New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool. Fifty-one IPMSSG members from 21 countries responded to the survey, and 50 approved the final statement. Consensus recommendations regarding use of existing first- and second-line therapies, as well as a proposed definition for inadequate treatment response, are presented. Recommendations for the use and evaluation of emerging therapies (currently in phase III clinical trials or recently approved for adult MS) are discussed. The IPMSSG endorses the inclusion of pediatric MS patients in trials evaluating appropriate new and emerging therapies. Mechanisms for conducting high-impact, multicenter studies, including long-term follow-up in pediatric MS, are required to ensure that all MS patients, irrespective of age, benefit from advances in MS therapeutics.
DuquettePMurrayTJPleinesJEbersGCSadovnickDWeldonP. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr1987; 111: 359–363.
2.
BoikoAVorobeychikGPatyDDevonshireVSadovnickD. Early onset multiple sclerosis: a longitudinal study. Neurology2002; 59: 1006–1010.
3.
GhezziADeplanoVFaroniJGrassoMGLiguoriMMarrosuG. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler1997; 3: 43–46.
4.
SindernEHaasJStarkEWursterU. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol Scand1992; 86: 280–284.
5.
ChitnisTGlanzBJaffinSHealyB. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler (Houndmills) 2009; 15: 627–631.
6.
PohlDWaubantEBanwellBChabasDChitnisTWeinstock-GuttmanB. Treatment of pediatric multiple sclerosis and variants. Neurology2007; 68(Suppl. 2): S54–S65.
KuntzNLChabasDWeinstock-GuttmanBChitnisTYehEAKruppL. Treatment of multiple sclerosis in children and adolescents. Expert Opin Pharmacother2010; 11: 505–520.
9.
GhezziABanwellBBoykoAAmatoMPAnlarBBlinkenbergM. The management of multiple sclerosis in children: a European view. Mult Scler (Houndmills) 2010; 16: 1258–1267.
10.
GoodinDSFrohmanEMGarmanyGPJr.HalperJLikoskyWHLublinFD. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology2002; 58: 169–178.
11.
KruppLBBanwellBTenembaumS. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology2007; 68(Suppl. 2): S7–S12.
12.
GormanMPHealyBCPolgar-TurcsanyiMChitnisT. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol2009; 66: 54–59.
13.
AmatoMPGorettiBGhezziALoriSZipoliVPortaccioE. Cognitive and psychosocial features of childhood and juvenile MS. Neurology2008; 70: 1891–1897.
14.
MacAllisterWSBelmanALMilazzoMWeisbrotDMChristodoulouCScherlWF. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology2005; 64: 1422–1425.
15.
AmatoMPGorettiBGhezziALoriSZipoliVMoiolaL. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology2010; 75: 1134–1140.
16.
RenouxCVukusicSMikaeloffYEdanGClanetMDuboisB. Natural history of multiple sclerosis with childhood onset. N Eng J Med2007; 356: 2603–2613.
17.
SimoneILCarraraDTortorellaCLiguoriMLeporeVPellegriniF. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology2002; 59: 1922–1928.
18.
TrojanoMPaolicelliDBellacosaAFuianiACataldiSDi MonteE. Atypical forms of multiple sclerosis or different phases of a same disease?Neurol Sci2004; 25(Suppl. 4): S323–S325.
19.
WaubantEChabasDOkudaDTGlennOMowryEHenryRG. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol2009; 66: 967–971.
20.
YehEAWeinstock-GuttmanBRamanathanMRamasamyDPWillisLCoxJL. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain2009; 132: 3392–3400.
21.
WaubantEHietpasJStewartTDymeZHerbertJLacyJ. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics2001; 32: 211–213.
22.
MikaeloffYMoreauTDebouverieMPelletierJLebrunCGoutO. Interferon-beta treatment in patients with childhood-onset multiple sclerosis. J Pediatr2001; 139: 443–446.
23.
GhezziAAmatoMPCapobiancoMGalloPMarrosuGMartinelliV. Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study. Mult Scler (Houndmills) 2005; 11: 420–424.
24.
GhezziAAmatoMPCapobiancoM. Treatment of early-onset multiple sclerosis with intramuscular interferonbeta-1a: long-term results. Neurol Sci. 2007Jun;28(3):127–32.
