Pediatric multiple sclerosis

CURRENT VIEWS OF FIRST-LINE TREATMENT IN PEDIATRIC MS

The efficacy and safety of IFN-β and GA in pediatric MS has been assessed by several phase 4 observational studies whereas comparable information is not currently available on the use of teriflunomide, dimethyl fumarate, and fingolimod. Pediatric trials with these agents are ongoing and their use in children with MS should generally occur in the context of controlled clinical trials, or considered with extreme caution in selected cases, until data on their effectiveness, tolerability, and safety are available.

Two position papers^1,3 have reported data on the use of IFN-β and GA in pediatric patients: results are summarized in table 1.^15,–,25 Data from observational studies are available in about 600 patients treated with IFN-β: 7 studies included >20 patients; 6 have a follow-up of 2 years or more.

Two studies have compared pediatric patients with MS treated with IFN-β with a control group.^24,26 In one unblinded study, 16 patients were randomized to intramuscular IFN-β-1a, half of adult dose, once a week or to no treatment. After 4 years, relapse rates (p = 0.04), disability progression (p = 0.01), and new T2 lesions (p = 0.006) were lower in treated vs untreated patients.²⁶ In another study, controls were extracted from a database: after a mean follow-up of 5.5 years, patients treated with IFN-β demonstrated significantly reduced occurrence of relapses, especially in the first 2 years of exposure, and a decrease in development of severe disability, although not statistically significant²⁴ (table 1).

Most studies have demonstrated a favorable effect of IFN-β on pediatric MS evolution, with a decline of relapse rate during the treatment phase, compared to the pretreatment period. The level of disability remained unchanged at the last observation in the majority of studies. There are no data suggesting that one drug is better than another, so the final choice is made by the treating physician after consideration of side effects, route, and frequency of administration with the patient and parents.

With the obvious limitations of the observational design of these studies, the general conclusion is that IFN-β is effective in the majority of patients, though about 30% of pediatric patients do not respond as expected, requiring more aggressive treatments²⁷ (see “Pediatric multiple sclerosis: Escalation and emerging treatments,” p. S103).

Data on adverse events have not been collected in a standardized fashion, and the definition of an adverse event differs across published studies, as well as the accuracy of detection. Flu-like symptoms have been reported in 8%–85% of children treated with interferon, myalgia in 5%–23%, headache in 8%–20%, gastrointestinal symptoms in 7%–10%, injection site reaction in 7%–75%, elevation of liver enzymes in 0%–38%, blood cell abnormalities in 2%–39%, and thyroid dysfunction in 1%–10%. Other rare adverse events have been reported in single cases (no more than 2 cases) and comprise menstrual disorders, depression, psychological disturbances, suicide attempt, arthritis, cartilage disorders, autoimmune disorders, serious infections, and malignancy.

There is limited information on the effect of IFN-β on body development. Data have been provided on 16 cases from a cohort of 52 pediatric patients with MS exposed to IFN-β treatment for a mean time of 43 months²⁸: in 10 girls who reached a mean age of 21.2 ± 5.0 years and in 6 boys who reached a mean age of 15.0 ± 2.5 years, weight and height resulted within the 10th–90th percentile of the normal population. Based on available data of scientific literature, there is no sign of a possible negative effect of IFN-β on body development.

A recent phase 4 multicenter study including 307 patients treated with IFN-β-1a 22/44 μg 3 times weekly confirmed the favorable safety profile of IFN-β as well as the reduction of release rate during the treatment phase.²² Rare adverse events (less than 2%) noted in this study included allergic reactions in 5 patients (1.6%), epilepsy and convulsive disorders in 5 (1.6%), thyroid dysfunction in 3 (1.0%), and autoimmune disorders, bone/cartilage disorders, and serious infections in 2 patients, respectively (0.7%). One child required omentectomy, classified under malignancy in Medical Dictionary for Regulatory Activities Query, and considered not related to IFN-β treatment by the treating physician.

