, Volume 61, Issue 12, pp 1693–1703 | Cite as

Interferon- β Therapy in Multiple Sclerosis

Evidence for a Clinically Relevant Dose Response
Leading Article


There have been considerable advances made recently in the treatment of multiple sclerosis (MS). In particular, interferon (IFN)β has been demonstrated in several independent, multicentre clinical trials to lower unequivocally the biological activity of this illness. The results of these trials have been remarkably consistent, demonstrating a reduction in both disease activity and cumulative disability, using a combination of clinical and magnetic resonance imaging outcome measures. Nevertheless, the importance of the total weekly IFNβ dose in the clinical management of individual patients has been controversial.

However, there is considerable information available regarding the effect of IFNβ dose on the various biochemical and clinical markers that are affected by IFNβ, which is derived both from pre-clinical studies and multicentre clinical trials. On balance, convincing evidence is provided to support the notion that there is a clinically relevant dose-response in the use of IFNβ to treat patients with relapsing/remitting MS. However, many of the clinical trials of IFNβ in MS have confounded the potential effects of dose with the possible effects of frequency of IFNβ administration. As a result, it is possible that the apparent dose-response observed in these clinical trials may be due, in part, to the more frequent dose administration schedule rather than the total weekly dose.


Multiple Sclerosis Neopterin Experimental Allergic Encephalomyelitis Rebif Avonex 
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.



The author of this manuscript has participated (or is currently participating) in several industry-sponsored clinical therapeutic trials in multiple sclerosis. The sponsoring pharmaceutical companies for these trials have included (or do include): Biogen, Inc; Berlex Laboratories; Immunex Corp; Serono, Inc; and Teva Marion Partners. In addition, the author has lectured extensively at both medical conferences and in public on various aspects of the diagnosis and management of multiple sclerosis. In many cases these talks have been sponsored by non-restricted educational grants from one or another of each of the above-listed companies or by Athena Neurosciences.


