms of axonal damage in inflammatory central nervous systems diseases. Curr Opin Neurol 2003; 16: 247–52CrossRef

31.

Trapp BD, Ransohoff R, Rudick R. Axonal pathology inmultiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999; 12: 295–302PubMedCrossRef

32.

Trapp BD, Ransohoff RM, Fisher E, et al. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist 1999; 5: 48–57CrossRef

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: 222–8PubMedCrossRef

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: 373–7CrossRef

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: 981–8PubMedCrossRef

36.

Muzio L, Martino G, Furlan R. Multifaceted aspects of inflammation in multiple sclerosis: the role of microglia. J Neuroimmunol 2007; 191: 39–44PubMedCrossRef

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: 1799–806PubMedCrossRef

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: 11–22PubMedCrossRef

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: 4712–6PubMed

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: 249–56PubMedCrossRef

41.

Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the life-span of mice. Nat Immunol 2007; 8: 191–7PubMedCrossRef

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: 248–54PubMedCrossRef

43.

Kozovska ME, Hong J, Zang YC, et al. Interferon beta induces T-helper 2 immune deviation in MS. Neurology 1999; 53: 1692–7PubMedCrossRef

44.

Liu Z, Pelfrey CM, Cotleur A, et al. Immunomodulatory effects of interferon beta-1a in multiple sclerosis. J Neuroimmunol 2001; 112: 153–62PubMedCrossRef

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: 2525–36PubMedCrossRef

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: 1680–90PubMedCrossRef

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: 68–78PubMedCrossRef

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: 675–86PubMedCrossRef

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: 622–30PubMedCrossRef

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: 796–804PubMedCrossRef

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: 824–30PubMedCrossRef

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: 1–9PubMedCrossRef

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: 604–12PubMedCrossRef

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: 186–94PubMedCrossRef

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: 123–31PubMedCrossRef

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: 441–6PubMedCrossRef

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: 76–83PubMedCrossRef

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: 569–73PubMedCrossRef

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: 267–72PubMedCrossRef

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: 227–30PubMedCrossRef

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: 13–20PubMedCrossRef

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: 28–31PubMedCrossRef

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: 846–52PubMedCrossRef

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: 853–63PubMedCrossRef

65.

Jin S, Kawanokuchi J, Mizuno T, et al. Interferon-beta is neuroprotective against the toxicity induced by activated microglia. Brain Res 2007; 1179: 140–6PubMedCrossRef

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: 563–8PubMedCrossRef

67.

Boutros T, Croze E, Yong VW. Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 1997; 69: 939–46PubMedCrossRef

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: 121–6PubMedCrossRef

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): 125–8PubMedCrossRef

70.

Sellebjerg F, Datta P, Larsen J, et al. Gene expression analysis of interferon-beta treatment in multiple sclerosis. Mult Scler 2008; 14: 615–21PubMedCrossRef

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: 113–25PubMedCrossRef

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: 328–57PubMed

73.

Balashov KE, Aung LL, Vaknin-Dembinsky A, et al. Interferon-β inhibits toll-like receptor 9 processing inmultiple sclerosis. Ann Neurol 2010; 68: 899–906PubMedCrossRef

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: 432–9PubMedCrossRef

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: 158–64PubMedCrossRef

76.

Tintoré M, Rovira A, Río J, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006; 67: 968–72PubMedCrossRef

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: 236–42PubMedCrossRef

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: 287–93PubMedCrossRef

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: 773–80PubMedCrossRef

80.

Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002; 59: 1412–20PubMedCrossRef

81.

Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–82PubMedCrossRef

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: 1419–28

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: 898–904PubMedCrossRef

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: 185–92

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; Madrid

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: 662–7PubMedCrossRef

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: 1498–504CrossRef

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: 1698–704PubMedCrossRef

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: 490–501PubMed

90.

Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5: 256–66PubMedCrossRef

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: 285–94PubMedCrossRef

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; Prague

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: 655–61

94.

CHAMPIONS Study Group. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66: 678–84CrossRef

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 P446

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: 1576–82PubMedCrossRef

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: 1242–9PubMedCrossRef

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: 1496–506PubMedCrossRef

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: 1453–60PubMedCrossRef

100.

Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 2001; 40: 539–51PubMedCrossRef

Title: The Mechanism of Action of Interferon-β in Relapsing Multiple Sclerosis
Author: Prof. Bernd C. Kieseier
Publication date: 01-06-2011
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 6/2011
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/11591110-000000000-00000

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2011

Assessing QT Interval Prolongation and its Associated Risks with Antipsychotics

Lower IQ is Associated with Decreased Clinical Response to Atomoxetine in Children and Adolescents with Attention-Deficit Hyperactivity Disorder

Oral Paliperidone

Fentanyl Pectin Nasal Spray

Suicidal Ideation during Antidepressant Treatment

Pharmacotherapy for Primary CNS Lymphoma