Disability accrual in primary and secondary progressive multiple sclerosis
Sam Harding-Forrester 1, Izanne Roos 1 2, Ai-Lan Nguyen 1 2, Charles B Malpas 1 2, Ibrahima Diouf 1 2, Nahid Moradi 1 2, Sifat Sharmin 1 2, Guillermo Izquierdo 3, Sara Eichau 3, Francesco Patti 4, Dana Horakova 5, Eva Kubala Havrdova 5, Alexandre Prat 6 7, Marc Girard 6 8, Pierre Duquette 6 8, Francois Grand'Maison 9, Marco Onofrj 10, Alessandra Lugaresi 11 12, Pierre Grammond 13, Serkan Ozakbas 14, Maria Pia Amato 15 16, Oliver Gerlach 17, Patrizia Sola 18, Diana Ferraro 19 20, Katherine Buzzard 21, Olga Skibina 21, Jeannette Lechner-Scott 22 23, Raed Alroughani 24, Cavit Boz 25, Vincent Van Pesch 26, Elisabetta Cartechini 27, Murat Terzi 28, Davide Maimone 29, Cristina Ramo-Tello 30, Bassem Yamout 31 32, Samia Joseph Khoury 31 33, Daniele La Spitaleri 34, Maria Jose Sa 35 36, Yolanda Blanco 37, Franco Granella 38, Mark Slee 39, Ernest Butler 40, Youssef Sidhom 41, Riadh Gouider 42, Roberto Bergamaschi 43, Rana Karabudak 44, Radek Ampapa 45, José Luis Sánchez-Menoyo 46, Julie Prevost 47, Tamara Castillo-Trivino 48, Pamela A McCombe 49, Richard Macdonell 50, Guy Laureys 51, Liesbeth Van Hijfte 51, Jiwon Oh 52, Ayse Altintas 53 54, Koen de Gans 55, Recai Turkoglu 56, Anneke van der Walt 57, Helmut Butzkueven 58 59, Steve Vucic 60, Michael Barnett 61, Edgardo Cristiano 62, Suzanne Hodgkinson 63, Gerardo Iuliano 64, Ludwig Kappos 65 66, Jens Kuhle 65 66, Vahid Shaygannejad 67, Aysun Soysal 68, Bianca Weinstock-Guttman 69, Bart Van Wijmeersch 70 71, Tomas Kalincik 72 2; MSBase investigators
Affiliations
Affiliations
- 1CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
- 2Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
- 3Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena, Sevilla, Andalucía, Spain.
- 4Neuroscience, Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', University of Catania, Catania, Italy.
- 5Department of Neurology and Centre of Clinical Neuroscience, Charles University First Faculty of Medicine, Praha, Czech Republic.
- 6Centre Hospitalier, Université de Montréal, Montreal, Québec, Canada.
- 7Department of Neuroscience, Université de Montréal, Montreal, Québec, Canada.
- 8Faculté de Médecine, Université de Montréal, Montreal, Québec, Canada.
- 9Neuro Rive-Sud, Longueuil, Quebec, Canada.
- 10Department of Neurosciences, Imaging and Clinical Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy.
- 11UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
- 12Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
- 13Centre intégré de santé et de services sociaux de Chaudière-Appalaches du Québec Centre de Recherche, Levis, Québec, Canada.
- 14Department of Neurology, Dokuz Eylul University, İzmir, Turkey.
- 15Department of Neurological Siences, University of Florence, Florence, Italy.
- 16IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
- 17Department of Neurology, Zuyderland Medical Centre, Sittard-Geleen, The Netherlands.
- 18Neurology Unit, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy.
- 19Department of Neuroscience, Azienda Ospedaliero-Universitaria di Modena, Modena, Emilia-Romagna, Italy.
- 20Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
- 21Department of Neurology, Box Hill Hospital, Box Hill, Victoria, Australia.
- 22School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia.
- 23Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia.
- 24Department of Medicine, Al-Amiri Hospital, Kuwait City, Kuwait.
- 25Department of Neurology, Karadeniz Technical University, Trabzon, Turkey.
- 26Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- 27UOC Neurologia, Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy.
- 28Ondokuz Mayis Üniversitesi, Samsun, Turkey.
- 29UO Neurologia, Ospedale Garibaldi, Catania, Italy.
- 30Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
- 31Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
- 32Department of Neurology, American University of Beirut, Beirut, Lebanon.
- 33American University of Beirut, Beirut, Lebanon.
- 34UOC Neurologia e Stroke, AORN San Giuseppe Moscati, Avellino, Italy.
- 35Department of Neurology, Centro Hospitalar de São João, Porto, Portugal.
- 36Health Sciences Faculty, Fernando Pessoa University, Porto, Portugal.
- 37Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain.
- 38Multiple Sclerosis Centre, Neurosciences, University of Parma, Parma, Italy.
- 39Department of Neurology, Flinders Medical Centre, Adelaide, South Australia, Australia.
- 40Department of Neurology, Monash Medical Centre Clayton, Clayton, Victoria, Australia.
- 41Department of Neurology, Hopital Razi, La Manouba, Tunisia.
- 42Department of Neurology, Razi Hospital, Rasht, Gilan, Iran.
- 43Multiple Sclerosis Centre, Neurological Institute C.Mondino, Pavia, Italy.
- 44Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
- 45Department of Neurology, Nemocnice Jihlava, Jihlava, Czech Republic.
- 46Department of Neurology, Hospital Galdakao-Usansolo, Galdacano, País Vasco, Spain.
