Abstract
Objective: To identify predictors of clinical disease activity after treatment change to higher-dose interferon beta-1a in relapsing-remitting multiple sclerosis (MS).Methods: This was a retrospective-prospective observational multicenter study. We enrolled patients with at least one relapse on platform injectable therapy who were changed to 44 μg interferon beta-1a. Our primary endpoint was the clinical disease activity-free (cDAF) status at 6, 12, 18, and 24 months. Secondary endponts included relapse-free status and disability progression-free status at different timepoints. The primary predictor of interest was the monosymptomatic vs. polysymptomatic index relapse, based on the number of affected functional systems from the Kurtzke scale during the last relapse prior to baseline. Other secondary predictors of clinical disease activity were analyzed based on different demographic and relapse characteristics. Kaplan-Meier estimates of the cumulative probability of remaining in cDAF status were performed. The time to clinical disease activity was compared between groups using univariate Kaplan-Meier analysis and multivariate Cox regression. Multivariate analyses were processed in the form of CART (Classification & Regression Trees).Results: A total of 300 patients entered the study; 233 (77.7%) of them completed the 24-month study period and 67 patients (22.3%) terminated early. The proportion of patients in cDAF status was 84.7, 69.5, 57.5, and 54.2% at 6, 12, 18, and 24 months. After 2 years of follow-up, 55.9% of patients remained relapse-free and 87.8% of patients remained disability progression-free. At all timepoints, the polysymptomatic index relapse was the most significant predictor of clinical disease activity of all studied variables. Hazard ratio of cDAF status for patients with monosymptomatic vs. polysymptomatic index relapse was 1.94 (95% CI 1.38–2.73). CART analyses also confirmed the polysymptomatic index relapse being the strongest predictor of clinical disease activity, followed by higher number of pre-baseline relapses with the most significant effect in the monosymptomatic index relapse group. The next strongest predictors of clinical disease activity were cerebellar syndrome as the most disabled Kurtzke functional system for the monosymptomatic relapse group, and age at first MS symptom ≥ 45 for the polysymptomatic relapse group.Conclusions: Patients with a polysymptomatic index relapse and/or higher number of relapses within 2 years prior to baseline are at high risk of clinical disease activity, despite treatment change to higher-dose interferon beta-1a from other platform injectable therapy.Trial registration: State Institute of Drug Control (SUKL), URL: http://www.sukl.eu/modules/nps/index.php?h=study&a=detail&id=958&lang=2, registration number 1205090000.
Highlights
The primary goal of disease-modifying treatments (DMTs) in multiple sclerosis (MS) is to change the natural course of the disease by reducing the number and severity of relapses and by preventing progression of disability
Patients with a polysymptomatic index relapse and/or higher number of relapses within 2 years prior to baseline are at high risk of clinical disease activity, despite treatment change to higher-dose interferon beta-1a from other platform injectable therapy
The patients in the monosymptomatic relapse group were significantly younger at baseline and at their first MS symptom, had lower Expanded Disability Status Scale (EDSS), fewer relapses in the 2 years prior to baseline and longer duration of DMT use compared to patients in the polysymptomatic relapse group (Table 1)
Summary
The primary goal of disease-modifying treatments (DMTs) in multiple sclerosis (MS) is to change the natural course of the disease by reducing the number and severity of relapses and by preventing progression of disability. Injectable first line DMTs have proven to reduce frequency of relapses by about one third [1,2,3] They reduced the severity of relapses and had a significant effect on magnetic resonance imaging (MRI) measures of disease activity. Results of an extension of the pivotal PRISMS trial demonstrated a continued benefit in patients originally randomized to 44 μg dose of interferon beta-1a (IFN β-1a) compared with those receiving 22 μg dose or whose treatment had been delayed [4,5,6,7]. In a cross-over extension of the EVIDENCE trial patients receiving IFN β-1a improved on clinical and MRI outcome measures after they changed from 30 μg once-weekly to 44 μg three times a week (tiw) [10, 12]. In the INCOMIN (Independent Comparison of Interferon) study, 250 μg of interferon beta-1b (IFN β-1b) every other day has been shown to have greater clinical and MRI benefits in RRMS patients compared with 30 μg of IFN β-1a once weekly [13]
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