The Effect of Different National Treatment Strategies on Disability Outcome in Relapsing-Remitting Multiple Sclerosis: A Propensity Score Adjusted Comparison between Denmark and Sweden

Abstract

Background: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The objective was to investigate the influence of such differences on disease modifying treatment (DMT) and disability outcome. Methods: Patients with RRMS commencing their first DMT 2013-2016 were retrospectively included from the Swedish and Danish MS registries. Time to the 24-week confirmed disability worsening (CDW, primary outcome) and 24-week confirmed disability improvement (CDI, secondary outcome) and milestone expanded disability status scale (EDSS) score 3 and 4 end-points (secondary outcomes) were analyzed using Inverse Probability of Treatment Weighting (IPTW)-based Cox regression models with robust standard errors. The IPTW model used a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the two countries. Findings: A total of 2700 patients from the Swedish registry and 2161 patients from the Danish MS registry commencing a first DMT between 2013 and 2016 were included in the analysis and observed for an average of 4 years. The proportion of patients initiating with a low-moderate as compared to highly effective DMT was 92.4% (teriflunomide 42%) and 7.6% in Denmark and 62.4% (teriflunomide 2.4%) and 35% in Sweden, respectively. Swedish patients were associated with a 29% reduction in the rate of post-baseline 24-week CDW relative to Danish patients (IPTW HR 0.71; 95% CI 0.57-0.90; p=0.004). The Swedish cohort was associated with a 27% and 26% reduction in the rate of reaching EDSS 3 and 4 respectively, relative to Danish patients (HR 0.73; 95% CI 0.62-0.85; p<0.001; and 0.74; 95% CI 0.59-0.93; p=0.009, reference = Denmark). Interpretation: We show for the first time that differences in treatment strategies of RRMS have an impact on disability outcomes at a national level. Escalation of treatment efficacy seemed inferior to using more efficacious DMT as initial treatment. Funding Statement: This study was supported by the Swedish Research Council, the Swedish Brain foundation, the Karolinska University Hospital & the Patient-Centered Outcomes Research Institute (PCORI), the Swedish Multiple Sclerosis Research Foundation, the Swedish Federal Government (LUA/ALF Agreement ALFGBG-722081), the Swedish Association of Persons with Neurological Disabilities, the Research Foundation of the Multiple Sclerosis Society of Gothenburg, the Edit Jacobson Foundation, and NEURO Sweden. Declaration of Interests: TS has received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen Inc; speaker honoraria from Novartis. MM has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. FP has received research grants from Biogen and Novartis. AS reports no conflicts of interest FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. PVR has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, and Alexion, has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, has received support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. MK reports no conflicts of interest HJ has received honoraria for participating in advisory board from Biogen. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Novartis, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, BiogenIdec, Merck- Serono, TEVA, Sanofi-Genzyme and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM and SanofiGenzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, and Novartis. Ethics Approval Statement: The study was approved by the The Swedish Ethical Review Authority (Dnr: 2019-00839/1199-18), and The Danish Data Protection Authority (Org. number 202100 2973).