25.
GhezziAAmatoMPAnnovazziPCapobiancoMGalloPLa MantiaL. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci2009; 30: 193–199.
26.
PohlDRostasyKGartnerJHanefeldF. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology2005; 64: 888–890.
27.
TenembaumSNSeguraMJ. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology2006; 67: 511–513.
28.
BanwellBRederATKruppLTenembaumSEraksoyMAlexeyB. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology2006; 66: 472–476.
29.
KornekBBernertGBalassyCGeldnerJPrayerDFeuchtM. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics2003; 34: 120–126.
30.
WaldmanATGormanMPRenselMRAustinTEHertzDPKuntzNL. Management of pediatric central nervous system demyelinating disorders: consensus of United States neurologists. J Child Neurol2011; 26: 675–682.
31.
GhezziABanwellBBoykoAAmatoMPAnlarBBlinkenbergM. The management of multiple sclerosis in children: a European view. Mult Scler2010; 16: 1258–1267.
32.
YehEAWaubantEKruppLBNessJChitnisTKuntzN. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurology2011; 68: 437–444.
33.
BykovaOVKuzenkovaLMMaslovaOI. [The use of beta-interferon-1b in children and adolescents with multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova2006; 106: 29–33.
34.
CallenDJShroffMMBransonHMLiDKLotzeTStephensD. Role of MRI in the differentiation of ADEM from MS in children. Neurology2009; 72: 968–973.
35.
CallenDJShroffMMBransonHMLotzeTLiDKStephensD. MRI in the diagnosis of pediatric multiple sclerosis. Neurology2009; 72: 961–967.
36.
WilejtoMShroffMBuncicJRKennedyJGoiaCBanwellB. The clinical features, MRI findings, and outcome of optic neuritis in children. Neurology2006; 67: 258–262.
37.
MikaeloffYAdamsbaumCHussonBValleeLPonsotGConfavreuxC. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain2004; 127: 1942–1947.
38.
CohenBAKhanOJefferyDRBashirKRizviSAFoxEJ. Identifying and treating patients with suboptimal responses. Neurology2004; 63(Suppl. 6): S33–S40.
39.
FreedmanMSCohenBDhib-JalbutSJefferyDRederATSandberg-WollheimM. Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command. Curr Med Res Opin2009; 25: 2459–2470.
40.
RioJNosCTintoreMBorrasCGalanIComabellaM. Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta: implications for clinical trials. Ann Neurol2002; 52: 400–406.
41.
GhezziAPozzilliCGrimaldiLMBrescia MorraVBortolonFCapraR. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology2010; 75: 912–917.
42.
YehEAWaubantEKruppLBNessJChitnisTKuntzN. Multiple sclerosis therapies in pediatric patients With refractory multiple sclerosis. Arch Neurol2011; 68: 437–444.
43.
PolmanCHBertolottoADeisenhammerFGiovannoniGHartungHPHemmerB. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol2010; 9: 740–750.
44.
BorrielloGProsperiniLLuchettiAPozzilliC. Natalizumab treatment in pediatric multiple sclerosis: a case report. Eur J Paediatr Neurol2009; 13: 67–71.
45.
HuppkePStarkWZurcherCHuppkeBBruckWGartnerJ. Natalizumab use in pediatric multiple sclerosis. Arch Neurol2008; 65: 1655–1658.
46.
MakhaniNGormanMPBransonHMStazzoneLBanwellBLChitnisT. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology2009; 72: 2076–2082.
47.
ChabasDCastillo-TrivinoTMowryEMStroberJBGlennOAWaubantE. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype?Neurology2008; 71: 1090–1093.
48.
ChabasDNessJBelmanAYehEAKuntzNGormanMP. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology2010; 74: 399–405.
49.
McLaughlinKAChitnisTNewcombeJFranzBKennedyJMcArdelS. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol2009; 183: 4067–4076.
50.
ChitnisTBar-OrA. Pediatric MS: Biological presentation and research up-date. In: ChabasDWaubantE (eds), Cambridge University Press. Pediatric Multiple Sclerosis2011.
51.
BanwellBBar-OrAGiovannoniGDaleRCTardieuM. Therapies for multiple sclerosis: considerations in the pediatric patient. Nature Rev Neurol2011; 7: 109–122.
