First-Line Disease-Modifying Therapies in Paediatric Multiple Sclerosis A Comprehensive Overview

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. IFN beta is a type 1 IFN produced by fibroblasts. The therapeutic effect achieved by IFN beta 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 IFN beta used therapeutically for MS: IFN beta-1a and IFN beta-1b. Two formulations of IFN beta-1a exist, one administered as an intramuscular injection once weekly and the other by subcutaneous injection three times per week. Only one type of IFN beta-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 antigenic 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 IFN beta 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 IFN beta 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.