Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis
Nathaniel Lizak 1 2, Alessandra Lugaresi 3, Raed Alroughani 4, Jeannette Lechner-Scott 5, Mark Slee 6, Eva Havrdova 7, Dana Horakova 7, Maria Trojano 8, Guillermo Izquierdo 9, Pierre Duquette 10, Marc Girard 10, Alexandre Prat 10, Pierre Grammond 11, Raymond Hupperts 12, Francois Grand'Maison 13, Patrizia Sola 14, Eugenio Pucci 15, Roberto Bergamaschi 16, Celia Oreja-Guevara 17, Vincent Van Pesch 18, Cristina Ramo 19, Daniele Spitaleri 20, Gerardo Iuliano 21, Cavit Boz 22, Franco Granella 23, Javier Olascoaga 24, Freek Verheul 25, Csilla Rozsa 26, Edgardo Cristiano 27, Shlomo Flechter 28, Suzanne Hodgkinson 29, Maria Pia Amato 30, Norma Deri 31, Vilija Jokubaitis 1 32, Tim Spelman 1 32, Helmut Butzkueven 1 32 33, Tomas Kalincik; MSBase Study Group
Affiliations
Affiliations
- 1Department of Medicine, University of Melbourne, Melbourne, Australia.
- 2Monash School of Medicine, Monash University, Melbourne, Australia.
- 3Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
- 4Department of Neurology, Amiri Hospital, Kuwait City, Kuwait.
- 5Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
- 6Flinders University and Medical Centre, Adelaide, Australia.
- 71st Faculty of Medicine, Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Praha, Czech Republic.
- 8Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
- 9Hospital Universitario Virgen Macarena, Sevilla, Spain.
- 10Hôpital Notre Dame, Montreal, Canada.
- 11Hotel-Dieu de Levis, Quebec, Canada.
- 12Zuyderland Ziekenhuis, Sittard, The Netherlands.
- 13Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada.
- 14Neurology Unit, Department of Neuroscience, Nuovo Ospedale Civile Sant'Agostino/Estense, Modena, Italy.
- 15Neurology Unit, ASUR Marche-AV 3, Macerata, Italy.
- 16C. Mondino National Neurological Institute, Pavia, Italy.
- 17University Hospital San Carlos, IdISSC, Madrid, Spain.
- 18Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- 19Hospital Germans Trias i Pujol, Badalona, Spain.
- 20AORN San Giuseppe Moscati, Avellino, Italy.
- 21Ospedali Riuniti di Salerno, Salerno, Italy.
- 22Karadeniz Technical University, Trabzon, Turkey.
- 23University of Parma, Parma, Italy.
- 24Department of Neurology, Donostia University Hospital, San Sebastian, Spain.
- 25Groen Hart Ziekenhuis, Gouda, The Netherlands.
- 26Jahn Ferenc Teaching Hospital, Budapest, Hungary.
- 27Hospital Italiano, Buenos Aires, Argentina.
- 28Assaf Harofeh Medical Center, Beer-Yaakov, Israel.
- 29Liverpool Hospital, Sydney, Australia.
- 30Section of Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy.
- 31Hospital Fernàndez, Buenos Aires, Argentina.
- 32Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
- 33Box 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.
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