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Multiple sclerosis
Original research
Disability accrual in primary and secondary progressive multiple sclerosis
  1. Sam Harding-Forrester1,
  2. Izanne Roos1,2,
  3. Ai-Lan Nguyen1,2,
  4. Charles B Malpas1,2,
  5. Ibrahima Diouf1,2,
  6. Nahid Moradi1,2,
  7. Sifat Sharmin1,2,
  8. Guillermo Izquierdo3,
  9. Sara Eichau3,
  10. Francesco Patti4,
  11. Dana Horakova5,
  12. Eva Kubala Havrdova5,
  13. Alexandre Prat6,7,
  14. Marc Girard6,8,
  15. Pierre Duquette6,8,
  16. Francois Grand'Maison9,
  17. Marco Onofrj10,
  18. Alessandra Lugaresi11,12,
  19. Pierre Grammond13,
  20. Serkan Ozakbas,14,
  21. Maria Pia Amato15,16,
  22. Oliver Gerlach17,
  23. Patrizia Sola18,
  24. Diana Ferraro19,20,
  25. Katherine Buzzard21,
  26. Olga Skibina21,
  27. Jeannette Lechner-Scott22,23,
  28. Raed Alroughani24,
  29. Cavit Boz25,
  30. Vincent Van Pesch26,
  31. Elisabetta Cartechini27,
  32. Murat Terzi28,
  33. Davide Maimone29,
  34. Cristina Ramo-Tello30,
  35. Bassem Yamout31,32,
  36. Samia Joseph Khoury31,33,
  37. Daniele La Spitaleri34,
  38. Maria Jose Sa35,36,
  39. Yolanda Blanco37,
  40. Franco Granella38,
  41. Mark Slee39,
  42. Ernest Butler40,
  43. Youssef Sidhom41,
  44. Riadh Gouider42,
  45. Roberto Bergamaschi43,
  46. Rana Karabudak44,
  47. Radek Ampapa45,
  48. José Luis Sánchez-Menoyo46,
  49. Julie Prevost47,
  50. Tamara Castillo-Trivino48,
  51. Pamela A McCombe49,
  52. Richard Macdonell50,
  53. Guy Laureys51,
  54. Liesbeth Van Hijfte51,
  55. Jiwon Oh52,
  56. Ayse Altintas53,54,
  57. Koen de Gans55,
  58. Recai Turkoglu56,
  59. Anneke van der Walt57,
  60. Helmut Butzkueven58,59,
  61. Steve Vucic60,
  62. Michael Barnett61,
  63. Edgardo Cristiano62,
  64. Suzanne Hodgkinson63,
  65. Gerardo Iuliano64,
  66. Ludwig Kappos65,66,
  67. Jens Kuhle65,66,
  68. Vahid Shaygannejad67,
  69. Aysun Soysal68,
  70. Bianca Weinstock-Guttman69,
  71. Bart Van Wijmeersch70,71,
  72. Tomas Kalincik1,2
  73. on behalf of the MSBase investigators
  1. 1 CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
  2. 2 Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  3. 3 Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena, Sevilla, Andalucía, Spain
  4. 4 Neuroscience, Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', University of Catania, Catania, Italy
  5. 5 Department of Neurology and Centre of Clinical Neuroscience, Charles University First Faculty of Medicine, Praha, Czech Republic
  6. 6 Centre Hospitalier, Université de Montréal, Montreal, Québec, Canada
  7. 7 Department of Neuroscience, Université de Montréal, Montreal, Québec, Canada
  8. 8 Faculté de Médecine, Université de Montréal, Montreal, Québec, Canada
  9. 9 Neuro Rive-Sud, Longueuil, Quebec, Canada
  10. 10 Department of Neurosciences, Imaging and Clinical Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
  11. 11 UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
  12. 12 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
  13. 13 Centre intégré de santé et de services sociaux de Chaudière-Appalaches du Québec Centre de Recherche, Levis, Québec, Canada
  14. 14 Department of Neurology, Dokuz Eylul University, İzmir, Turkey
  15. 15 Department of Neurological Siences, University of Florence, Florence, Italy
  16. 16 IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
  17. 17 Department of Neurology, Zuyderland Medical Centre, Sittard-Geleen, The Netherlands
  18. 18 Neurology Unit, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
  19. 19 Department of Neuroscience, Azienda Ospedaliero-Universitaria di Modena, Modena, Emilia-Romagna, Italy
  20. 20 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
  21. 21 Department of Neurology, Box Hill Hospital, Box Hill, Victoria, Australia
  22. 22 School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
  23. 23 Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia
  24. 24 Department of Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
  25. 25 Department of Neurology, Karadeniz Technical University, Trabzon, Turkey
  26. 26 Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  27. 27 UOC Neurologia, Azienda Sanitaria Unica Regionale Marche—AV3, Macerata, Italy
  28. 28 Ondokuz Mayis Üniversitesi, Samsun, Turkey
  29. 29 UO Neurologia, Ospedale Garibaldi, Catania, Italy
  30. 30 Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
  31. 31 Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  32. 32 Department of Neurology, American University of Beirut, Beirut, Lebanon
  33. 33 American University of Beirut, Beirut, Lebanon
  34. 34 UOC Neurologia e Stroke, AORN San Giuseppe Moscati, Avellino, Italy
  35. 35 Department of Neurology, Centro Hospitalar de São João, Porto, Portugal
  36. 36 Health Sciences Faculty, Fernando Pessoa University, Porto, Portugal
