Analysis of the efficacy and safety of first- and second-line disease-modifying drugs for multiple sclerosis in treatment of pediatric multiple sclerosis

Background. Moderately effective therapy (MET) is recommended for the treatment of multiple sclerosis (MS) with childhood onset, except when the course is highly active or primary progressive, then highly effective therapy (HET) is used. The results of randomized controlled trials as well as cohort observational studies have shown advantages of HET over MET.

Aim. To evaluate the efficacy of first-line disease-modifying drugs in MS in children and compare it with the efficacy of second-line disease-modifying drugs in MS.

Materials and methods. On the basis of the paediatric neurology department of the M.F. Vladimirskiy Moscow State Medical Institute a cohort study was conducted that included 50 patients with MS who had experienced their first symptoms during childhood. These patients were receiving disease-modifying therapy for a period of more than one year, and had undergone a total of 87 attempts at therapy. A total of 67 courses of MET (interferon, glatiramer acetate, teriflunomide) and 20 courses of HET (fingolimod, ocrelizumab, rituximab before 18 years of age; natalizumab, ocrelizumab and alemtuzumab after 18 years of age) were administered.

Results. The efficacy of MET was 16 % (11 cases out of 67) and of HET was 80 % (16 cases out of 20). In 30 % of cases, the decision to switch from the MET course to the HET course was taken. Significant adverse events occurred in 19 % of cases in the MET group, and in 5 % of cases in the HET group. The frequency of MET drug cancellation was 49 %, while the frequency of HET cancellation was 15 %.

Conclusion. In the present study, the efficacy of MET in MS with a childhood onset was found to be 5 times lower than that of HET. Adverse events were observed to occur with a frequency four times higher in the context of MET than in the context of HET. The frequency of treatment discontinuation was found to be more than three times higher in cases of MET than in cases of HET. The results demonstrated that HET was associated with enhanced tolerability and adherence to treatment. Furthermore, emphasis was placed on the underutilisation of HET in children, with the recommendation that its utilisation be expanded at the pediatric onset MS.

1. Bembeeva R.Ts. Early diagnosis and treatment of multiple sclerosis in pediatric practice (lecture). Detskaya bolnitsa = Children’s Hospital 2010;4(42):62–8. (In Russ.).

2. Boyko A.N., Bykova O.V., Sivertseva S.A. Multiple sclerosis in children and adolescents. Мoscow: Meditsinskoe informatsionnoe agentstvo, 2016. (In Russ.). DOI: 10.17116/jnevro201711722114

3. Clinical guidelines “Multiple sclerosis”. Available at: https://cr.minzdrav.gov.ru/recomend/739_1. (In Russ.).

4. Lebedev V.M. Pediatric multiple sclerosis: features of pathogenesis, clinical and radiological picture, modern approaches to diagnostics and treatment. Nevrologicheskiy vestnik = Neurological Bulletin 2023;(3):40–54. (In Russ.). DOI: 10.17816/nb508722

5. Arkar U., Vipotnik Vesnaver T. et al. Multiple sclerosis in a 4-year-old boy: A case report and literature review. Front Neurol 2024;15: 1359938. DOI: 10.3389/fneur.2024.1359938

6. Arnold D.L., Banwell B., Bar-Or A. et al. PARADIGMS Study Investigators. Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study. J Neurol Neurosurg Psychiatry 2020;91(5):483–92. DOI: 10.1136/jnnp-2019-322138

7. Banwell B., Krupp L., Kennedy J. et al. Clinical features and viral serologies in children with multiple sclerosis: A multinational observational study. Lancet Neurol 2007;6(9):773–81. DOI: 10.1016/S1474-4422(07)70196-5

8. Baroncini D., Ghezzi A., Guaschino C. et al. MS Study Group of the Italian Neurological Society. Long-term follow-up (up to 11 years) of an Italian pediatric MS cohort treated with natalizumab: A multicenter, observational study. Neurol Sci 2022;43(11):6415–23. DOI: 10.1007/s10072-022-06211-8

