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Background: Three large cohort studies have previously examined factors influencing disability accumulation in moderately advanced multiple sclerosis (MS), but arrived to contradictory results. The effect of therapy during this disease stage remains unclear.
Objectives: To identify modifiers of disability trajectories in moderately advanced MS, including disease activity and immunomodulatory therapy during the early and moderately advanced stages of MS. We hypothesized that individual disability trajectories are not homogenous and can be predicted based on demographic and clinical characteristics.
Methods: The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6, and 6-6.5 were analyzed. Patients with relapse-onset multiple sclerosis, 6-month confirmed progression to the initial EDSS step (baseline), and ³12 months pre-baseline follow-up were identified in MSBase, a large international observational multiple sclerosis cohort study. Multivariable survival models examined the impact of relapse rate and proportion of time treated (prior to and during each epoch), age and disease duration at baseline, on progression to the outcome EDSS (6 or 6.5). Sensitivity analyses varying outcome definition and inclusion criteria were conducted.
Results: For the 3-6, 4-6, and 6-6.5 epochs, 1,560, 1,504, and 1,231 patients were identified, respectively. Pre- and post-baseline disability trajectories showed large coefficients of variance (0.85-0.92 and 1.95-2.26, respectively) and did not correlate. Probability of reaching the outcome EDSS was not associated with pre-baseline variables, but was increased by higher relapse rates during each epoch (hazard ratios: 1.58-3.07; P<0.001). Greater proportion of each epoch treated with higher-efficacy therapies was associated with lower risk of the outcome EDSS (hazard ratios: 0.27-0.68; P²0.02). These results were confirmed by sensitivity analyses.
Conclusion: Disease progression during moderately advanced multiple sclerosis is amnesic to prior disease activity. Lower relapse rates and greater persistence on higher-efficacy immunomodulatory therapy after reaching EDSS steps 3, 4, and 6 are associated with a decreased risk of accumulating further disability. These observations justify treatment even after moderately advanced disability has been attained.
Authors
Nathaniel Lizak
University of Melbourne
Monash University
Alessandra Lugaresi
MS Centre, Neuroscience, Imaging and Clinical Sciences, University ‘G. d’Annunzio’, Chieti, Italy
Raed Alroughani
Amiri Hospital, Kuwait City, Kuwait
Jeanette Lechner-Scott
Hunter Medical Research Institute
Mark Slee
Flinders University and Medical Centre
Vilija Jokubaitis
University of Melbourne
Royal Melbourne Hospital
Tim Spelman
University of Melbourne
Royal Melbourne Hospital
Helmut Butzkueven
University of Melbourne
Royal Melbourne Hospital
Box Hill Hospital, Monash University
Tomas Kalincik
University of Melbourne
Royal Melbourne Hospital
Objectives: To identify modifiers of disability trajectories in moderately advanced MS, including disease activity and immunomodulatory therapy during the early and moderately advanced stages of MS. We hypothesized that individual disability trajectories are not homogenous and can be predicted based on demographic and clinical characteristics.
Methods: The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6, and 6-6.5 were analyzed. Patients with relapse-onset multiple sclerosis, 6-month confirmed progression to the initial EDSS step (baseline), and ³12 months pre-baseline follow-up were identified in MSBase, a large international observational multiple sclerosis cohort study. Multivariable survival models examined the impact of relapse rate and proportion of time treated (prior to and during each epoch), age and disease duration at baseline, on progression to the outcome EDSS (6 or 6.5). Sensitivity analyses varying outcome definition and inclusion criteria were conducted.
Results: For the 3-6, 4-6, and 6-6.5 epochs, 1,560, 1,504, and 1,231 patients were identified, respectively. Pre- and post-baseline disability trajectories showed large coefficients of variance (0.85-0.92 and 1.95-2.26, respectively) and did not correlate. Probability of reaching the outcome EDSS was not associated with pre-baseline variables, but was increased by higher relapse rates during each epoch (hazard ratios: 1.58-3.07; P<0.001). Greater proportion of each epoch treated with higher-efficacy therapies was associated with lower risk of the outcome EDSS (hazard ratios: 0.27-0.68; P²0.02). These results were confirmed by sensitivity analyses.
Conclusion: Disease progression during moderately advanced multiple sclerosis is amnesic to prior disease activity. Lower relapse rates and greater persistence on higher-efficacy immunomodulatory therapy after reaching EDSS steps 3, 4, and 6 are associated with a decreased risk of accumulating further disability. These observations justify treatment even after moderately advanced disability has been attained.
Authors
Nathaniel Lizak
University of Melbourne
Monash University
Alessandra Lugaresi
MS Centre, Neuroscience, Imaging and Clinical Sciences, University ‘G. d’Annunzio’, Chieti, Italy
Raed Alroughani
Amiri Hospital, Kuwait City, Kuwait
Jeanette Lechner-Scott
Hunter Medical Research Institute
Mark Slee
Flinders University and Medical Centre
Vilija Jokubaitis
University of Melbourne
Royal Melbourne Hospital
Tim Spelman
University of Melbourne
Royal Melbourne Hospital
Helmut Butzkueven
University of Melbourne
Royal Melbourne Hospital
Box Hill Hospital, Monash University
Tomas Kalincik
University of Melbourne
Royal Melbourne Hospital
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