TY - JOUR
T1 - Association of Sustained Immunotherapy with Disability Outcomes in Patients with Active Secondary Progressive Multiple Sclerosis
AU - Kalincik, Tomas
AU - Lizak, Nathaniel
AU - Malpas, Charles B.
AU - Sharmin, Sifat
AU - Havrdova, Eva Kubala
AU - Horakova, Dana
AU - Izquierdo, Guillermo
AU - Eichau, Sara
AU - Lugaresi, Alessandra
AU - Duquette, Pierre
AU - Girard, Marc
AU - Prat, Alexandre
AU - Larochelle, Catherine
AU - Trojano, Maria
AU - Grand'maison, Francois
AU - Grammond, Pierre
AU - Sola, Patrizia
AU - Ferraro, Diana
AU - Hupperts, Raymond
AU - Bergamaschi, Roberto
AU - Boz, Cavit
AU - Van Pesch, Vincent
AU - Spitaleri, Daniele
AU - Terzi, Murat
N1 - Funding Information:
Funding/Support: This study was supported by grants 1129189, 1071124, and 1140766 from the National Health and Medical Research Council (Dr Kalincik). The MSBase Foundation is a nonprofit organization that receives funding from Bayer, bioCSL, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
Sanofi-Aventis, Sanofi Genzyme, and Teva; and travel compensation from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi-Aventis, Sanofi Genzyme, and Teva outside the submitted work. Dr Boz reported receiving travel compensation from Bayer, Biogen, Merck, Novartis, and Teva Pharmaceuticals and participating in clinical trials sponsored by Novartis, Roche, and Sanofi-Aventis outside the submitted work. Dr Van Pesch reported receiving research grants from Bayer and Novartis; speaking and consulting honoraria from Bayer, Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva through his institution; and travel compensation from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals outside the submitted work. Dr Spitaleri reported receiving consulting honoraria as a scientific advisory board member from Bayer, Merck, Novartis, and Sanofi-Aventis and travel compensation from Biogen, Novartis, Sanofi Aventis, and Teva Pharmaceuticals outside the submitted work. Dr Terzi reported receiving travel compensation from Bayer, Merck, Novartis, and Teva Pharmaceuticals, and participating in clinical trials sponsored by Novartis, Roche, and Sanofi-Aventis outside the submitted work. Dr Kalincik reported receiving research funding from Biogen and travel compensation and/or speaking honoraria from bioCSL, Biogen, Merck, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, and WebMD Global, and serving on the scientific advisory boards of Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and on the steering committee of the Brain Atrophy Initiative of Sanofi Genzyme outside the submitted work.
Funding Information:
receiving travel compensation from Merck outside the submitted work. Dr Kubala Havrdova reported receiving research funding from the Czech Ministry of Education (Project Progres Q27/LF1) and speaking honoraria and consulting fees from Actelion Pharmaceuticals, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva Pharmaceuticals outside the submitted work. Dr Horakova reported receiving research funding from Biogen and the Czech Ministry of Education (Project Progres Q27/LF1) and speaking honoraria and consulting fees from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva Pharmaceuticals outside the submitted work. Dr Izquierdo reported receiving speaking honoraria from Almirall, Biogen, Merck, Novartis, Roche, Sanofi, and Teva Pharmaceuticals outside the submitted work. Dr Lugaresi reported receiving research grants from Bayer, Biogen, Fondazione Italiana Sclerosi Multipla, Merck, Novartis, Sanofi, and Teva Pharmaceuticals through her institution; receiving travel compensation and speaking honoraria from Biogen, Fondazione Italiana Sclerosi Multipla, Merck, Novartis, Roche, Sanofi, and Teva Pharmaceuticals; and serving on the advisory boards of Bayer, Biogen, Merck, and Sanofi Genzyme outside the submitted work. Dr Duquette reported receiving grants from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada; receiving funding for investigator-initiated clinical trials from Biogen, Novartis, and Sanofi Genzyme; and serving on the editorial boards of and receiving financial support for meeting attendance from Biogen, EMD Serono, Novartis, Sanofi Genzyme, and Teva Neuroscience outside the submitted work. Dr Girard reported receiving grants from the Canadian Institutes of Health Research; consulting fees from Biogen, Novartis, Sanofi Genzyme, and Teva Canada Innovation; and speaking honoraria from EMD Serono, Novartis, and Teva Canada Innovation outside the submitted work. Dr Trojano reported receiving research grants from Biogen, Merck, and Novartis through her institution and speaking honoraria from Almirall, Bayer Schering Pharma, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva Pharmaceuticals outside the submitted work. Dr Grand'Maison reported receiving research funding and/or speaking honoraria from Biogen, Mitsubishi Tanabe Pharma, Novartis, Ono Pharmaceutical, Sanofi Genzyme, and Teva Neuroscience outside the submitted work. Dr Grammond reported serving on the advisory boards of Biogen, Merck, Novartis, Sanofi Genzyme, and Teva Neuroscience; being a consultant for Merck; receiving speaking honoraria from the Canadian Multiple Sclerosis Society, Merck, and Teva Neuroscience; and receiving travel compensation from Novartis and Teva Neuroscience outside the submitted work. Dr Sola reported receiving research grants from Bayer, Biogen, Merck, Novartis, Sanofi, and Teva Pharmaceuticals through her institution; serving on the scientific advisory boards of Biogen and Teva; and receiving travel compensation and speaking honoraria from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva outside the submitted work. Dr Ferraro reported receiving travel compensation and/or speaking honoraria from Biogen, Merck, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals outside the submitted work. Dr Hupperts reported receiving research funding from Biogen and Merck; consulting honoraria as a scientific advisory board member from Biogen, Merck, Sanofi Genzyme, and Teva Pharmaceuticals; and speaking honoraria from Novartis and Sanofi Genzyme outside the submitted work. Dr Bergamaschi reported receiving research grants from Bayer, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva Pharmaceuticals; speaking honoraria from Bayer, Biogen, Merck, Novartis,
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: The rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
AB - Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: The rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
UR - https://www.scopus.com/pages/publications/85089381563
U2 - 10.1001/jamaneurol.2020.2453
DO - 10.1001/jamaneurol.2020.2453
M3 - Article
C2 - 32716480
AN - SCOPUS:85089381563
SN - 2168-6149
VL - 77
SP - 1398
EP - 1407
JO - JAMA Neurology
JF - JAMA Neurology
IS - 11
ER -