Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry
Sifat Sharmin 1, Charles B Malpas 1 2, Izanne Roos 1 2, Ibrahima Diouf 1, Raed Alroughani 3, Serkan Ozakbas 4, Guillermo Izquierdo 5, Sara Eichau 5, Dana Horakova 6, Eva K Havrdova 6, Francesco Patti 7, Murat Terzi 8, Cavit Boz 9, Bassem Yamout 10 11, Samia J Khoury 10, Marco Onofrj 12, Alessandra Lugaresi 13 14, Ayse Altintas 15, Alexandre Prat 16, Marc Girard 16, Pierre Duquette 16, Maria José Sá 17, Daniele La Spitaleri 18, Youssef Sidhom 19, Riadh Gouider 19, Saloua Mrabet 20, Aysun Soysal 21, Recai Turkoglu 22, Maria Pia Amato 23, Yara D Fragoso 24, Tomas Kalincik 25 2
Affiliations
Affiliations
- CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
- Neuroimmunology, Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
- Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait.
- Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey.
- Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain.
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
- Department of Medical and Surgical Sciences and Advanced Technologies, Multiple Sclerosis Center, University of Catania, Catania, Italy.
- Medical Faculty, 19 Mayis University, Samsun, Turkey.
- Department of Neurology, Karadeniz Technical University, Trabzon, Turkey.
- Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
- Neurology Department, American University of Beirut, Beirut, Lebanon.
- Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
- UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
- Department of Neurology, School of Medicine, Koc University, Istanbul, Turkey.
- CHUM MS Center and Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada.
- Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto, Portugal.
- Department of Neurology, AORN San Giuseppe Moscati, Avellino, Italy.
- Department of Neurology, Razi Hospital, Manouba, Tunisia.
- Clinical Investigation Center Neurosciences and Mental Health, Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia.
- Department of Neurology, Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
- Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.
- Department NEUROFARBA, University of Florence, Florence, Italy.
- Department of Neurology, Universidade Metropolitana de Santos, Santos, Brazil.
- CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia tomas.kalincik@unimelb.edu.au.
Abstract
Background: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time.
Objective: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS.
Methods: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data.
Results: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(β)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)).
Conclusions: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.
Keywords: multiple sclerosis; neuroepidemiology; neuroimmunology; paediatric neurology.
Conflict of interest statement
Competing interests: SS has nothing to disclose. CM has nothing to disclose. IR served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. ID has nothing to disclose. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. SO has nothing to disclose. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education (project Progres Q27/LF1). EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, MS, Novartis and SG; and has been supported by the Czech Ministry of Education research project PROGRES Q27/LF1. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by SA, Roche and Novartis. BY has nothing to disclose. SJK received personal compensation for participation in the Roche MaeStro Exchange Program and in Merck-Serono medical advisory board. MO has nothing to disclose. AL has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Bristol Myers Squibb, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme and Teva. Her institutions have received research grants from Novartis (last 4 years). AA received personal fees and speaker honoraria from Teva, Merck, Biogen - Gen Pharma, Roche, Novartis, Bayer and Sanofi-Genzyme; and received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme and Bayer. AP has nothing to disclose. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme. MJS has nothing to disclose. DS received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. YS has nothing to disclose. RG has nothing to disclose. AS has nothing to disclose. RT has nothing to disclose. MPA received honoraria as a consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. YF has nothing to disclose. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck.
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