Drugs

, Volume 72, Issue 9, pp 1195–1211

First-Line Disease-Modifying Therapies in Paediatric Multiple Sclerosis

A Comprehensive Overview
  • Jessica Johnston
  • Tsz-Yin So
Review Article

Abstract

Paediatric multiple sclerosis (MS) is defined as the onset of MS before the age of 18 years. Immunomodulatory disease-modifying therapies (i.e. the interferons [IFNs] and glatiramer acetate) are considered first-line treatments in adult patients with MS, but they are largely understudied in the paediatric population.

IFNβ is a type 1 IFN produced by fibroblasts. The therapeutic effect achieved by IFNβ in MS is believed to be the result of a variety of mechanisms, including the inhibition of T-cell proliferation and a shift in cytokine production. There are currently two forms of recombinant IFNβ used therapeutically for MS: IFNβ-1a and IFNβ-1b. Two formulations of IFNβ-1a exist, one administered as an intramuscular injection once weekly and the other by subcutaneous injection three times per week. Only one type of IFNβ-1b product is on the market, a subcutaneous injection administered every other day. Pharmacokinetic studies of these agents in children do not exist and available data are primarily from studies in healthy adults. It does not appear that the various formulations differ significantly in terms of bioavailability or efficacy in adults. The toxicity profiles of the interferon formulations are similar, with the most common adverse effects in children including flu-like symptoms, injection site reactions and transient elevations in liver enzymes.

Glatiramer acetate is a mixture of synthetic polypeptide chains consisting of four different amino acids. Glatiramer acetate appears to mimic the anti-genic properties of myelin basic protein (MBP), and by doing so, alters T-cell activation in the periphery. Glatiramer acetate is administered as a once-daily subcutaneous injection. Similar to the IFNβ formulations, there are no pharmacokinetic studies of this agent in children. The most common adverse effects include injection site reactions and transient chest tightness.

Fingolimod, a sphingosine 1-phosphate receptor modulator, is a new disease-modifying therapy that was approved by the US FDA in 2010 for the first-line treatment of relapsing forms of MS in adults. However, due to a lack of information and clinical data on this agent in the paediatric population, it is not included in this discussion.

Dose-finding studies of the IFNs and glatiramer acetate in the paediatric population are limited. Dosing recommendations are largely based on tolerability studies, with most children and adolescents tolerating the full adult doses. Clinical studies of IFNs in children have not been objectively designed to establish the efficacy of these therapies, and evidence is limited to that of observational trials and retrospective case reports. However, the largest cohort (130 cases) of paediatric MS patients studied to date reported a reduction in annual relapse rate with all three of the different IFNβ formulations and glatiramer acetate after a follow-up period of more than 4 years.

Treatment with one of the first-line agents should be offered to any patient after the occurrence of a second demyelinating episode. The efficacy of the four first-line disease-modifying agents is considered to be relatively equivalent, and the choice of agent should be determined on an individual patient basis, taking into account potential adverse effects and patient preferences.

Current data suggest that the IFNs and glatiramer acetate are safe and effective therapies in paediatric patients with MS. However, further studies evaluating the pharmacokinetics, appropriate dosing and comparisons of efficacy among these agents are needed to determine the most appropriate and evidence-based treatment decisions in this population.