  1. 1.
    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. iI. Clinical results of a multicenter, randomised, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61CrossRefGoogle Scholar
  2. 2.
    Paty DW, Li DKB, UBC MS/MRI Study Group, et al. Interferon beta- 1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomised, double-blind, placebo-controlled trial. Neurology 1993; 43: 662–7Google Scholar
  3. 3.
    The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomised controlled trial. Neurology 1995; 45:1277–85CrossRefGoogle Scholar
  4. 4.
    Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94PubMedCrossRefGoogle Scholar
  5. 5.
    Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon β-1a for relapsing multiple sclerosis. Ann Neurol 1996; 43: 79–87CrossRefGoogle Scholar
  6. 6.
    PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing-remitting multiple sclerosis. Lancet 1998; 352: 1498–1504CrossRefGoogle Scholar
  7. 7.
    Li DH, Paty DW, UBC MS/MRI Analysis Research Group, et al. Magnetic resonance imaging results of the PRISMS trial: a randomised, double-blind, placebo-controlled study of interferon-β1a in relapsing-remitting multiple sclerosis. Ann Neurol 1999; 4: 197–206CrossRefGoogle Scholar
  8. 8.
    PRISMS Study Group. PRISMS-4: long term efficacy of interferon β-1a in relapsing MS. Neurology 2001; 56: 1628–36CrossRefGoogle Scholar
  9. 9.
    OWIMS Study Group. Evidence of interferon β-1a dose response in relapsing remitting MS. The OWIMS study. Neurology 1999; 53: 679–86Google Scholar
  10. 10.
    European Study Group on Interferon β-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon β- 1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–7Google Scholar
  11. 11.
    Oger J, Freedman M. Consensus statement on the Canadian MS clinical network on: the use of disease modifying agents in multiple sclerosis. Can J Neurol Sci 1999; 26: 274PubMedGoogle Scholar
  12. 12.
    National Multiple Sclerosis Society disease management consensus statement. The National Multiple Sclerosis Society, New York, NY, USA, 1999Google Scholar
  13. 13.
    Jacobs LD, Beck RW, Simon JH, et al. and the CHAMPS Study Group. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Eng J Med 2000; 343: 898–904Google Scholar
  14. 14.
    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
  15. 15.
    Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999; 12: 295–302PubMedCrossRefGoogle Scholar
  18. 18.
    Goodkin DE. Interferon therapy for multiple sclerosis. Lancet 1998; 352: 1486–7PubMedCrossRefGoogle Scholar
  19. 19.
    Johnson KP, Panitch HJ, Herndon RM, et al. Interferon therapy for multiple sclerosis. Lancet 199; 353: 494–8Google Scholar
  20. 20.
    Goodin DS. Perils and pitfalls in the interpretation of clinical trials. A reflection on the recent experience in multiple sclerosis. Neuroepidemiology 1999; 18: 53–63Google Scholar
  21. 21.
    Bar-Or A, Oliviera EML, Anderson DE, et al. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100: 252–9PubMedCrossRefGoogle Scholar
  22. 22.
    Conlon P, Oksenberg JR, Zhang J. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis 6; 1999: 149–66PubMedCrossRefGoogle Scholar
  23. 23.
    Trapp BD, Bo L, Mork S, et al. Pathogenesis of tissue injury in MS lesions. J Neuroimmunol 1999; 98: 49–56PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    Stuve 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(6): 853–63PubMedCrossRefGoogle Scholar
  26. 26.
    Leppert D, Waubant E, Burk MR, et al. Interferon beta-lb inhibits gelatinase secretion and in vitro migration of human T-cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996; 40(6): 846–852PubMedCrossRefGoogle Scholar
  27. 27.
    Lou J, Gasche Y, Zheng L, et al. Interferon β inhibits activated leucocyte migration through human brain microvascular endothelial cell monolayer. Lab Invest 1999; 79: 1015–25PubMedGoogle Scholar
  28. 28.
    Miller A, Lanir N, Shapiro S, et al. Immunoregulatory effects of interferon-β and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis and other autoimmune diseases. J Neuroimmunol 1996; 64: 151–61Google Scholar
  29. 29.
    Noronha A, Toscas A, Jensen MA. Interferon β decreases T-cell activation and interferon γ production in multiple sclerosis. J Neuroimmunol 1993; 46: 145–54PubMedCrossRefGoogle Scholar
  30. 30.
    Mosmann TR, Moore KW. The role of IL-10 in crossregulation ofTHl and TH2 responses. Immunol Today 1991; 12: 49–53CrossRefGoogle Scholar
  31. 31.
    Wang P, Wu P, Anthes JC, et al. Interleukin-10 inhibits interleukin-8 production in human neutrophils. Blood 1994; 83: 2678–83PubMedGoogle Scholar
  32. 32.
    Joyce DA, Gibbons DP, Green P, et al. Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumour necrosis factor receptor by cultured monocytes. Eur J Immunol 1994; 24: 2699–705PubMedCrossRefGoogle Scholar
  33. 33.
    Itoh K, Inoue T, Ito K, et al. The interplay of interleukin-10 (IL-10) and interleukin-2 (IL-2) in humoral immune responses: IL-10 synergizes with IL-2 to enhance responses of human B lymphocytes in a mechanism which is different from upregulation of CD25 expression. Cell Immunol 1994; 157: 478–88PubMedCrossRefGoogle Scholar
  34. 34.
    Rudick RA, Ransohoff RM, Peppier R, et al. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40: 618–27PubMedCrossRefGoogle Scholar
  35. 35.
    Gold R, Hartung H-P, Toyka KV. Animal models for autoimmune demyelinating disorders of the nervous system. Mol Med Today 2000; 6: 88–91PubMedCrossRefGoogle Scholar
  36. 36.
    Steinman L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999; 24: 511–4PubMedCrossRefGoogle Scholar
  37. 37.
    Abreu SL, Tondreau J, Levine S, Sowinski R. Inhibition of passive localised experimental allergic encephalomyelitis by interferon. Int Archs Allerg Appl Immun 1983; 72: 30–3CrossRefGoogle Scholar
  38. 38.
