Article Text

Download PDFPDF
Original research
Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network
  1. Alessio Signori1,
  2. Johannes Lorscheider2,
  3. Sandra Vukusic3,
  4. Maria Trojano4,
  5. Pietro Iaffaldano4,
  6. Jan Hillert5,
  7. Robert Hyde6,
  8. Fabio Pellegrini6,
  9. Melinda Magyari7,
  10. Nils Koch-Henriksen8,
  11. Per Soelberg Sørensen7,
  12. Tim Spelman5,9,
  13. Anneke van der Walt10,
  14. Dana Horakova11,
  15. Eva Havrdova11,
  16. Marc Girard12,
  17. Sara Eichau13,
  18. Francois Grand'Maison14,
  19. Oliver Gerlach15,16,
  20. Murat Terzi17,
  21. Serkan Ozakbas18,
  22. Olga Skibina19,20,
  23. Vincent Van Pesch21,
  24. Maria Jose Sa22,23,
  25. Julie Prevost24,
  26. Raed Alroughani25,
  27. Pamela A McCombe26,
  28. Riadh Gouider27,
  29. Saloua Mrabet28,29,
  30. Tamara Castillo-Trivino30,
  31. Chao Zhu31,
  32. Koen de Gans32,
  33. José Luis Sánchez-Menoyo33,
  34. Bassem Yamout34,
  35. Samia Khoury34,
  36. Maria Pia Sormani1,
  37. Tomas Kalincik35,36,
  38. Helmut Butzkueven31,37
  39. on behalf of the Big MS Data Network
  1. 1 Department of Health Sciences, University of Genoa, Genoa, Italy
  2. 2 Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
  3. 3 Service de Neurologie A, Hopital Neurologique, Hospices Civils de Lyon, Lyon Bron, France
  4. 4 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy
  5. 5 Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
  6. 6 Biogen International, Zurich, Switzerland
  7. 7 Department of Neurology, Danish Multiple Sclerosis Center, Rigshospitalet, Copenhagen, Denmark
  8. 8 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
  9. 9 Department of Neurology, Box Hill Hospital, Melbourne, Victoria, Australia
  10. 10 Monash University Central Clinical School, Melbourne, Victoria, Australia
  11. 11 Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
  12. 12 CHUM and Universite de Montreal, Montreal, Quebec, Canada
  13. 13 Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain
  14. 14 Neuro Rive-Sud, Quebec, Quebec, Canada
  15. 15 Department of Neurology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
  16. 16 School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
  17. 17 Ondokuz Mayis Üniversitesi, Samsun, Turkey
  18. 18 Dokuz Eylul University, İzmir, Turkey
  19. 19 Neurology, Box Hill Hospital, Melbourne, Victoria, Australia
  20. 20 Department of Neuroscience, Monash University Central Clinical School, Melbourne, Victoria, Australia
  21. 21 Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  22. 22 Neurology, Centro Hospitalar de São João, Porto, Portugal
  23. 23 Faculty of Health Sciences, University Fernando Pessoa, Porto, Portugal
  24. 24 Centre integre de sante et de services sociaux des Laurentides point de service de Saint-Jerome, Saint-Jerome, Quebec, Canada
  25. 25 Amiri Hospital, Kuwait City, Kuwait
  26. 26 UQCCR, The University of Queensland, Brisbane, Queensland, Australia
  27. 27 Department of Neurology, Razi Hospital, Manouba, Tunisia
  28. 28 Department of Neurology, Razi University Hospital, Manouba, Tunisia
  29. 29 Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
  30. 30 Neurology, Donostia University Hospital, San Sebastian, Spain
  31. 31 Neuroscience, Centre Clinical School, Monash University, Victoria, Australia
  32. 32 Groene Hart Ziekenhuis, Gouda, The Netherlands
  33. 33 Neurology, Galdakao Hospital, Vizcaya, Spain
  34. 34 Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  35. 35 CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  36. 36 Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  37. 37 Managing Director, MSBase Foundation, Melbourne, Victoria, Australia
  1. Correspondence to Dr Alessio Signori, Department of Health Sciences, University of Genoa, 16132 Genoa, Italy; alessio.signori{at}


Background Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time.

