Confirmed disability progression provides limited predictive information regarding future disease progression in multiple sclerosis.
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ABSTRACT: Background
Although confirmed disability progression (CDP) is a common outcome in multiple sclerosis (MS) clinical trials, its predictive value for long-term outcomes is uncertain.Objective
To investigate whether CDP at month 24 predicts subsequent disability accumulation in MS.Methods
The Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital includes participants with relapsing-remitting MS or clinically isolated syndrome with Expanded Disability Status Scale (EDSS) scores ≤5 (N = 1214). CDP was assessed as a predictor of time to EDSS score 6 (EDSS 6) and to secondary progressive MS (SPMS) using a Cox proportional hazards model; adjusted models included additional clinical/participant characteristics. Models were compared using Akaike's An Information Criterion.Results
CDP was directionally associated with faster time to EDSS 6 in univariate analysis (HR = 1.61 [95% CI: 0.83, 3.13]). After adjusting for month 24 EDSS, CDP was directionally associated with slower time to EDSS 6 (adjusted HR = 0.65 [0.32, 1.28]). Models including CDP had worse fit statistics than those using EDSS scores without CDP. When models included clinical and magnetic resonance imaging measures, T2 lesion volume improved fit statistics. Results were similar for time to SPMS.Conclusions
CDP was less predictive of time to subsequent events than other MS clinical features.
SUBMITTER: Healy BC
PROVIDER: S-EPMC8042549 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceAccumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a feature of primary and secondary progressive multiple sclerosis.ObjectiveTo investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments.Design, setting, and participantsAnalyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set.InterventionsParticipants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period.Main outcomes and measuresConfirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW).ResultsIn the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean [SD] age, 37.2 [9.2] vs 37.1 [9.2] years; 552 [66.6%] vs 541 women [65.4%]). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 [78.0%] and 137 of 170 [80.6%], respectively) and ocrelizumab (147 of 167 [88.0%] and 115 of 129 [89.1%], respectively); a minority had CDA explained by RAW events (69 of 390 [17.7%] and 52 of 299 [17.4%], respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 [4.4%] for 12-week and 15 of 299 [5.0%] for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio [HR], 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events.Conclusions and relevanceMost disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA.Trial registrationClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).
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