Objectives To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients.
Methods Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8–5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years.
Results At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing–remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (β)=0.97), higher EDSS (β=0.41), higher cord lesion number (β=0.41), lower normalised cortical volume (β=−0.15) and lower cord area (β=−0.28) (C-index=0.81). Older age (β=0.86), higher EDSS (β=1.40) and cord lesion number (β=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (β=1.49), cord lesion number (β=1.02) and lower normalised cortical volume (β=−0.56) (C-index=0.88). Baseline age (β=0.30), higher EDSS (β=2.03), higher cord lesion number (β=0.66) and lower cord area (β=−0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (β=1.87) and cord lesion number (β=0.54) predicted EDSS=6.0 (C-index=0.91).
Conclusions Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.
- MULTIPLE SCLEROSIS
Data availability statement
Data are available upon reasonable request. The data set used and analysed during the current study are available from the corresponding author on reasonable request.
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Collaborators The MAGNIMS Study Group (https://www.magnims.eu) is a group of European clinicians and scientists with an interest in undertaking collaborative studies using MRI methods in multiple sclerosis, independent of any other organization and is run by a Steering Committee whose members are F. Barkhof (Amsterdam, London), O. Ciccarelli (London), N. de Stefano (Siena), C. Enzinger (Graz, Co-Chair), M. Filippi (Milan), C. Gasperini (Rome), L. Kappos (Basel), J. Palace (Oxford), M.A. Rocca (Milan, Co-Chair), À. Rovira (Barcelona), J. Sastre-Garriga (Barcelona), H. Vrenken (Amsterdam), and T. Yousry (London). The members of the MAGNIMS Study Group Steering Committee have reviewed, revised and approved the submitted paper. Steering Committee members: Frederik Barkhof, MD, PhD (Amsterdam UMC, Amsterdam, the Netherlands AND University College London, London, UK; Author, Collaborator (Steering Committee member)); Olga Ciccarelli, MD, PhD (University College London, UK; Author, Collaborator (Steering Committee member)); Nicola de Stefano, MD, PhD (University of Siena, Italy; Collaborator (Steering Committee member)); Christian Enzinger, MD, PhD (Medical University Graz, Austria; Collaborator (Steering Committee member)); Massimo Filippi, MD, PhD (San Raffaele, Milan, Italy; Author, Steering Committee member / Co-investigator); Claudio Gasperini, MD, PhD (San Camillo-Forlanini Hospital, Rome, Italy; Collaborator (Steering Committee member)); Ludwig Kappos, MD, PhD (University Hospital, Basel, Switzerland; Collaborator (Steering Committee member)); Jacqueline Palace, MD, PhD (University of Oxford, UK; Author, Steering Committee member / Co-investigator); Maria A. Rocca, MD (Co-Chair) (San Raffaele, Milan, Italy; Author, Collaborator (Steering Committee member)); Àlex Rovira, MD, PhD (Vall d’Hebron Hospital, Barcelona, Spain; Authors, Collaborator (Steering Committee member)); Jaume Sastre-Garriga, MD (Co-Chair) (Vall d’Hebron Hospital, Barcelona, Spain; Author, Collaborator (Steering Committee member)); Hugo Vrenken, PhD (Amsterdam UMC, Amsterdam, the Netherlands; Author, Collaborator (Steering Committee member)); Tarek Yousry, MD, PhD (University College London, UK; Collaborator (Steering Committee member)).
Contributors Concept and design: MF and MAR. Acquisition, analysis or interpretation of data: MAR, PV, AM, CG, CZ, FB, MMS, EMS, HV, AGal, AB, OC, MY, AR, JS-G, JP, LM, AGas, PE, CL, BB, MM, PP and MF. Drafting of the manuscript: MAR, PV, AM, MM, PP and MF. Critical revision of the manuscript for important intellectual content: CG, CZ, FB, MMS, EMS, HV, AGal, AB, OC, MY, AR, JS-G, JP, LM, AGas, PE, CL and BB. Statistical analysis: AM. Guarantor: MF. Authors are members of the MAGNIMS network (Magnetic Resonance Imaging in multiple sclerosis; https://www.magnims.eu/), which is a group of European clinicians and scientists with an interest in undertaking collaborative studies using MRI methods in multiple sclerosis, independent of any other organisation and is run by a steering committee whose members are: MAR (Milan, Co-Chair), JS-G (Barcelona, Co-Chair), FB (Amsterdam), OC (London), Nicola De Stefano (Siena; collaborator), Christian Enzinger (Graz; collaborator), MF (Milan), Claudio Gasperini (Rome; collaborator), Ludwig Kappos (Basel; collaborator), JP (Oxford), ÀR (Barcelona), HV (Amsterdam) and Tarek Yousry (London; collaborator).
