BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Centro Per La Diagnosi E Cura Della SM E Delle Malattie Demielinizzanti Dipt Radiologia Diagnostica Interventistica e Stroke AOUP P Giaccone di Palermo Palermo Italy

Centro Per Lo Studio E La Cura Della Sclerosi Multipla E Malattie Demielinizzanti Dipartimento Di Neuroscienze Riabilitazione Oftalmologia Genetica E Scienze Materno Infantili Clinica Neurologica Ospedale Policlinico San Martino Genova Italia

Centro Sclerosi Multipla ASST Della Valle Olona Ospedale Di Gallarate Gallarate VA Italy

Centro SM Dipartimento di Scienze Mediche di Base Neuroscienze ed Organi di Senso Universita' di Bari Bari Italy

CORe Department of Medicine University of Melbourne Melbourne VIC Australia

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy

Department of NEUROFARBA University of Florence Florence Italy

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Neurology Hospital Universitario Virgen Macarena Sevilla Spain

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Izmir University of Economics Medical Point Hospital Izmir Turkey

Multiple Sclerosis Centre AOU Policlinico G Rodolico San Marco University of Catania Catania Italy

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne VIC Australia

Neurology Unit and MS Center Neurorehabilitation Unit Neurophysiology Service and Neuroimaging Research Unit Division of Neuroscience IRCCS Ospedale San Raffaele Milan Italy

Pediatric MS Center Department of Precision and Regenerative Medicine and Ionian Area University of Bari Aldo Moro Bari Italy

SCDO Neurologia Centro Di Riferimento Regionale Sclerosi Multipla AOU San Luigi Turin Italy

School of Medicine University of Bari Aldo Moro Bari Italy

Unità Operativa Semplice Dipartimentale Sclerosi Multipla AOU Policlinico Federico 2 Naples Italy

Vita Salute San Raffaele University Milan Italy

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