Newer Treatment Approaches in Pediatric-Onset Multiple Sclerosis
Purpose of review
With the recognition that pediatric-onset multiple sclerosis (POMS) is characterized by more prominent disease activity, earlier age at onset of disability milestones, and more prominent cognitive impairment compared with physical disability earlier in the disease course compared with adult-onset multiple sclerosis (AOMS), there has been increasing interest in identifying optimal and safe treatment approaches to achieve better disease control in this group. Injectable therapies have been traditionally used as first line in this population, although not formally approved. This review focuses on current treatment and monitoring approaches in POMS.
In the past few years, and despite the paucity of FDA-approved medications for use in POMS, an increasing trend toward using newer disease-modifying therapies (DMTs) in this group is observed. However, escalation (as opposed to induction) remains the most frequent approach, and many children continue to be untreated before age 18, particularly before age 12. The only FDA- and EMA-approved disease-modifying therapy in POMS is fingolimod; however, dimethyl fumarate, teriflunomide, natalizumab, ocrelizumab, and alemtuzumab either have been evaluated in observational studies or are being currently investigated in formal randomized controlled trials for use in POMS and appear to be safe in this group. Autologous hematopoietic stem cell transplantation has also been evaluated in a small series. Clinical outcome measures and MS biomarkers have been poorly studied in POMS; however, the use of composite functional scores, neurofilament light chain, optical coherence tomography, and imaging findings is being increasingly investigated to improve early diagnosis and efficient monitoring of POMS.
Off-label use of newer DMTs in POMS is increasing, and based on retrospective data, and phase 2 trials, this approach appears to be safe in children. Results from ongoing trials will help clarify the safety and efficacy of these therapies in the future. Fingolimod is the only FDA-approved medication for use in POMS. Outcome measures and biomarkers used in AOMS are being studied in POMS and are greatly needed to quantify treatment response in this group.
KeywordsMultiple sclerosis Pediatric Treatment Outcome measures Safety Efficacy
Compliance with Ethical Standards
Conflict of Interest
Gabrielle Macaron receives fellowship funding from the National Multiple Sclerosis Society Institutional Clinician Training Award ICT 0002 and has received fellowship funding from Biogen Fellowship Grant 6873-P-FEL. She has served on a scientific advisory board for Genentech.
Jenny Feng receives funding via a Sylvia Lawry Physician Fellowship Grant through the National Multiple Sclerosis Society (No. FP-1707-28768). She has served on scientific advisory board for Sanofi.
Manikum Moodley receives funding from the National Multiple Sclerosis Society.
Mary Rensel serves as a consultant or speaker for Biogen, Teva, Genzyme, and Novartis. She receives grant funding from the National Multiple Sclerosis Society. She also serves on the advisory board for Serono and received research support from MedImmune and Genentech.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients--FDA. Final rule. Fed Regist. 1998;63(231):66631–72.Google Scholar
- 7.•• Krysko KM, Graves J, Rensel M, Weinstock-Guttman B, Aaen G, Benson L, et al. Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US. Neurology. 2018;91(19):e1778–87 Important analysis on trends in using newer disease-modifying therapies in pediatric-onset multiple sclerosis.PubMedPubMedCentralGoogle Scholar
- 10.Krupp LB, Pohl D, Ghezzi A, Boyko A, Tenembaum S, Chen L, et al. Subcutaneous interferon β-1a in pediatric patients with multiple sclerosis: regional differences in clinical features, disease management, and treatment outcomes in an international retrospective study. J Neurol Sci. 2016;363:33–8.PubMedGoogle Scholar
- 16.• Brown JWL, Coles A, Horakova D, Havrdova E, Izquierdo G, Prat A, et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321(2):175–87 Recent publication on the potential benefit of induction approach on long-term outcomes in adults with multiple sclerosis.PubMedPubMedCentralGoogle Scholar
- 22.•• Ruano L, Branco M, Portaccio E, Goretti B, Niccolai C, Patti F, et al. Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: an Italian collaborative study. Mult Scler. 2018;24(9):1234–42 Recent study on the prevalence of cognitive impairment in pediatric multiple sclerosis compared with adult multiple sclerosis.PubMedGoogle Scholar
- 24.•• Huppke P, Huppke B, Ellenberger D, Rostasy K, Hummel H, Stark W, et al. Therapy of highly active pediatric multiple sclerosis. Mult Scler J. 2019;25(1):72–80 Important paper on the prevalence of highly active disease in pediatric multiple sclerosis and benefit of natalizumab and fingolimod in this group.Google Scholar
- 30.• Wassmer E, Chitnis T, Pohl D, Amato MP, Banwell B, Ghezzi A, et al. International Pediatric MS Study Group Global Members Symposium report. Neurology. 2016;87(9):S110–6 Expert consensus on advances and challenges in the diagnosis and management of pediatric multiple sclerosis and other neuroinflammatory CNS disorders.PubMedGoogle Scholar
- 32.Food and Drug Association. Press Announcements - FDA expands approval of Gilenya to treat multiple sclerosis in pediatric patients. Office of the Commissioner; 2018 [cited 2019 Mar 31]. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm607501.htm.
