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Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis

Educational Objective
To determine whether disability outcomes at 5 years differ between people with multiple sclerosis who have an early intensive approach to disease-modifying therapy vs those who have an escalation approach.
1 Credit CME
Key Points

Question  How do 5-year disability outcomes compare between people with multiple sclerosis who have an early intensive approach to disease-modifying therapy vs those who have an escalation approach?

Findings  In this cohort study including 592 people, those who received high-efficacy treatment initially had a smaller increase in Expanded Disability Status Scale score at 5 years vs those who first received moderate-efficacy disease-modifying therapy.

Meaning  These findings suggest that real-world escalation approaches may be inadequate to prevent unfavorable long-term outcomes and support the need for a prospective clinical trial to compare disease-modifying therapy algorithms.


Importance  Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.

Objective  To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.

Design, Setting and Participants  In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).

Exposures  Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

Main Outcomes and Measures  Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.

Results  Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = −0.85; 95% CI, −1.38 to −0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

Conclusions and Relevance  In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

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Article Information

Corresponding Author: Neil Robertson, MD, Helen Durham Centre for Neuroinflammatory Disease, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, United Kingdom (robertsonnp@cardiff.ac.uk).

Accepted for Publication: December 13, 2018.

Published Online: February 18, 2019. doi:10.1001/jamaneurol.2018.4905

Author Contributions: Dr Harding 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: Harding, Williams, Robertson, Tallantyre.

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

Drafting of the manuscript: Harding, Rimmer, Joseph, Robertson, Tallantyre.

Critical revision of the manuscript for important intellectual content: Harding, Williams, Willis, Hrastelj, Joseph, Tomassini, Wardle, Pickersgill, Robertson, Tallantyre.

Statistical analysis: Harding.

Administrative, technical, or material support: Hrastelj, Rimmer, Joseph, Tomassini, Wardle, Pickersgill, Robertson.

Supervision: Robertson, Tallantyre.

Conflict of Interest Disclosures: Dr Harding reports grants from Novartis UK outside the submitted work. Dr Joseph reports honoraria and support to attend educational meetings from Biogen and Teva Pharmaceutical Industries. Dr Pickersgill reports honoraria from Roche and MedDay Pharma and travel expenses from Genzyme and Novartis. Dr Robertson reports honoraria from Biogen and Merck & Co and grants from Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries outside the submitted work. Dr Tallantyre reports honoraria and support to attend educational meetings from Merck and Novartis, support to attend educational meetings from Biogen, and salary as a UK MS Register fellow from Biogen outside the submitted work. No other disclosures were reported.

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