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Research paper
Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis
  1. Nathaniel Lizak1,2,
  2. Alessandra Lugaresi3,
  3. Raed Alroughani4,
  4. Jeannette Lechner-Scott5,
  5. Mark Slee6,
  6. Eva Havrdova7,
  7. Dana Horakova7,
  8. Maria Trojano8,
  9. Guillermo Izquierdo9,
  10. Pierre Duquette10,
  11. Marc Girard10,
  12. Alexandre Prat10,
  13. Pierre Grammond11,
  14. Raymond Hupperts12,
  15. Francois Grand'Maison13,
  16. Patrizia Sola14,
  17. Eugenio Pucci15,
  18. Roberto Bergamaschi16,
  19. Celia Oreja-Guevara17,
  20. Vincent Van Pesch18,
  21. Cristina Ramo19,
  22. Daniele Spitaleri20,
  23. Gerardo Iuliano21,
  24. Cavit Boz22,
  25. Franco Granella23,
  26. Javier Olascoaga24,
  27. Freek Verheul25,
  28. Csilla Rozsa26,
  29. Edgardo Cristiano27,
  30. Shlomo Flechter28,
  31. Suzanne Hodgkinson29,
  32. Maria Pia Amato30,
  33. Norma Deri31,
  34. Vilija Jokubaitis1,32,
  35. Tim Spelman1,32,
  36. Helmut Butzkueven1,32,33,
  37. Tomas Kalincik1,32 on behalf of the MSBase Study Group
  1. 1Department of Medicine, University of Melbourne, Melbourne, Australia
  2. 2Monash School of Medicine, Monash University, Melbourne, Australia
  3. 3Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
  4. 4Department of Neurology, Amiri Hospital, Kuwait City, Kuwait
  5. 5Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia
  6. 6Flinders University and Medical Centre, Adelaide, Australia
  7. 71st Faculty of Medicine, Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Praha, Czech Republic
  8. 8Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  9. 9Hospital Universitario Virgen Macarena, Sevilla, Spain
  10. 10Hôpital Notre Dame, Montreal, Canada
  11. 11Hotel-Dieu de Levis, Quebec, Canada
  12. 12Zuyderland Ziekenhuis, Sittard, The Netherlands
  13. 13Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada
  14. 14Neurology Unit, Department of Neuroscience, Nuovo Ospedale Civile Sant'Agostino/Estense, Modena, Italy
  15. 15Neurology Unit, ASUR Marche—AV 3, Macerata, Italy
  16. 16C. Mondino National Neurological Institute, Pavia, Italy
  17. 17University Hospital San Carlos, IdISSC, Madrid, Spain
  18. 18Cliniques Universitaires Saint-Luc, Brussels, Belgium
  19. 19Hospital Germans Trias i Pujol, Badalona, Spain
  20. 20AORN San Giuseppe Moscati, Avellino, Italy
  21. 21Ospedali Riuniti di Salerno, Salerno, Italy
  22. 22Karadeniz Technical University, Trabzon, Turkey
  23. 23University of Parma, Parma, Italy
  24. 24Department of Neurology, Donostia University Hospital, San Sebastian, Spain
  25. 25Groen Hart Ziekenhuis, Gouda, The Netherlands
  26. 26Jahn Ferenc Teaching Hospital, Budapest, Hungary
  27. 27Hospital Italiano, Buenos Aires, Argentina
  28. 28Assaf Harofeh Medical Center, Beer-Yaakov, Israel
  29. 29Liverpool Hospital, Sydney, Australia
  30. 30Section of Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy
  31. 31Hospital Fernàndez, Buenos Aires, Argentina
  32. 32Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
  33. 33Box Hill Hospital, Monash University, Melbourne, Australia
  1. Correspondence to Professor Helmut Butzkueven, L4 Centre, Melbourne Brain Centre at Royal Melbourne Hospital, Grattan St, Parkville, VIC 3050, Australia; butz{at}


Objective To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy.

Methods The epochs between Expanded Disability Status Scale (EDSS) steps 3–6, 4–6 and 6–6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted.

Results For the EDSS 3–6, 4–6 and 6–6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92–1.11) and postbaseline (2.15–2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58–3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72–0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results.

Conclusions Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.

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