TY - JOUR
T1 - Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis
T2 - a longitudinal analysis of global and national registries
AU - Writing Group
AU - Italian Multiple Sclerosis and Related Disorders Register and MSBase Study Group
AU - Sharmin, Sifat
AU - Roos, Izanne
AU - Malpas, Charles B.
AU - Iaffaldano, Pietro
AU - Simone, Marta
AU - Filippi, Massimo
AU - Kubala Havrdova, Eva
AU - Ozakbas, Serkan
AU - Brescia Morra, Vincenzo
AU - Alroughani, Raed
AU - Zaffaroni, Mauro
AU - Patti, Francesco
AU - Eichau, Sara
AU - Salemi, Giuseppe
AU - Di Sapio, Alessia
AU - Inglese, Matilde
AU - Portaccio, Emilio
AU - Trojano, Maria
AU - Amato, Maria Pia
AU - Kalincik, Tomas
AU - Horakova, Dana
AU - Prat, Alexandre
AU - Girard, Marc
AU - Duquette, Pierre
AU - Boz, Cavit
AU - Pozzilli, Carlo
AU - Cocco, Eleonora
AU - Gallo, Paolo
AU - Yamout, Bassem
AU - Khoury, Samia J.
AU - Lugaresi, Alessandra
AU - Onofrj, Marco
AU - Lus, Giacomo
AU - Clerici, Valentina Torri
AU - Maniscalco, Giorgia Teresa
AU - Romano, Silvia
AU - Tortorella, Carla
AU - Valentino, Paola
AU - Rovaris, Marco
AU - Shaygannejad, Vahid
AU - Ferraro, Diana
AU - Vianello, Marika
AU - Grammond, Pierre
AU - Bergamaschi, Roberto
AU - Gallo, Antonio
AU - Cavalla, Paola
AU - Sa, Maria Jose
AU - Lechner-Scott, Jeannette
AU - Pesci, Ilaria
AU - Buzzard, Katherine
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85189874919&partnerID=8YFLogxK
U2 - 10.1016/S2352-4642(24)00047-6
DO - 10.1016/S2352-4642(24)00047-6
M3 - Article
C2 - 38547883
AN - SCOPUS:85189874919
SN - 2352-4642
VL - 8
SP - 348
EP - 357
JO - The Lancet Child and Adolescent Health
JF - The Lancet Child and Adolescent Health
IS - 5
ER -