Two studies evaluated the effect of GA in a small number of patients (21 cases): the clinical outcome was favorable in both studies, and no major adverse events have been recorded. However, acute hepatotoxicity confirmed by hepatic biopsy in an adolescent treated with GA has recently been reported.²⁹ Of note, this girl had been treated before with IFN-β-1a 44 mg and had developed elevation of liver enzymes, resulting in IFN-β-1a discontinuation and a switch to GA. Nevertheless, the exact causative mechanism of this adverse event remains to be elucidated.

RESULTS IN YOUNG CHILDREN VS ADOLESCENTS

Some studies have included children under the age of 10 years or 12 years, analyzing those subgroups separately: the clinical outcome was not different compared to patients with a higher age as well as the occurrence of adverse events; the only exception was increased rate of elevation of liver enzymes in the younger group of patients with MS in one study²³ (table 2).

Based on the results from a recently published study by Tenembaum et al.,²² the label of IFN-β-1a 22 or 44 μg has been modified in the European Union as follows: “The results of this study suggest that the safety profile in children (2–11 years old) and in adolescents (12–17 years old) receiving Rebif 22 or 44 μg subcutaneous 3 times per week is similar to that seen in adults. The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif should not be used in this age group.”

DMT IN CLINICAL PRACTICE

In recent years, 2 position papers have been published on the use of DMTs in the pediatric MS population.^1,3 The European document suggested early use of DMTs to prevent relapses, accumulation of disability, and accumulation of brain damage, recommending careful clinical and MRI follow-up.³ Similarly, the International Pediatric Multiple Sclerosis Study Group consensus statement recommends the use of first-line therapies as the standard of care for all pediatric patients with a diagnosis of MS.¹

The general approach is shown in the figure.

• Download figure
• Open in new tab
• Download powerpoint

Figure Diagram shows the main steps in the treatment of pediatric multiple sclerosis (MS)

It is suggested to start MS treatment with current first-line medications early. Patients with adverse events or poor tolerability can be offered to change the first-line therapy, switching to glatiramer acetate (GA) if previously treated with interferon-β (IFN-β) or vice versa. Switching to a second-line therapy can be considered for patients who do not adequately respond to current first-line therapies.

Pediatric patients with MS should start DMT treatment soon after diagnosis, with regular follow-up:

1. To assess clinical response with regular clinical evaluations (every 3–6 months, according to label/regulatory/local guidelines) and brain MRI every 6–12 months (according to label/regulatory/local guidelines)

2. To check the tolerability/safety profile (every 3–6 months, according to label/regulatory/local guidelines); periodic assessment of blood cell count, liver function, and thyroid and kidney function should be performed

There are no pharmacodynamic/pharmacokinetic studies of IFN-β and GA in pediatric MS. In general, it is recommended to initiate IFN-β therapy with 25%–50% of the adult dose. If well-tolerated, it is recommended to titrate up to full adult dose, especially for children over 12 years of age with a body weight more than 30 kg.

Adverse events should be appropriately managed: acetaminophen or ibuprofen before IFN-β injection or at appearance of flu-like symptoms reduce their frequency and severity. An educational program for patients and parents is also an important aspect when starting a DMT therapy, as they should be carefully informed on realistic expectations and management of adverse events, and trained on injection technique.

Patients treated with IFN-β can develop neutralizing antibodies resulting in a reduced biological activity of this medication and an increased risk of relapses^30,31: according to these recommendations, testing for the presence of neutralizing antibodies (NAbs), if available, should be performed in patients at 12 and 24 months of therapy or if there is evidence of breakthrough disease activity. Positive titers of NAbs may be relevant to guide treatment decisions: if confirmed at repeated measurements with 3- to 6-month intervals, IFN-β should be discontinued.

Recent reports have described the occurrence of thrombotic microangiopathy in adults treated with IFN-β³² as well as the association between glomerulonephritis and sarcoid-like lung disease with long-term IFN-β treatment.³³ Patients should be carefully monitored for safety evaluation and to discover possible rare adverse events: this issue is particularly important in pediatric patients, when children are being exposed to medications during key periods of growth and body development.