Methods All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3–4.

Results A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria.

Conclusions Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.


Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are from different international registries. Each registry responsible should give their own permission to share collected data.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are from different international registries. Each registry responsible should give their own permission to share collected data.

View Full Text


  • Twitter @saloua_mrabet

  • AS and JL contributed equally.

  • TK and HB contributed equally.

  • Contributors Guarantor - AS. Conceptualisation—AS, JL, MPS, TK, HB. Data analysis—AS, MPS, TK, HB. Funding acquisition—HB. Resources—SV, MT, PI, JH, RH, FP, MM, NK-H, PSS, TS, AvdW, DH, EH, MG, SE, FG, OG, MT, SO, OS, VVP, MJS, JP, RA, PAM, RG, SM, TC-T, CZ, KdG, JLS-M, BY, SK. Writing—AS, AvdW, TK, HB.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AS received research support from MSBase. JL received research support from Innosuisse—Swiss Innovation Agency, Biogen and Novartis; he served on advisory boards for Biogen, Novartis, Roche and Teva. SV received consulting and lecture fees, travel grants and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono and Novartis. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis; and speaker’s fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as PI for projects or received unrestricted research support from Biogen Idec, Merck Serono, TEVA, Sanofi-Genzyme and Bayer-Schering; his MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. RH is an employee of Biogen and holds a stock. FP is an employee of Biogen. MM has served on scientific advisory board for Biogen Idec and Teva; and has received honoraria for lecturing from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva. NK-H has received honoraria for lecturing and participating in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish Multiple Sclerosis Treatment Register from Bayer-Schering, Merck Serono, Biogen Idec, Teva, Sanofi-Aventis and Novartis. PSS has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi-Aventis and Biogen Idec; has received research support from Biogen Idec, Novartis and Sanofi-Aventis; and received speaker honoraria from Merck Serono, Novartis, Teva, Sanofi-Aventis, Biogen Idec and Genzyme. TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. AvdW reported receiving grants from National Health and Medical Research Council (NHMRC), Novartis, Roche and MS Research Australia; and personal fees from Biogen, Merck, Novartis and Roche. DH received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck Healthcare (Darmstadt, Germany), Bayer, Sanofi, Roche and Teva, as well as support for research activities from Biogen. She was also supported by the Charles University: Cooperation Program in neuroscience. EH received honoraria/research support from Biogen, Merck Serono, Novars, Roche and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars and Sanofi Genzyme. 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. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. OG has nothing to disclose. MT received travel grants from Novartis, Bayer-Schering, Merck and Teva; and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. SO has nothing to disclose. OS has received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme companies. VVP received travel grants from Merck Healthcare (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. MJS received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva; and speaking honoraria from Biogen, Novartis, Genzyme and Teva. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. PAM received speakers fees and travel grants from Novartis, Biogen, T’évalua and Sanofi. RG has nothing to disclose. SM has received a MENACTRIMS clinical fellowship grant (2020). TC-T received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. CZ has nothing to disclose. KdG has nothing to disclose. JLS-M accepted travel compensation from Novartis, Merck and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and has participated in clinical trials by Biogen, Merck and Roche. BY and SK have nothing to disclose. MPS has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro and MedDay. TK reported receiving grants from MS Research Australia and grants, personal fees and non-financial support from Biogen; personal fees and non-financial support from Sanofi Genzyme and Merck; personal fees from Roche, Novartis, WebMD Global, Teva and BioCSL; and grants from NHMRC, MS Research Australia, ARSEP-OFSEP, UK MS Society and Medical Research Future Fund. HB’s institution (Monash University) received compensation for consulting, talks, and advisory/steering board activities from Alfred Health, Biogen, Merck, Novartis, Roche and UCB pharma; research support from Biogen, Merck, Roche, MS Australia, National Health and Medical Research (Australia) and the Medical Research Future Fund (Australia), the Pennycook Foundation, Novartis and Roche. He has received personal compensation for steering group activities from Oxford Health Policy Forum.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.