Nathaniel Lizak1,2, Alessandra Lugaresi3, Raed Alroughani4, Jeannette Lechner-Scott5, Mark Slee6, Eva Havrdova7, Dana Horakova7, Maria Trojano8, Guillermo Izquierdo9, Pierre Duquette10, Marc Girard10, Alexandre Prat10, Pierre Grammond11, Raymond Hupperts12, Francois Grand'Maison13, Patrizia Sola14, Eugenio Pucci15, Roberto Bergamaschi16, Celia Oreja-Guevara17, Vincent Van Pesch18, Cristina Ramo19, Daniele Spitaleri20, Gerardo Iuliano21, Cavit Boz22, Franco Granella23, Javier Olascoaga24, Freek Verheul25, Csilla Rozsa26, Edgardo Cristiano27, Shlomo Flechter28, Suzanne Hodgkinson29, Maria Pia Amato30, Norma Deri31, Vilija Jokubaitis1,32, Tim Spelman1,32, Helmut Butzkueven1,32,33, Tomas Kalincik. 1. Department of Medicine, University of Melbourne, Melbourne, Australia. 2. Monash School of Medicine, Monash University, Melbourne, Australia. 3. Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 4. Department of Neurology, Amiri Hospital, Kuwait City, Kuwait. 5. Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia. 6. Flinders University and Medical Centre, Adelaide, Australia. 7. 1st Faculty of Medicine, Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Praha, Czech Republic. 8. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. 9. Hospital Universitario Virgen Macarena, Sevilla, Spain. 10. Hôpital Notre Dame, Montreal, Canada. 11. Hotel-Dieu de Levis, Quebec, Canada. 12. Zuyderland Ziekenhuis, Sittard, The Netherlands. 13. Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada. 14. Neurology Unit, Department of Neuroscience, Nuovo Ospedale Civile Sant'Agostino/Estense, Modena, Italy. 15. Neurology Unit, ASUR Marche-AV 3, Macerata, Italy. 16. C. Mondino National Neurological Institute, Pavia, Italy. 17. University Hospital San Carlos, IdISSC, Madrid, Spain. 18. Cliniques Universitaires Saint-Luc, Brussels, Belgium. 19. Hospital Germans Trias i Pujol, Badalona, Spain. 20. AORN San Giuseppe Moscati, Avellino, Italy. 21. Ospedali Riuniti di Salerno, Salerno, Italy. 22. Karadeniz Technical University, Trabzon, Turkey. 23. University of Parma, Parma, Italy. 24. Department of Neurology, Donostia University Hospital, San Sebastian, Spain. 25. Groen Hart Ziekenhuis, Gouda, The Netherlands. 26. Jahn Ferenc Teaching Hospital, Budapest, Hungary. 27. Hospital Italiano, Buenos Aires, Argentina. 28. Assaf Harofeh Medical Center, Beer-Yaakov, Israel. 29. Liverpool Hospital, Sydney, Australia. 30. Section of Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy. 31. Hospital Fernàndez, Buenos Aires, Argentina. 32. Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. 33. Box Hill Hospital, Monash University, Melbourne, Australia.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Johannes Lorscheider; Vilija G Jokubaitis; Tim Spelman; Guillermo Izquierdo; Alessandra Lugaresi; Eva Havrdova; Dana Horakova; Maria Trojano; Pierre Duquette; Marc Girard; Alexandre Prat; François Grand'Maison; Pierre Grammond; Eugenio Pucci; Cavit Boz; Patrizia Sola; Diana Ferraro; Daniele Spitaleri; Jeanette Lechner-Scott; Murat Terzi; Vincent Van Pesch; Gerardo Iuliano; Roberto Bergamaschi; Cristina Ramo-Tello; Franco Granella; Celia Oreja-Guevara; Helmut Butzkueven; Tomas Kalincik Journal: Neurology Date: 2017-08-09 Impact factor: 9.910
Authors: Oscar Fernández; Guillermo Izquierdo; Eduardo Aguera; Cristina Ramo; Miguel Hernandez; Diego Silva; Rob Walker; Helmut Butzkueven; Chenyu Wang; Michael Barnett Journal: Mult Scler J Exp Transl Clin Date: 2020-09-13
Authors: Thomas F Scott; Troy Desai; Chris Hackett; Edward J Gettings; Teresa Hentosz; Wisam Elmalik; Carol J Schramke Journal: Int J MS Care Date: 2019-12-05
Authors: Stefanos E Prouskas; Nancy D Chiaravalloti; Neeltje Kant; Karlene K Ball; Vincent de Groot; Bernard Mj Uitdehaag; Jeroen Jg Geurts; Elizabeth A Kooij; Hanneke E Hulst Journal: Mult Scler J Exp Transl Clin Date: 2021-12-10