52.
USFDA. Guidance for Industry: General Considerations for Pediatric Pharmacokinetic STudies for Drugs and Biological Products. Washington, DC: US Department of Health and Human Services FaDACfDEaRC, Center for Biologics Evaluation and Research (CBER)1998.
53.
KoukouritakiSBSimpsonPYeungCKRettieAEHinesRN. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr Res2002; 51: 236–243.
54.
LambertGHSchoellerDAKotakeANFloresCHayD. The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol Ther1986; 9: 375–388.
55.
ArantBSJr.Developmental patterns of renal functional maturation compared in the human neonate. J Pediatr1978; 92: 705–712.
56.
TaubDDLongoDL. Insights into thymic aging and regeneration. Immunological reviews. 2005; 205: 72–93.
57.
WekslerME. Changes in the B-cell repertoire with age. Vaccine2000; 18: 1624–1628.
58.
VallejoAN. Age-dependent alterations of the T cell repertoire and functional diversity of T cells of the aged. Immunol Res2006; 36: 221–228.
59.
GoronzyJJLeeWWWeyandCM. Aging and T-cell diversity. Exp Gerontol2007; 42: 400–406.
60.
GorczynskiRMKennedyMMacRaeS. Altered lymphocyte recognition repertoire during ageing. III. Changes in MHC restriction patterns in parental T lymphocytes and diminution in T suppressor function. Immunology1984; 52: 611–620.
61.
CossarizzaAOrtolaniCPaganelliRBarbieriDMontiDSansoniP. CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory. Mech Ageing Dev1996; 86: 173–195.
62.
FariaAMde MoraesSMde FreitasLHSpezialiESoaresTFFigueiredo-NevesSP. Variation rhythms of lymphocyte subsets during healthy aging. Neuroimmunomodulation2008; 15: 365–379.
63.
PolmanCHO’ConnorPWHavrdovaEHutchinsonMKapposLMillerDH. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Eng J Med2006; 354: 899–910.
64.
RudickRAStuartWHCalabresiPAConfavreuxCGalettaSLRadueEW. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Eng J Med2006; 354: 911–923.
65.
GorelikLLernerMBixlerSCrossmanMSchlainBSimonK. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol2010; 68: 295–303.
66.
KeanJMRaoSWangMGarceaRL. Seroepidemiology of human polyomaviruses. PLoS Path2009; 5: e1000363.
67.
KnowlesWAPipkinPAndrewsNVyseAMinorPBrownDW. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol2003; 71: 115–123.
68.
EllisRBoggildM. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?Mult Scler2009; 15: 505–508.
69.
MarriottJJMiyasakiJMGronsethGO’ConnorPW. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology2010; 74: 1463–1470.
70.
KornekBBernertGRostasyKMlczochEFeuchtMPrayerD. Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis. Neuropediatrics2011; 42: 7–12.
71.
HauserSLDawsonDMLehrichJRBealMFKevySVPropperRD. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Eng J Med1983; 308: 173–180.
72.
WeinerHLMackinGAOravEJHaflerDADawsonDMLaPierreY. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology1993; 43: 910–918.
73.
BacaVLavalleCGarciaRCatalanTSaucedaJMSanchezG. Favorable response to intravenous methylprednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J Rheumatol1999; 26: 432–439.
74.
Yildirim-TorunerCDiamondB. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol2011; 127: 303–312; quiz 13–14.
75.
AdamsAMacDermottEJLehmanTJ. Pharmacotherapy of lupus nephritis in children: a recommended treatment approach. Drugs2006; 66: 1191–1207.
76.
HauserSLWaubantEArnoldDLVollmerTAntelJFoxRJ. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Eng J Med2008; 358: 676–688.
77.
TzaribachevNKoetterIKuemmerle-DeschnerJBSchedelJ. Rituximab for the treatment of refractory pediatric autoimmune diseases: a case series. Cases J2009; 2: 6609.
78.
CarsonKRFocosiDMajorEOPetriniMRicheyEAWestDP. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol2009; 10: 816–824.
79.
RosenHAlfonsoCSurhCDMcHeyzer-WilliamsMG. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc Natl Acad Sci USA2003; 100: 10,907–10,912.
