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Original Investigation
November 2018

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis

Author Affiliations
  • 1CORe, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
  • 2Department of Medicine, University of Melbourne, Melbourne, Australia
  • 3Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
  • 4Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio”, Chieti, Italy
  • 5Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
  • 6IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
  • 7Zuyderland Ziekenhuis, Sittard, the Netherlands
  • 8Hospital Universitario Virgen Macarena, Sevilla, Spain
  • 9Hopital Notre Dame, Montreal, Quebec, Canada
  • 10CHUM and Universite de Montreal, Montreal, Quebec, Canada
  • 11Neuro Rive-Sud, Greenfield Park, Quebec, Canada
  • 12CISSS Chaudière-Appalache, Levis, Quebec, Canada
  • 13Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
  • 14Hospital Germans Trias i Pujol, Badalona, Spain
  • 15Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  • 16Flinders University, Adelaide, Australia
  • 17Isfahan University of Medical Sciences, Isfahan, Iran
  • 18KTU Medical Faculty Farabi Hospital, Trabzon, Turkey
  • 19School of Medicine and Public Health, University Newcastle, Newcastle, Australia
  • 20Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia
  • 21Cliniques Universitaires Saint-Luc, Brussels, Belgium
  • 22UOC Neurologia, Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy
  • 23Ospedale P. A. Micone, Genova, Italy
  • 24Groene Hart Ziekenhuis, Gouda, the Netherlands
  • 25Medical Faculty, 19 Mayis University, Samsun, Turkey
  • 26University of Parma, Parma, Italy
  • 27Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
  • 28Amiri Hospital, Kuwait City, Kuwait
  • 29Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia
JAMA Neurol. 2018;75(11):1407-1415. doi:10.1001/jamaneurol.2018.2109
Key Points

Question  What is the role of inflammatory relapses in disability accumulation for patients with progressive-onset multiple sclerosis?

Findings  In this longitudinal, prospective cohort study of 1419 patients with progressive-onset multiple sclerosis, superimposed relapse was associated with a reduced likelihood of confirmed disability progression. Time spent on disease-modifying therapy reduced the likelihood of progression in progressive-onset patients with relapse but not in those without relapse.

Meaning  Disease-modifying therapy may prevent relapse-related disability accrual in patients with progressive-onset multiple sclerosis.


Importance  The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested.

Objective  To examine the association of superimposed relapses in progressive-onset MS on disease outcomes.

Design, Setting, and Participants  Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44 449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed.

Exposures  Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse.

Main Outcomes and Measures  Cumulative hazard of disability progression.

Results  Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P = .003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P = .01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P = .26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P = .16).

Conclusions and Relevance  In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.