References

  1. 1.
    Noseworthy J, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000; 343 (13): 938–52CrossRefPubMedGoogle Scholar
  2. 2.
    Ghezzi A, Deplanov V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997; 3 (1): 43–6CrossRefPubMedGoogle Scholar
  3. 3.
    Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 1987; 111 (3): 359–63CrossRefPubMedGoogle Scholar
  4. 4.
    Boiko A, Vorobeychik G, Paty D, et al. Early onset multiple sclerosis: a longitudinal study. Neurology 2002; 59 (7): 1006–10CrossRefPubMedGoogle Scholar
  5. 5.
    Gadoth N. Multiple sclerosis in children. Brain Dev 2003; 25 (4): 229–32CrossRefPubMedGoogle Scholar
  6. 6.
    Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69 (2): 292–3CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Krupp LB, Banwell B, Tenembaum S, et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurol 2007; 68 Suppl. 2: S7–12CrossRefGoogle Scholar
  8. 8.
    Gilenya [package insert]. Stein: Novartis AG, 2010Google Scholar
  9. 9.
    Yong VW, Chabot S, Stuve O, et al. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998; 51 (3): 682–9CrossRefPubMedGoogle Scholar
  10. 10.
    Chofflon M. Mechanisms of action for treatments in multiple sclerosis: does a heterogeneous disease demand a multi-targeted therapeutic approach?. BioDrugs 2005; 19 (5): 299–308CrossRefPubMedGoogle Scholar
  11. 11.
    Markowitz CE. Interferon beta mechanisms of action and dosing issues. Neurology 2007; 68 (24 Suppl. 4): S8–11CrossRefPubMedGoogle Scholar
  12. 12.
    Chabas D, Ness J, Belman A, et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurol 2010; 74 (5): 399–405CrossRefGoogle Scholar
  13. 13.
    Gorman MP, Healy BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009; 66 (1): 54–9CrossRefPubMedGoogle Scholar
  14. 14.
    Yeh EA, Weinstock-Guttman B, Ramanathan M, et al. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain 2009; 132 (12): 3392–400CrossRefPubMedGoogle Scholar
  15. 15.
    Clerico M, Contessa G, Durelli L. Interferon-beta 1a for the treatment of multiple sclerosis. Expert Opin Biol Ther 2007; 7 (4): 535–42CrossRefPubMedGoogle Scholar
  16. 16.
    Runkel L, Meier W, Pepinsky RB, et al. Structural and functional differences between glycosylated and non-glycosylated forms of human inteferon-beta (IFN-beta). Pharm Res 1998; 15 (4): 641–9CrossRefPubMedGoogle Scholar
  17. 17.
    Deisenhammer F, Mayringer I, Harvey J, et al. A comparative study of the relative bioavailability of different interferon beta preparations. Neurology 2000; 54 (11): 2055–60CrossRefPubMedGoogle Scholar
  18. 18.
    Noronha A, Toscas A, Jensen MA. Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol 1993; 46 (1–2): 145–53CrossRefPubMedGoogle Scholar
  19. 19.
    Barna BP, Chou SM, Jacobs B, et al. Interferon-beta impairs induction of HLA-DR antigen expression in cultured adult human astrocytes. J Neuroimmunol 1989; 23 (1): 45–53CrossRefPubMedGoogle Scholar
  20. 20.
    Drulovic J, Mostarica-Stojkovic M, Levic Z, et al. Interleukin-12 and tumor necrosis factor-alpha levels in cerebrospinal fluid of multiple sclerosis patients. J Neurol Sci 1997; 147 (2): 145–50CrossRefPubMedGoogle Scholar
  21. 21.
    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 (3): 604–12CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rudick RA, Ransohoff RM, Peppler R, et al. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40 (4): 618–27CrossRefPubMedGoogle Scholar
  23. 23.
    Stone LA, Frank JA, Albert PS, et al. The effect of interferon-beta on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis. Ann Neurol 1995; 37 (5): 611–9CrossRefPubMedGoogle Scholar
  24. 24.
    Anharoni R, Teitelbaum D, Sela M, et al. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 1997; 94 (20): 10821–6CrossRefGoogle Scholar
  25. 25.
    Teitelbaum D, Milo R, Arnon R, et al. Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci U S A 1992; 89 (1): 137–41CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Miller A, Shapiro S, Gershtein R, et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone™): implicating mechanisms of Th1 to Th2/Th3 immune deviation. J Neuroimmunol 1998; 92 (1–2): 113–21CrossRefPubMedGoogle Scholar
  27. 27.
    Duda PW, Schmied MC, Cook SL, et al. Glatiramer acetate (Copaxone™) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000; 105 (7): 967–76CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Horwitz MS, Evans CF, McGavern DB, et al. Primary demyelination in transgenic mice expression interferon-gamma. Nat Med 1997; 3 (9): 1037–41CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Munafo A, Trinchard-Lugan II, Nguyen TX, et al. Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol 1998; 5 (2): 187–93CrossRefPubMedGoogle Scholar