  37. 37 Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
  38. 38 Multiple Sclerosis Centre, Neurosciences, University of Parma, Parma, Italy
  39. 39 Department of Neurology, Flinders Medical Centre, Adelaide, South Australia, Australia
  40. 40 Department of Neurology, Monash Medical Centre Clayton, Clayton, Victoria, Australia
  41. 41 Department of Neurology, Hopital Razi, La Manouba, Tunisia
  42. 42 Department of Neurology, Razi Hospital, Rasht, Gilan, Iran
  43. 43 Multiple Sclerosis Centre, Neurological Institute C.Mondino, Pavia, Italy
  44. 44 Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey
  45. 45 Department of Neurology, Nemocnice Jihlava, Jihlava, Czech Republic
  46. 46 Department of Neurology, Hospital Galdakao-Usansolo, Galdacano, País Vasco, Spain
  47. 47 Centre integre de sante et de services sociaux des Laurentides point de service de Saint-Jerome, Saint-Jerome, Quebec, Canada
  48. 48 Department of Neurology, Donostia University Hospital, San Sebastian, Spain
  49. 49 UQCCR, The University of Queensland, Saint Lucia, Queensland, Australia
  50. 50 Department of Neurology, Austin Health, Heidelberg, Victoria, Australia
  51. 51 Department of Neurology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium
  52. 52 Division of Neurology, Department of Medicine, St Michael's Hospital, Toronto, Ontario, Canada
  53. 53 Department of Neurology, Koc Universitesi, Istanbul, Turkey
  54. 54 Koç University Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey
  55. 55 Department of Neurology, Groene Hart Ziekenhuis, Gouda, Zuid-Holland, The Netherlands
  56. 56 Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
  57. 57 Multiple Sclerosis and Neuroimmunology Unit, Monash University Central Clinical School, Melbourne, Victoria, Australia
  58. 58 Department of Neuroscience, Monash University Central Clinical School, Melbourne, Victoria, Australia
  59. 59 Department of Neurology, The Alfred, Melbourne, Victoria, Australia
  60. 60 Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia
  61. 61 Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
  62. 62 Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Buenos Aires, Federal District, Argentina
  63. 63 Department of Neurology, Liverpool Hospital, Liverpool, New South Wales, Australia
  64. 64 Ospedali Riuniti di Salerno, Salerno, Italy
  65. 65 Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, Basel, Switzerland
  66. 66 Research Centre for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, Basel, Switzerland
  67. 67 Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran
  68. 68 Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
  69. 69 Department of Neurology, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA
  70. 70 Universitair MS Centrum, Hasselt University, Hasselt-Pelt, Belgium
  71. 71 Rehabilitation & MS Centre, Pelt, Belgium
  1. Correspondence to Professor Tomas Kalincik, CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia; tomas.kalincik{at}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.

  • multiple sclerosis

Data availability statement

Data are available upon reasonable request. MSBase is a data processor and warehouses data from individual principal investigators who agree to share their datasets on a project-by-project basis. Data access to external parties can be granted at the sole discretion of each MSBase Principal Investigator (the data controllers), who will need to be approached individually for permission.

https://doi.org/10.1136/jnnp-2022-330726

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    Data availability statement

    Data are available upon reasonable request. MSBase is a data processor and warehouses data from individual principal investigators who agree to share their datasets on a project-by-project basis. Data access to external parties can be granted at the sole discretion of each MSBase Principal Investigator (the data controllers), who will need to be approached individually for permission.

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    Footnotes

    • Contributors Concept and design: SH-F, TK. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: SH-F. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: SH-F, TK. Obtained funding: TK. Administrative, technical or material support: TK. Supervision: TK. SH-F and TK had full access to all of the data in the study, and take responsibility for the overall content of the study as guarantors.

    • Funding This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766). The MSBase Foundation is a not-for-profit organisation that has received support from Biogen, CSL, Merck, Novartis, Roche, Sanofi and Teva; this study was conducted independently of the sponsors.

    • 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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