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Treatment Escalation vs Immediate Initiation of Highly Effective Treatment for Patients With Relapsing-Remitting Multiple SclerosisData From 2 Different National Strategies

Educational Objective
To investigate whether different national disease-modifying treatment strategies for relapsing-remitting multiple sclerosis were associated with disability outcomes.
1 Credit CME
Key Points

Question  How are differences in national treatment strategies for multiple sclerosis associated with clinical outcomes?

Findings  In this cohort study comparing patients in the Danish and Swedish multiple sclerosis registries, the use of highly effective disease-modifying treatment was far more frequent in the Swedish cohort and was associated with significant reductions in the rate of confirmed disability worsening and relapse outcomes.

Meaning  This study suggests that escalation of treatment was inferior to using a more effective disease-modifying treatment as initial treatment for multiple sclerosis.


Importance  Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with clinical outcomes is unknown.

Objective  To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes.

Design, Setting, and Participants  This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019).

Exposures  All MS-specific DMTs initiated during the observation period were included in the analysis.

Main Outcomes and Measures  The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting–based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries.

Results  A total of 2700 patients from the Swedish MS registry (1867 women [69.2%]; mean [SD] age, 36.1 [9.5] years) and 2161 patients from the Danish MS registry (1472 women [68.1%]; mean [SD] age, 37.3 [9.4 years]) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P = .004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P = .03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P = .01) relative to Danish patients.

Conclusions and Relevance  The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment.

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Article Information

Accepted for Publication: June 18, 2021.

Published Online: August 16, 2021. doi:10.1001/jamaneurol.2021.2738

Corresponding Author: Tim Spelman, PhD, MD, Department of Clinical Neuroscience, Karolinska Institute, Tomtebodavägen 18A, SE-171 77 Stockholm, Sweden (tim.spelman@ki.se).

Author Contributions: Dr Spelman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Spelman, Magyari, Hillert, Lycke.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Spelman, Magyari, Lycke.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Spelman.

Obtained funding: Piehl, Hillert, Lycke.

Administrative, technical, or material support: Magyari, Piehl, Sellebjerg, Lycke.

Supervision: Lycke.

Conflict of Interest Disclosures: Dr Spelman reported receiving compensation for serving on scientific advisory boards, honoraria for consultancy, and funding for travel from Biogen Inc; and speaker honoraria from Novartis. Dr Magyari reported receiving personal fees and grants from Biogen, Novartis, Merck, Sanofi, and Roche; personal fees from AbbVie, Alexion, and Bristol Myers Squibb; and grants from Teva outside the submitted work. Dr Piehl reported receiving grants from Swedish Medical Research Council and County of Stockholm during the conduct of the study; grants from Genzyme, Merck KGaA, UCB, Biogen, and Novartis; and personal fees from Parexel serving as chair of DMC in clinical trials outside the submitted work. Dr Rasmussen reported receiving personal fees from Novartis, Biogen, Alexion, Roche, Bristol Myers Squibb, Sanofi, and Merck outside the submitted work. Dr Sellebjerg reported receiving grants and personal fees from Biogen, Novartis, Merck, Roche, and Sanofi Genzyme; and personal fees from Bristol Myers Squibb and Alexion outside the submitted work. Ms Joensen reported receiving personal fees from Biogen outside the submitted work. Dr Hillert reported receiving grants and personal fees from Biogen, Celgene, Merck, Novartis, and Sanofi; grants from Roche; personal fees from Janssen, Bayer Schering, and Teva; funding from Swedish Research Council and the Swedish Brain Foundation; and serving as principal investigator for or receiving unrestricted research support from Biogen Idec, Merck Serono, TEVA, Sanofi Genzyme, and Bayer Schering outside the submitted work. Dr Lycke reported receiving grants from the Swedish Federal Government during the conduct of the study; personal fees from Biogen, Novartis, Merck, Alexion, Roche, Sanofi Genzyme, and BMS; and grants from Biogen and Novartis; and serving on the editorial board of the Acta Neurologica Scandinavica outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the Swedish Research Council, the Swedish Brain Foundation, the Karolinska University Hospital, the Patient-Centered Outcomes Research Institute, 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 Edith Jacobson Foundation, and NEURO Sweden.

Role of the Funder/Sponsor: The funding sources 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.

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