Funding Part of this work was supported by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no. 01GI1601I and grant no. 01GI0914.
Competing interests MAR received speakers’ honoraria from Bayer, Biogen Idec, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. PV received speakers’ honoraria from Biogen Idec. AM received speakers’ honoraria from Biogen Idec. Ente Ospedaliero Cantonale (EOC, employer) received compensation for CG’s speaking activities, consulting fees or research grants from AbbVie, Almirall, Biogen Idec, Bristol Myers Squibb, Genzyme, Lundbeck, Merck, Novartis, Teva Pharma, Roche. EOC received compensation for CZ’s speaking activities, consulting fees or research grants from AbbVie, Almirall, Biogen Idec, Bristol Myers Squibb, Genzyme, Lundbeck, Merck, Novartis, Teva Pharma, Roche. CZ holds a grant from EOC for senior researchers. FB serves as an Editorial Board member of Neuroradiology, Neurology, Multiple Sclerosis Journal and Radiology; he has serves as steering committee or IDMC member for Biogen, Merck, Prothena, EISAI accepted consulting fees from Biogen-IDEC, IXICO Ltd, Jansen Merck Serono, Novartis, and Roche. He has received grants from the Amyloid Imaging to Prevent Alzheimer’s Disease Initiative (Innovative Medicines Initiative), the European Progression of Neurological Disease Initiative (H2020), UK MS Society, Dutch MS Society, NIHR University College London Hospital Biomedical Research Centre, the European Committee for Treatment and Research in Multiple Sclerosis and the MRI in MS network. MMS serves on the Editorial Boards of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, ARSEP, Amsterdam Neuroscience and ZonMW and has received compensation for consulting services or speaker honoraria from Atara Biotherapeutics, Biogen, Celgene/Bristol Myers Squibb, Sanofi-Genzyme, MedDay and Merck. EMS has nothing to disclose. HV has received research grants from Merck Serono, Novartis and Teva, speaker honoraria from Novartis, and consulting fees from Merck Serono; all funds paid directly to his institution. AG received speaker and consulting fees from Biogen, Bristol Myers Squibb, Coloplast, Merck Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. AB received speaker’s honoraria and/or compensation for consulting service and/or speaking activities from Biogen, Roche, Merck, Celgene, Coloplast and Genzyme. OC is NIHR Research Professor (RP-2017-08-ST2-004). She also receives funding from MRC, UK and National MS Society and, NIHR and Rosetrees Trust. MY has nothing to disclose. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, SyntheticMR and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries, Novartis, Roche, BMS and Biogen Idec. JS-G declares grants and personal fees from Genzyme, Almirall, Biogen, Celgene, Merck, Bayer, Biopass, Bial, Novartis, Roche and Teva, outside the submitted work; JS-G is Associate Editor of Multiple Sclerosis Journal and Scientific Director of Revista de Neurologia. JP has received support for scientific meetings and honoraria for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, Sanofi. Grants from Alexion, Roche, Medimmune, Amplo biotechnology and UCB. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZeneca. Acknowledges Partial funding by Highly specialised services NHS England. LM was funded by an MRC fellowship (G0901996). AG has received honoraria for lecturing, travel expenses for attending meetings and financial support for research from Novartis, Biogen, Merck Serono, Sanofi-Genzyme, Roche. PE has received travel expenses from Bayer Health Care and is member of the Editorial Board of the Journal of Neuroimaging. CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I, has received consulting and speaker’s honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. BB received financial support by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I. MM reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almirall. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. PP received speakers’ honoraria from Biogen Idec, Novartis, Bristol, Myers Squibb, Genzyme and Excemed and was supported by a senior research fellowship FISM—Fondazione Italiana Sclerosi Multipla—cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding. MF is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences and Radiology; received compensation for consulting services and/or speaking activities from Almirall, Alexion, Bayer, Biogen Idec, Celgene, Eli Lilly, Genzyme, Merck-Serono, Neopharmed Gentili, 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).
Provenance and peer review Not commissioned; externally peer reviewed.
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