    Yu M, Nishiyama A, Trapp BD, et al. Interferon-β inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 1996; 64: 91–100PubMedCrossRefGoogle Scholar
  39. 39.
    Merrill JE, Ignarro LJ, Sherman MP, et al. Microglial cel cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol 1993; 151: 2132–41PubMedGoogle Scholar
  40. 40.
    Hua LL, Liu JS, Brosnan CF, et al. Selective inhibition of human glial inducible nitric oxide synthase by interferon-beta: implications for multiple sclerosis. Ann Neurol 1998; 43(3): 384–7PubMedCrossRefGoogle Scholar
  41. 41.
    Althaus HH, Klöppner S, Schmidt-Schulz T, et al. Nerve growth factor induces proliferation and enhances fibre regeneration in oligodendrocytes isolated from adult pig brain. Neurosci Lett 1992; 135: 219–23PubMedCrossRefGoogle Scholar
  42. 42.
    Boutros T, Croze E, Yong VW. Interferon-β is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 1997; 69: 939–46PubMedCrossRefGoogle Scholar
  43. 43.
    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: 1799–1806PubMedCrossRefGoogle Scholar
  44. 44.
    Pestka S, Langer JA, Zoon KC, et al. IFNs and their actions. Ann Rev Biochem 1987; 56: 727–72PubMedCrossRefGoogle Scholar
  45. 45.
    Borden E, Paulnock D, Spear G, et al. Biological response modification in man: measurement of interferon induced proteins. In: Baron S, Dianzani F, et al., (editors). The interferon system: acurrentreview.University ofTexas, Austin (TX), 1986:1–7Google Scholar
  46. 46.
    Liberati AM, Horisberger MA, Palmisano L, et al. Doubleblind randomised phase 1 study on the clinical tolerance and biological effects of natural and recombinant human interferon beta. J Interferon Res 1992; 12: 329–36PubMedCrossRefGoogle Scholar
  47. 47.
    Alam J, Goelz S, Rioux P, et al. Comparative pharmacokinetics and pharmacodynamics of two recombinant human interferon beta-1a (IFNβ-1a) products administered intramuscularly in healthy male and female volunteers. Pharmaceut Res 1997; 14(4): 546–9CrossRefGoogle Scholar
  48. 48.
    Munafo A, Trinchard-Lugan I, Nguyen TXQ, et al. Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol 1998; 5: 187–93PubMedCrossRefGoogle Scholar
  49. 49.
    Witt PL, Storer BE, Bryan GT, et al. Pharmacodynamics of biological response in vivo after single and multiple doses of interferon-β. J Immunother 1993; 13(3): 191–200CrossRefGoogle Scholar
  50. 50.
    Stürzebecher S, Maibauer R, Heuner A, et al. Pharmacodynamic comparison of single doses of IFNβ1a and IFNβ1b in healthy volunteers. J Interferon Cytokine Res 1999; 19:1257–64PubMedCrossRefGoogle Scholar
  51. 51.
    Williams GJ, Witt PL. Comparative study of the pharmacodynamic and pharmacologic effects of Betaseron® and Avonex™. J Interferon Cytokine Res 1998; 18: 967–75PubMedGoogle Scholar
  52. 52.
    Rothuizen LE, Buclin T, Spertini F, et al. Influence of interferon β-1a dose frequency on PBMC cytokine secretion and biological effect markers. J Neuroimmunol 1999; 99: 131–41PubMedCrossRefGoogle Scholar
  53. 53.
    Deisenhammer F, Mayringer I, Harvey J, et al. A comparative study of the relative bioavailability of different interferon beta preparations. Neurology 2000; 54: 2055–60PubMedCrossRefGoogle Scholar
  54. 54.
    Knobler RL, Greenstein JI, Johnson KP, et al. Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up. J Interferon Res 1993; 13: 333–40PubMedCrossRefGoogle Scholar
  55. 55.
    Alam J, McAllister A, Scaramucci J, et al. Pharmacokinetics and pharmacodynamics of interferon beta-1a in healthy volunteers after intravenous, subcutaneous or intramuscular administration. Clin Drug Invest 1997; 14: 35–43CrossRefGoogle Scholar
  56. 56.
    Biogen Inc., 1995. Summary basis of approval. FDA official document for license of interferon beta-1a (Avonex™). Available from URL: www.fda.gov/cber/products/ifnbbio051796.htm
  57. 57.
    Durelli L, Ferrero T, Ghezzi G, et al. The independent comparison of interferon (INCOMIN) trial: a multicenter randomized trial comparing clinical and MRI efficacy of IFN beta-1a and beta-1b in multiple sclerosis [abstract]. Neurology 2001; 56 Suppl. 3: A148CrossRefGoogle Scholar
  58. 58.
    Coyle P. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS [abstract]. J Neuro Sci 2001; 187 Suppl. 2: S436Google Scholar
  59. 59.
    Clanet M, Kappos L, Radue EW, et al. Results of the European interferon beta- 1a (Avonex) dose-comparison study. J Neurol 2001; 248 Suppl. 2: 11/63.Google Scholar
  60. 60.
    Guan R, Yeoh KG, Yap I, et al. Subcutaneously administered recombinant humen β-interferon in the treatment of chronic hepatitis B virus infection. Aliment Pharmacol Ther 1996; 10: 807–14PubMedCrossRefGoogle Scholar
  61. 61.
    Takano S, Satomura Y, Omata M, and Japan Acute Hepatitis Cooperative Study Group. Effects of interferon beta on non-A, non-B acute hepatitis: a prospective, randomised, controlled-dose study. Gastroenterology 1994; 107: 805–11PubMedCrossRefGoogle Scholar
  62. 62.
    Ravandi F, Estrov Z, Kurzrock R, et al. A phase I study of recombinant interferon-β in patients with advanced malignant disease. Clin Cancer Res 1999; 5: 3990–8PubMedGoogle Scholar
  63. 63.
    Borden EC, Rinehart JJ, Storer BE, et al. Biological and clinical effects of interferon βser at two doses. J Interferon Res 1990; 10: 559–70PubMedCrossRefGoogle Scholar
  64. 64.
    Fine HA, Wen PY, Robertson M, et al. A phase I trial of a new recombinant human β-interferon (BG9015) for the treatment of patients with recurrent gliomas. Clin Cancer Res 1997; 3: 381–7PubMedGoogle Scholar
  65. 65.
    Bonnez W, Oakes D, Bailey-Farchione A, et al. A randomised, double-blind trial of parenteral low dose versus high dose interferon-β in combination with cryotherapy for treatment of condyloma acuminatum. Antiviral Research 1997; 35: 41–52PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Neurology, Rm M-794University of CaliforniaSan FranciscoUSA

Personalised recommendations