9. Benallegue N., Rollot F., Wiertlewski S. et al; OFSEP (Observatoire Français de la Sclérose en Plaques) Investigators. Highly effective therapies as first-line treatment for pediatric-onset multiple sclerosis. JAMA Neurol 2024;81(3):273–82. DOI: 10.1001/jamaneurol.2023.5566

10. Buron M.D., Christensen J.R., Pontieri L. et al. Natalizumab treatment of multiple sclerosis – a Danish nationwide study with 13 years of follow-up. Mult Scler Relat Disord 2023;74:104713. DOI: 10.1016/j.msard.2023.104713

11. Chitnis T., Aaen G., Belman A. et al. US Network of Paediatric Multiple Sclerosis Centers. Improved relapse recovery in paediatric compared to adult multiple sclerosis. Brain 2020;143(9):2733–41. DOI: 10.1093/brain/awaa199

12. Chitnis T., Arnold D.L., 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):1017–27. DOI: 10.1056/NEJMoa1800149

13. Chitnis T., Arnold D.L., Quartier P. et al. Safety, efficacy, and tolerability of alemtuzumab in pediatric patients with active relapsing-remitting multiple sclerosis: The LemKids study. Mult Scler 2025;31(1):23–35. DOI: 10.1177/13524585241295554

14. Chitnis T., Banwell B., Kappos L. et al. Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS. Mult Scler 2024;30(7):833–42. DOI: 10.1177/13524585241242050

15. Chitnis T., Banwell B., Kappos L. et al. TERIKIDS Investigators. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): A multicentre, double-blind, phase 3, randomised, placebo-controlled trial. Lancet Neurol 2021;20(12):1001–011. DOI: 10.1016/S1474-4422(21)00364-1

16. Chitnis T., Tenembaum S., Banwell B. et al. International Pediatric Multiple Sclerosis Study Group. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 2012;18(1):116–27. DOI: 10.1177/1352458511430704

17. Deiva K., Huppke P., Banwell B. et al. Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: Further insights from PARADIGMS. J Neurol Neurosurg Psychiatry 2020;91(1):58–66. DOI: 10.1136/jnnp-2019-321124

18. De Meo E., Filippi M., Trojano M. et al. Comparing natural history of early and late onset pediatric multiple sclerosis. Ann Neurol 2022;91:483–95.

19. Ealsh R., Van Haren K. Effectiveness and safety of high-efficacy disease-modifying therapy in pediatric multiple sclerosis: A retrospective analysis at a single center. Neurology 2024;102. DOI: 10.1212/WNL.0000000000206701

20. Freedman M.S., Devonshire V., Duquette P. et al. Treatment optimization in multiple sclerosis: Canadian MS Working Group Recommendations. Can J Neurol Sci 2020;47(4):437–55. DOI: 10.1017/cjn.2020.66

21. Ghezzi A. Old and new strategies in the treatment of pediatric multiple sclerosis: A personal view for a new treatment approach. Neurol Ther 2024;13(4):949–63. DOI: 10.1007/s40120-024-00633-6

22. Ghezzi A., Baroncini D., Zaffaroni M. et al. Pediatric versus adult MS: Similar or different? Mult Scler Demyelinating Disord 2017;2:5.

23. Johnen A., Elpers C., Riepl E. et al. Early effective treatment may protect from cognitive decline in paediatric multiple sclerosis. Eur J Paediatr Neurol 2019;23:783–91.

24. Kotulska K., Valeriani M., Mar S. et al. Ocrelizumab dose selection for treatment of pediatric relapsing-remitting multiple sclerosis: Pharmacokinetic, safety, and efficacy results from OPERETTA 1 (NCT04075266). Available at: https://medically.roche.com/global/ en/neuroscience/ectrims-2024/medical-material/ECTRIMS2024-presentation-kotulska-ocrelizumab-dose-selection-fortreatment-pdf.html.

