Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis.
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.
Department of Medicine, University of Melbourne, Melbourne, Australia.|Monash School of Medicine, Monash University, Melbourne, Australia.
Nathaniel
N
Lizak
Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
Alessandra
A
Lugaresi
Department of Neurology, Amiri Hospital, Kuwait City, Kuwait.
Raed
http://orcid.org/0000-0001-5436-5804
R
Alroughani
Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
Jeannette
J
Lechner-Scott
Flinders University and Medical Centre, Adelaide, Australia.
Mark
M
Slee
1st Faculty of Medicine, Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Praha, Czech Republic.
Eva
E
Havrdova
1st Faculty of Medicine, Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Praha, Czech Republic.
Dana
D
Horakova
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
Maria
M
Trojano
Hospital Universitario Virgen Macarena, Sevilla, Spain.
Guillermo
G
Izquierdo
Hôpital Notre Dame, Montreal, Canada.
Pierre
P
Duquette
Hôpital Notre Dame, Montreal, Canada.
Marc
M
Girard
Hôpital Notre Dame, Montreal, Canada.
Alexandre
A
Prat
Hotel-Dieu de Levis, Quebec, Canada.
Pierre
P
Grammond
Zuyderland Ziekenhuis, Sittard, The Netherlands.
Raymond
R
Hupperts
Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada.
Francois
F
Grand'Maison
Neurology Unit, Department of Neuroscience, Nuovo Ospedale Civile Sant'Agostino/Estense, Modena, Italy.
Patrizia
P
Sola
Neurology Unit, ASUR Marche-AV 3, Macerata, Italy.
Eugenio
E
Pucci
C. Mondino National Neurological Institute, Pavia, Italy.
Roberto
R
Bergamaschi
University Hospital San Carlos, IdISSC, Madrid, Spain.
Celia
C
Oreja-Guevara
Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Vincent
V
Van Pesch
Hospital Germans Trias i Pujol, Badalona, Spain.
Cristina
C
Ramo
AORN San Giuseppe Moscati, Avellino, Italy.
Daniele
D
Spitaleri
Ospedali Riuniti di Salerno, Salerno, Italy.
Gerardo
G
Iuliano
Karadeniz Technical University, Trabzon, Turkey.
Cavit
C
Boz
University of Parma, Parma, Italy.
Franco
F
Granella
Department of Neurology, Donostia University Hospital, San Sebastian, Spain.
Javier
J
Olascoaga
Groen Hart Ziekenhuis, Gouda, The Netherlands.
Freek
F
Verheul
Jahn Ferenc Teaching Hospital, Budapest, Hungary.
Csilla
C
Rozsa
Hospital Italiano, Buenos Aires, Argentina.
Edgardo
E
Cristiano
Assaf Harofeh Medical Center, Beer-Yaakov, Israel.
Shlomo
S
Flechter
Liverpool Hospital, Sydney, Australia.
Suzanne
S
Hodgkinson
Section of Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy.
Maria Pia
MP
Amato
Hospital Fernàndez, Buenos Aires, Argentina.
Norma
N
Deri
Department of Medicine, University of Melbourne, Melbourne, Australia.|Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
Vilija
http://orcid.org/0000-0002-3942-4340
V
Jokubaitis
Department of Medicine, University of Melbourne, Melbourne, Australia.|Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
Tim
T
Spelman
Department of Medicine, University of Melbourne, Melbourne, Australia.|Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.|Box Hill Hospital, Monash University, Melbourne, Australia.
Helmut
H
Butzkueven
Tomas
http://orcid.org/0000-0003-3778-1376
T
Kalincik
D015331:Cohort Studies; D004185:Disability Evaluation; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000276:immunology*; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology