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Real-world effectiveness of initial disease-modifying therapies in pediatric MS

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Krysko KM, Graves JS, Rensel M, Weinstock-Guttman B, Rutatangwa A, Aaen G, Belman A, Benson L, Chitnis T, Gorman M, Goyal MS, Harris Y, Krupp L, Lotze T, Mar S, Moodley M, Ness J, Rodriguez M, Rose J, Schreiner T, Tillema JM, Waltz M, Casper TC, Waubant E. US Network of Pediatric MS Centers. Real-world effectiveness of initial disease-modifying therapies in pediatric MS. 
Ann Neurol 2020 Apr 8.  doi: 10.1002/ana.25737. [Epub ahead of print]

Commentary by:

Uluç YİŞ, MD

Professor of Pediatric Neurology

Dokuz Eylül University, School of Medicine Department of Pediatrics, Division of Child Neurology


Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system. Approximately 3 to 10% of all MS cases present in childhood or adolescence.(1) Cases of pediatric MS have higher relapse rates, more rapid appearance of new magnetic resonance imaging (MRI) lesions and long-term motor and cognitive impairment. After a diagnosis of a pediatric MS has been made, treatment with a disease-modifying therapy (DMT) is essential to decrease relapses and prevent accumulating disability. DMTs include injections, infusions and oral medications. Safety and efficacy data of most DMTs is lacking in children, with only one FDA-approved DMT for use in children with MS.(2)

Currently, clinicians usually initiate treatment for pediatric MS with injectables such as interferon-β and glatiramer acetate, and escalate to oral or infusion DMTs for cases with higher relapse rates. While the PARADIGMS study showed decreased annual relapse rate and fewer new and enlarging T2 lesions on MRI with the use of the newer DMT fingolimod vs. weekly interferon-β1a in adults,(2) until now there was no data on early treatment with highly effective therapies in pediatric MS.

In the current multicenter cohort study, the authors evaluated relapse rate, development of MRI lesions and disability progression with initial treatment with newer compared to injectable DMTs in children with MS or clinically isolated syndrome (CIS). 741 children with a diagnosis of MS or CIS with a mean age of onset of 13.7 years were included, 66% of whom were female. 197 began treatment with a newer DMT, while 544 began with an injectable. Most commonly used newer DMTs were dimethyl fumarate, natalizumab, rituximab and fingolimod. The authors found a greater reduction in relapse rate with infusion than oral DMTs, and both demonstrated benefit over injectables. Those started on newer DMTs had significantly lower rate of new/enlarging T2 hyperintense and gadolinium-enhancing lesions. There was no statistically significant association between newer versus injectable DMTs on time to disability progression. Sensitivity analyses for relapse and MRI excluding the first 90 days of treatment were similar in favor of newer over injectable DMTs.

Limitations of the study include that outcomes on individual DMTs were not analyzed seperately in order to preserve a large sample for statistical modeling. In addition, different MRI protocols and scanners were used, and details regarding MRIs field strength and slice thickness were not avaliable. Data on adherence and safety data were also lacking for this cohort.

This study confirm that newer DMTs control clinical and radiologic disease activity better than injectables, at least over the short term. Additional randomized controlled trials are needed to explore the newer DMTs’ long-term efficacy, safety profile, tolerability and adherence.

Research Article


OBJECTIVE: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric MS and clinically isolated syndrome (CIS).

METHODS: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PS) were computed including pre-identified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2 hyperintense and gadolinium-enhancing lesions on MRI brain were modeled with midpoint survival analyses, adjusted for PS-quintile.

RESULTS: 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs. injectable 14.4 years, p=0.001) and less likely to have a monofocal presentation. In PS-quintile adjusted analysis, those on newer DMTs had lower relapse rate than those on injectables (rate ratio 0.45, 95%CI 0.29-0.70, p<0.001; rate difference 0.27, 0.14-0.40, p=0.004). One would need to treat with newer over injectable DMTs for 3.7 person-years to prevent one relapse. Those started on newer DMTs had lower rate of new/enlarging T2 (HR 0.51, 0.36-0.72, p<0.001) and gadolinium-enhancing lesions (HR 0.38, 0.23-0.63, p<0.001) than those on injectables.

INTERPRETATION: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required.



  1. Brenton JC, Kammeyer R, Gluck L, Schreiner T, Makhani N. Multiple sclerosis in children : current and emerging concepts. Semin Neurol 2020:40;192-200
  2. Chitnis T, Arnold DL, Banwell B, et al; PARADIGMS Study Group. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med 2018;379(11):1017–1027


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