Abstract
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.
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References
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: 655–61
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: 662–7
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; 45:1277–85
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94
Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon β-1a for relapsing multiple sclerosis. Ann Neurol 1996; 43: 79–87
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing-remitting multiple sclerosis. Lancet 1998; 352: 1498–1504
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: 197–206
PRISMS Study Group. PRISMS-4: long term efficacy of interferon β-1a in relapsing MS. Neurology 2001; 56: 1628–36
OWIMS Study Group. Evidence of interferon β-1a dose response in relapsing remitting MS. The OWIMS study. Neurology 1999; 53: 679–86
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: 1491–7
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: 274
National Multiple Sclerosis Society disease management consensus statement. The National Multiple Sclerosis Society, New York, NY, USA, 1999
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: 898–904
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; 1576–82
Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9
Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85
Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999; 12: 295–302
Goodkin DE. Interferon therapy for multiple sclerosis. Lancet 1998; 352: 1486–7
Johnson KP, Panitch HJ, Herndon RM, et al. Interferon therapy for multiple sclerosis. Lancet 199; 353: 494–8
Goodin DS. Perils and pitfalls in the interpretation of clinical trials. A reflection on the recent experience in multiple sclerosis. Neuroepidemiology 1999; 18: 53–63
Bar-Or A, Oliviera EML, Anderson DE, et al. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100: 252–9
Conlon P, Oksenberg JR, Zhang J. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis 6; 1999: 149–66
Trapp BD, Bo L, Mork S, et al. Pathogenesis of tissue injury in MS lesions. J Neuroimmunol 1999; 98: 49–56
Yong VW, Chabot S, Stuve O, et al. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998; 51: 682–9
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): 853–63
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): 846–852
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: 1015–25
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: 151–61
Noronha A, Toscas A, Jensen MA. Interferon β decreases T-cell activation and interferon γ production in multiple sclerosis. J Neuroimmunol 1993; 46: 145–54
Mosmann TR, Moore KW. The role of IL-10 in crossregulation ofTHl and TH2 responses. Immunol Today 1991; 12: 49–53
Wang P, Wu P, Anthes JC, et al. Interleukin-10 inhibits interleukin-8 production in human neutrophils. Blood 1994; 83: 2678–83
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: 2699–705
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: 478–88
Rudick RA, Ransohoff RM, Peppier R, et al. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40: 618–27
Gold R, Hartung H-P, Toyka KV. Animal models for autoimmune demyelinating disorders of the nervous system. Mol Med Today 2000; 6: 88–91
Steinman L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999; 24: 511–4
Abreu SL, Tondreau J, Levine S, Sowinski R. Inhibition of passive localised experimental allergic encephalomyelitis by interferon. Int Archs Allerg Appl Immun 1983; 72: 30–3
Yu M, Nishiyama A, Trapp BD, et al. Interferon-β inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 1996; 64: 91–100
Merrill JE, Ignarro LJ, Sherman MP, et al. Microglial cel cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol 1993; 151: 2132–41
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): 384–7
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: 219–23
Boutros T, Croze E, Yong VW. Interferon-β is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 1997; 69: 939–46
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: 1799–1806
Pestka S, Langer JA, Zoon KC, et al. IFNs and their actions. Ann Rev Biochem 1987; 56: 727–72
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), 1986:1–7
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: 329–36
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): 546–9
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: 187–93
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): 191–200
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; 19:1257–64
Williams GJ, Witt PL. Comparative study of the pharmacodynamic and pharmacologic effects of Betaseron® and Avonex™. J Interferon Cytokine Res 1998; 18: 967–75
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: 131–41
Deisenhammer F, Mayringer I, Harvey J, et al. A comparative study of the relative bioavailability of different interferon beta preparations. Neurology 2000; 54: 2055–60
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: 333–40
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: 35–43
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
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: A148
Coyle P. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS [abstract]. J Neuro Sci 2001; 187 Suppl. 2: S436
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.
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: 807–14
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: 805–11
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: 3990–8
Borden EC, Rinehart JJ, Storer BE, et al. Biological and clinical effects of interferon βser at two doses. J Interferon Res 1990; 10: 559–70
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: 381–7
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: 41–52
Acknowledgements
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.
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Goodin, D.S. Interferon- β Therapy in Multiple Sclerosis. Drugs 61, 1693–1703 (2001). https://doi.org/10.2165/00003495-200161120-00001
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DOI: https://doi.org/10.2165/00003495-200161120-00001