Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries.

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.
Competing Interests: Declaration of interests SS has received research support from the MSBase Foundation and MS Australia. IR served on scientific advisory boards and received conference travel support or speaker honoraria from Roche, Novartis, Merck, and Biogen. CBM has received conference travel support from Merck, Novartis, and Biogen, and research support from the National Health and Medical Research Council Australia, MS Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. PI has served on scientific advisory boards for Biogen Idec, Bayer, Bristol Myers Squibb (BMS), Teva, Roche, Merck Serono, Novartis, and Genzyme, and has received funding for travel or speaker honoraria from Sanofi Aventis, Genzyme, Roche, Biogen Idec, Teva, Merck Serono, Alexion, BMS, and Novartis. MF received compensation for consulting services or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). EKH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education (project Cooperatio LF1) and the National Institute for Neurological Research of the Czech Republic (programme EXCELES, project number LX22NPO5107) funded by the Next Generation EU. VBM received compensation for public speaking or consultancy from Merck, Novartis, Biogen, Genzyme, Teva, and Alrmirall. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. MZ received travel support and fees for lecturing or participating in advisory boards from Almirall, Biogen, Merck, Novartis, and Sanofi-Genzyme. FP received personal compensation for serving on advisory boards by Almirall, Alexion, Biogen, BMS, Janssen, Merck, Novartis, and Roche, and research grants from Alexion, Almirall, Biogen, BMS, Merck, Novartis, Roche, Fondazione Italiana Sclerosi Multipla, Reload Association (Onlus), Italian Health Minister, and University of Catania. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. GS received grants and honoraria from Roche, Sanofi, Merck, Biogen, and Novartis. ADS received speaker honoraria and consultant fees from Biogen, Novartis, Merck, Roche, Alexion, and Sanofi. EP received compensation for travel grants, participation in advisory boards, or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis, and serves on the editorial boards of Frontiers in Neurology and Brain Sciences. MT has served on scientific advisory boards for Biogen, Novartis, Roche, Merck, and Genzyme; received speaker honoraria from Biogen, Roche, Sanofi, Merck, Genzyme, and Novartis; and received research grants for her institution from Biogen, Merck, and Novartis. MPA served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, Novartis, Roche, BMS Celgene, and Sanofi Aventis, and is Editor of Multiple Sclerosis Journal. TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL, and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. All other authors declare no competing interests.
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