  30. 30.
    Buchwalder PA, Buclin T, Trinchard I, et al. Pharmacokinetics and pharmacodynamics of interferon beta-1a(IFNb-1a) in healthy volunteers. J Interferon Cytokine Res 2000; 20 (10): 857–66CrossRefPubMedGoogle Scholar
  31. 31.
    Avonex [package insert]. Cambridge (MA): Biogen Inc, 2003Google Scholar
  32. 32.
    Rebif [package insert]. Rockland (MA): Serono Inc, 2003Google Scholar
  33. 33.
    Chiang J, Gloff CA, Yoshizawa CN, et al. Pharmacokinetics of recombinant human interferon-beta ser in healthy volunteers and its effect on serum neopterin. Pharm Res 1993; 10 (4): 567–72CrossRefPubMedGoogle Scholar
  34. 34.
    Betaseron [package insert]. Montville (NJ): Bayer Health-Care Pharmaceuticals Inc, 2010Google Scholar
  35. 35.
    Copaxone [package insert]. Kansas City (MO): Teva Neuroscience Inc, 2009Google Scholar
  36. 36.
    Ziemssen T, Neuhaus O, Hohlfeld R, et al. Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 2001; 24 (13): 979–90CrossRefPubMedGoogle Scholar
  37. 37.
    Ghezzi A. Therapeutic strategies in childhood multiple sclerosis. Ther Adv Neurol Disord 2010; 3 (4): 217–28CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 2012; 18 (1): 116–27CrossRefPubMedGoogle Scholar
  39. 39.
    Drug topics red book. Montvale (NJ): Thomson Healthcare; 2010Google Scholar
  40. 40.
    Ghezzi A, Amato MP, Annovazzi P, et al. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci 2009; 30 (3): 193–9CrossRefPubMedGoogle Scholar
  41. 41.
    Pakdaman H, Fallah A, Sahraian MA, et al. Treatment of early onset multiple sclerosis with suboptimal dose of interferon beta-1a. Neuropediatrics 2006; 37 (4): 257–60CrossRefPubMedGoogle Scholar
  42. 42.
    Waubant E, Hieptas J, Stewart T, et al. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics 2001; 32 (4): 211–3CrossRefPubMedGoogle Scholar
  43. 43.
    Pohl D, Rostasy K, Gartner J, et al. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology 2005; 65 (5): 888–90CrossRefGoogle Scholar
  44. 44.
    Banwell B, Reder AT, Krupp L, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 2006; 66 (4): 472–6CrossRefPubMedGoogle Scholar
  45. 45.
    Kornek B, Bernert G, Balassy C, et al. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics 2003; 34 (3): 120–6CrossRefPubMedGoogle Scholar
  46. 46.
    Ghezzi A, the Immunomodulatory Treatment of Early onset MS (ITEMS) Group. Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Cooperative study. Neuro Sci 2005; 26: S183–6CrossRefGoogle Scholar
  47. 47.
    Ghezzi A, Amato MP, Capobianco M, et al. Treatment of early-onset multiple sclerosis with intramuscular interferonbeta-1a: long-term results. Neurol Sci 2007; 28 (3): 127–32CrossRefPubMedGoogle Scholar
  48. 48.
    National Multiple Sclerosis Society. Functional Systems Scores (FSS) and Expanded Disability Status Scale (EDSS) [online]. Available from URL: http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/fss-and-edss/index.aspx [Accessed 2012 Apr 6]
  49. 49.
    GoodkinDE. EDSS reliability. Neurology 1991; 41 (2Pt 1): 332Google Scholar
  50. 50.
    Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356 (25): 2603–13CrossRefPubMedGoogle Scholar
  51. 51.
    Ghezzi A, Banwell B, Boyko A, et al. The management of multiple sclerosis in children: a European view. Mult Scler 2010; 16 (10): 1258–67CrossRefPubMedGoogle Scholar
  52. 52.
    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 (9316): 1453–60CrossRefPubMedGoogle Scholar
  53. 53.
    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 (10): 1496–506CrossRefPubMedGoogle Scholar
  54. 54.
    O’Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009; 8 (10): 889–97CrossRefPubMedGoogle Scholar
  55. 55.
    Pohl D, Waubant E, Banwell B, et al. Treatment of pediatric multiple sclerosis and variants. Neurology 2007; 68 (16 Suppl. 2): S54–65CrossRefPubMedGoogle Scholar
  56. 56.
    Giovannoni G. Strategies to treat and prevent the development of neutralizing anti-interferon-beta antibodies. Neurology 2003; 61 (9 Suppl. 5): S13–7CrossRefPubMedGoogle Scholar
  57. 57.
    Hemmer B, Stüve O, Kieseier B, et al. Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol 2005; 4 (7): 403–12CrossRefPubMedGoogle Scholar
  58. 58.
    Polman CH, Bertolottoa A, Deisenhammer F, et al. Recommendations for clinical use of data on neutralizing antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 2010; 9 (7): 740–50CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Jessica Johnston
    • 1
  • Tsz-Yin So
    • 2
  1. 1.University of North Carolina at Chapel Hill, Eshelman School of PharmacyChapel HillUSA
  2. 2.Pediatric Clinical Pharmacist, Department of PharmacyMoses H. Cone HospitalGreensboroUSA

Personalised recommendations