- 40.Rossman I, Moodley M, Rensel M. Dimethyl fumarate is well tolerated in a small cohort of pediatric-onset multiple sclerosis patients (P3.010). Neurology. 2016;86(16 Supplement):3.010.Google Scholar
- 43.•• Chitnis T, Arnold DL, Banwell B, Brück W, Ghezzi A, Giovannoni G, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379(11):1017–27 Pivotal trial of fingolimod in pediatric multiple sclerosis, leading to FDA and EMA approval of this drug in children.PubMedGoogle Scholar
- 44.Kappos L, Radue E-W, O’Connor P, Polman CH, Hohlfeld R, Calabresi PA, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.Google Scholar
- 56.Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. Lancet. 2012;380(9856):1829–1839.Google Scholar
- 58.Durand-Dubief F, Marignier R, Berthezene Y, Cottin J, Nighoghossian N, Vukusic S. Spontaneous multiple cervical artery dissections after alemtuzumab. Mult Scler. 2019. https://doi.org/10.1177/1352458519828663.
- 60.Ontaneda D, Moore A, Bakshi R, Zajicheck A, Kattan M, Fox R. Risk estimates of progressive multifocal leukoencephalopathy related to fingolimod. In: ECTRIMS Online Library. 2018. p. 1775.Google Scholar
- 63.U.S. Food and Drug Administration. Press Announcements - FDA approves new oral drug to treat multiple sclerosis. Office of the Commissioner; [cited 2019 Apr 2]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634469.htm.
- 66.Chitnis T, Tardieu M, Banwell B, Gücüyener K, Deiva K, Skripchenko N, et al. Evaluation of teriflunomide in children and adolescents with relapsing MS: TERIKIDS phase 3 study design, enrollment update, and baseline data (P4.354). Neurology. 2018;90(15 Supplement):4.354.Google Scholar
- 67.U.S. Food and Drug Admnistration. Press Announcements - FDA approves new oral treatment for multiple sclerosis. [Cited 2019 Apr 2]; Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634837.htm.
- 82.Das B, Dimas V, Guleserian K, Lacelle C, Anton K, Moore L, et al. Alemtuzumab (Campath-1H) therapy for refractory rejections in pediatric heart transplant recipients. Pediatr Transplant. 2017;21(1).Google Scholar
- 88.• Burman J, Kirgizov K, Carlson K, Badoglio M, Mancardi GL, De Luca G, et al. Autologous hematopoietic stem cell transplantation for pediatric multiple sclerosis: a registry-based study of the Autoimmune Diseases Working Party (ADWP) and Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplant. Bone Marrow Transplant. 2017;52(8):1133–7 The only trial of hematopoetic stem cell transplantation in children with MS.PubMedGoogle Scholar
- 91.Tur C, Moccia M, Barkhof F, Chataway J, Sastre-Garriga J, Thompson AJ, et al. Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting. Nat Rev Neurol. 2018:3–5.Google Scholar
- 93.Kurtzke JF. Disability rating scales in multiple sclerosis. Ann N Y Acad Sci. 1983;436(1):347–60.Google Scholar
- 96.•• Waldman AT, Chahin S, Lavery AM, Liu G, Banwell BL, Liu GT, et al. Binocular low-contrast letter acuity and the symbol digit modalities test improve the ability of the Multiple Sclerosis Functional Composite to predict disease in pediatric multiple sclerosis. Mult Scler Relat Disord. 2016;10(2016):73–8 Important paper on the development of clinical outcome measures in pediatric multiple sclerosis.PubMedPubMedCentralGoogle Scholar
- 97.Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment. Mult Scler J. 1999;5(4):244–50.Google Scholar
- 98.Benedict RHB, Deluca J, Phillips G, Larocca N, Hudson LD. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler J. 2017;23(5):721–33.Google Scholar
- 100.•• van der Vuurst de Vries RM, Wong YYM, Mescheriakova JY, van Pelt ED, Runia TF, Jafari N, et al. High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome. Mult Scler J. 2018;1–10. Diagnostic value of NfL in children with an isolated demyelinating event.Google Scholar
- 101.Mar S, Piccio L. CSF Neurofilament light chain levels as a biomarker for pediatric demyelinating diseases (P5.349). Neurology. 2016;86(16 Supplement):5.349.Google Scholar
- 102.Reinert M, Barro C, Michalak Z, Bruck W, Huppke P, Kropshofer H, et al. Neurofilament light chain is a useful biomarker in paediatric multiple sclerosis. ECTRIMS online library 2018. p. 666.Google Scholar
- 103.Lambe J, Murphy OC, Saidha S. Can optical coherence tomography be used to guide treatment decisions in adult or pediatric multiple sclerosis? Curr Treat Options Neurol. 2018;20(4).Google Scholar
- 108.Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler J. 2013;19(10):1261–7.Google Scholar
- 110.Sinnecker T, Wuerfel E, Cerda Fuertes N, Meier D, Derfuss T, Gartner J, et al. The central vein sign in paediatric-onset multiple sclerosis. ECTRIMS online library 2018. P.346.Google Scholar
- 111.Sati P, Oh J, Todd Constable R, Evangelou N, Guttmann CRG, Henry RG, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714–22.PubMedGoogle Scholar
- 112.Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, et al. Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis. Brain. 2010;133(Pt 2):333–48.PubMedPubMedCentralGoogle Scholar
- 117.Schwartz CE, Grover SA, Powell VE, Noguera A, Mah JK, Mar S, et al. Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis. Mult Scler J. 2018;24(2):175–85.Google Scholar