- 47Centre integre de sante et de services sociaux des Laurentides point de service de Saint-Jerome, Saint-Jerome, Quebec, Canada.
- 48Department of Neurology, Donostia University Hospital, San Sebastian, Spain.
- 49UQCCR, The University of Queensland, Saint Lucia, Queensland, Australia.
- 50Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
- 51Department of Neurology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium.
- 52Division of Neurology, Department of Medicine, St Michael's Hospital, Toronto, Ontario, Canada.
- 53Department of Neurology, Koc Universitesi, Istanbul, Turkey.
- 54Koç University Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.
- 55Department of Neurology, Groene Hart Ziekenhuis, Gouda, Zuid-Holland, The Netherlands.
- 56Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.
- 57Multiple Sclerosis and Neuroimmunology Unit, Monash University Central Clinical School, Melbourne, Victoria, Australia.
- 58Department of Neuroscience, Monash University Central Clinical School, Melbourne, Victoria, Australia.
- 59Department of Neurology, The Alfred, Melbourne, Victoria, Australia.
- 60Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.
- 61Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
- 62Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Buenos Aires, Federal District, Argentina.
- 63Department of Neurology, Liverpool Hospital, Liverpool, New South Wales, Australia.
- 64Ospedali Riuniti di Salerno, Salerno, Italy.
- 65Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, Basel, Switzerland.
- 66Research Centre for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, Basel, Switzerland.
- 67Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
- 68Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey.
- 69Department of Neurology, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.
- 70Universitair MS Centrum, Hasselt University, Hasselt-Pelt, Belgium.
- 71Rehabilitation & MS Centre, Pelt, Belgium.
- 72CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia tomas.kalincik@unimelb.edu.au.
Abstract
Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS.
Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS.
Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence.
Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
Keywords: multiple sclerosis.
Conflict of interest statement
Competing interests: IR served on scientific advisory boards for Novartis and Merck, and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi Genzyme, and Merck. A-LN received grants from MS Research Australia; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Sanofi Genzyme. 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. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and the University of Catania. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, and support for research activities from Biogen and the Czech Ministry of Education (project PROGRES Q27/LF1). EVH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and received research support from the Czech Ministry of Education (project PROGRES Q27/LF1). MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Sanofi Genzyme; lecture payments from Teva Canada Innovation, Novartis, and EMD; and research support from the Canadian Institutes of Health Research. PD served on editorial boards for, and has been supported to attend meetings by, EMD, Biogen, Novartis, Genzyme, and Teva Neuroscience; he holds grants from the Canadian Institutes of Health Research and the MS Society of Canada, and received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. FG’M received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. AL received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva; her institutions have received research grants from Novartis (in the past 4 years). PG served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, and Pendopharm; received grant support from Genzyme and Roche; and received research grants for his institution from Biogen Idec, Sanofi Genzyme, and EMD Serono. MPA received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Teva, and Sanofi-Aventis, and received research grants by Biogen, Bayer Schering, Merck, Teva, and Novartis. PS served on scientific advisory boards for Biogen Idec and Teva; received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; and received research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. DF received travel grants and/or speaker honoraria from Merck, Teva, Novartis, Biogen, and Sanofi Genzyme. KB received honoraria and consulting fees from Biogen, Teva, Novartis, Sanofi Genzyme, Roche, Merck, CSL, and Grifols. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck; her institution received honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, Teva, and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. VVP received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche; his institution received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. MT received travel grants from Novartis, Bayer Schering, Merck, and Teva, and participated in clinical trials by Sanofi-Aventis, Roche, and Novartis. DM received speaker honoraria for advisory board service and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. CR-T received research funding, compensation for travel, or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. DLS received honoraria as a consultant on scientific advisory boards from Bayer Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi-Aventis, Teva, and Merck. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme, and Roche; and received funding for travel and speaker honoraria from Biogen, Merck, and Sanofi-Aventis. MS participated in, but did not receive honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi-Aventis, and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; and congress, travel, and accommodation expense compensations from Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva. RA received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck, and participated in clinical trials by Biogen, Novartis, Teva, and Actelion. JLS-M received travel compensation from Novartis and Biogen; received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in a clinical trial by Biogen. JP received travel compensation from Novartis, Biogen, Genzyme, and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. TC-T received speaking or consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. GL received travel and/or consultancy compensation from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, and Biogen. JO received research funding from the MS Society of Canada, the National MS Society, Brain Canada, Biogen Idec, Roche, and EMD Serono, and personal compensation for consulting or speaking from EMD Serono, Sanofi Genzyme, Biogen Idec, Roche, Celgene, and Novartis. 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. HB received compensation for consulting, talks, and advisory or steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health, and Oxford Health Policy Forum, and research support from Novartis, Biogen, Roche, Merck, the National Health and Medical Research Council of Australia, Pennycook Foundation, and MS Research Australia MB served on scientific advisory boards for Biogen, Novartis, and Genzyme, received conference travel support from Biogen and Novartis, and serves on steering committees for trials conducted by Novartis; his institution received research support from Biogen, Merck, and Novartis. EC Cristiano received honoraria as a consultant on scientific advisory boards for Biogen, Bayer Schering, Merck, Genzyme, and Novartis, and participated in clinical trials or other research projects by Merck, Roche, and Novartis. SH received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. GI received compensation for travel, accommodations, and meeting expenses from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, the Swiss MS Society, the Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. BW-G participated in speakers' bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon; received grant/research support from these same agencies; and serves on editorial boards for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. BVW received research and travel grants and honoraria for advisory and speaking fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. TK served on scientific advisory boards for BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for the 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 support for research or educational events from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.
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