25. Margoni M., Rinaldi F., Riccardi A. et al. No evidence of disease activity including cognition (NEDA-3 plus) in naive pediatric multiple sclerosis patients treated with natalizumab. J Neurol 2020;267:100–5.

26. Mirmosayyeb O., Brand S., Barzegar M. et al. Clinical characteristics and disability progression of early- and late-onset multiple sclerosis compared to adult-onset multiple sclerosis. J Clin Med 2020;9(5): 1326. DOI: 10.3390/jcm9051326

27. Novartis Pharmaceuticals. A 2-year randomized, 3-arm, doubleblind, non-inferiority study comparing the efficacy and safety of ofatumumab and siponimod versus fingolimod in pediatric patients with multiple sclerosis followed by an open-label extension (clinical trial registration NCT04926818; issue NCT04926818). 2024. Available at: https://clinicaltrials.gov/study/NCT04926818.

28. Portaccio E., Bellinvia A., Razzolini L. et al. Long-term cognitive outcomes and socioprofessional attainment in people with multiple sclerosis with childhood onset. Neurology 2022;98:e1626–36.

29. Roche H.-L. A phase III multicenter, randomized, double-blind, double-dummy study to evaluate safety and efficacy of ocrelizumab in comparison with fingolimod in children and adolescents with relapsing-remitting multiple sclerosis (clinical trial registration NCT05123703; issue NCT05123703). 2024. Available at: https://clinicaltrials.gov/study/NCT05123703.

30. Sandesjö F. Tremlett H., Fink K. et al. Incidence rate and prevalence of pediatric-onset multiple sclerosis in Sweden: A population-based register study. Eur J Neurol 2024;31(5):e16253. DOI: 10.1111/ene.16253

31. Saponaro A.C. Tully T., Maillart E. et al. KidBiosep cohort study. Treatments of paediatric multiple sclerosis: Efficacy and tolerance in a longitudinal follow-up study. Eur J Paediatr Neurol 2023;45:22–8. DOI: 10.1016/j.ejpn.2023.05.001

32. Spelman T., Simoneau G., Hyde R. et al. MSBase Investigators. Comparative effectiveness of natalizumab, fingolimod, and injectable therapies in pediatric-onset multiple sclerosis: A registry-based study. Neurology 2024;102(7):e208114. DOI: 10.1212/WNL.0000000000208114. Erratum in: Neurology 2024;103(1):e209573. DOI: 10.1212/WNL.0000000000209573

33. Spirek B., Brenton J.N. Safety and efficacy of fingolimod and ocrelizumab in pediatric patients with multiple sclerosis. Pediatr Neurol 2025;164:89–96. DOI: 10.1016/j.pediatrneurol.2024.12.015

34. Teleanu R.I., Niculescu A.G., Vladacenco O.A. et al. The state of the art of pediatric multiple sclerosis. Int J Mol Sci 2023;24(9):8251. DOI: 10.3390/ijms24098251

35. Usta N.C., Boz C., Terzi M. Early onset multiple sclerosis and the effect of disease onset age on neurological disability in multiple sclerosis. Clin Neurol Neurosurg 2023;224:107528. DOI: 10.1016/j.clineuro.2022.107528

36. Vermersch P., Scaramozza M., Levin S. et al. Effect of dimethyl fumarate vs interferon β-1a in patients with pediatric-onset multiple sclerosis: The CONNECT randomized clinical trial. JAMA Netw Open 2022;5(9):e2230439. DOI: 10.1001/jamanetworkopen.2022.30439

37. Walsh R., Chitnis T. Therapeutic advances in pediatric multiple sclerosis. Children (Basel) 2025;12(3):259. DOI: 10.3390/children12030259

38. Weier K., Fonov V., Aubert-Broche B. et al. Impaired growth of the cerebellum in pediatric-onset acquired CNS demyelinating disease. Mult Scler 2016;22:1266–78.