How patients with multiple sclerosis acquire disability

Abstract

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31-48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.

Keywords: disability; disease progression; multiple sclerosis; progression independent of relapse activity; relapse.

Figure 1

Schematic representations of RAW and PIRA event definitions. The EDSS-worsening threshold relative to baseline (or the ‘re-baseline’) is shown as a horizontal red dotted line; a disability event is defined by a clinically meaningful increase of the EDSS above the threshold, sustained until and confirmed by an EDSS assessment at least 3 or 6 months apart from the onset of the worsening. The bold black line represents the patient’s longitudinal disability trajectory (EDSS scores collected at visits). The onset and the confirmation are shown with vertical dotted brown lines. The vertical shaded area to the left in both schematics (peach) represents a relapse. The other vertical shaded areas (green) must be relapse free to fulfill the definition of RAW or PIRA, consistent with the definition in Kappos et al. In case a RAW or PIRA event could not be confirmed due to the occurrence of a relapse in the green interval, the confirmation was delayed to the next EDSS assessment. The onset of a RAW event has to occur ≤90 days since the start date of the most recent relapse. For PIRA events, the onset has to occur at >90 days from the onset of the most recent relapse. For PIRA events, if a relapse with incomplete recovery occurs, the baseline (i.e. the EDSS reference value) is reset >90 days after the relapse onset (‘re-baseline’; shown with vertical dotted line). The PIRA event is then relative to this new baseline. d = day.

Figure 2

Confirmed disability worsening by mechanism across multiple sclerosis phenotypes. Euler diagrams are presented by multiple sclerosis phenotype for (A) the full dataset (n = 27 328) and in patients from randomized phase 3 trials plus extensions (n  = 8346); (B) active-treated versus placebo-treated patients from phase 3 placebo-controlled trials (n  = 4970); and (C) in paediatric patients treated with fingolimod or interferon beta-1a. In the full dataset and for the subset of patients from phase 3 clinical trials, progression and relapse onset was restricted to the first 2 years of the trials. Six-month CDW was used in adult patients. Three-month CDW was used in paediatric patients, as the mean study duration was 20 versus 17 months for patients treated with fingolimod or interferon beta-1a, respectively. PIRA events were 6-month or 3-month confirmed and sustained until the end of the follow-up time in adult and paediatric patients, respectively. Coloured areas are proportional to the represented groups. Each diagram is divided vertically into a red area (patients who relapsed) and a blue area (patients who did not relapse); this vertical division extends to the bottom of the figure. Superimposed is the proportion of patients who experienced a 6-month CDW or 3-month CDW (dark grey box); the overlap between the grey box and red area represents patients who relapsed and had all-cause disability worsening; the overlap between the grey box and the blue area represents patients who had all-cause disability worsening but no relapses. Patients with CDW events were further classified into RAW (bronze), PIRA sustained until the end of the follow-up period (green) or both (yellow). Due to the definition of RAW and PIRA events (Supplementary Table 2B), some patients experienced a disability worsening that could be classified neither as a RAW nor a sustained PIRA event (dark grey)—these unclassified events also include 6-month confirmed PIRA events that were not sustained in the longitudinal data. The baseline characteristics of patients who are diagnosed as RRMS but experienced PIRA events without having any relapses in the study are summarized in Supplementary Table 4 and an assessment of the MRI activity is provided in Supplementary Table 5.

Figure 3

Relapse-affected functional systems in RRMS and SPMS patients by level of disability level (EDSS total score category) prior to the relapse (mild, moderate and severe). A–C describe the full dataset, randomized phase 3 trials plus extensions and phase 3 placebo-controlled trials, respectively. The number of patients corresponds to the number of patients with relapses with corresponding EDSS functional score assessments. Similar illustrations for complete and incomplete recovery are provided in Supplementary Fig. 2.

Figure 4

Prognostic factors of a complete relapse recovery and probability of a complete relapse recovery (as judged by the Investigator; full dataset). (A) The number of patients represents the number of patients with relapses with corresponding EDSS functional score assessments and other covariates. Risk factors for an incomplete relapse recovery were analysed in a logistic regression model with adjustments for sex, age and EDSS score (prior to relapse), as well as for functional systems involved in the relapse. Odds ratios are displayed with 95% CIs; odds ratios significantly (<1) indicate risk factors for an incomplete recovery. (B) The number of patients noted in each panel corresponds to the number of patients with relapses and status of recovery available. The charts represent the mean probability of a complete relapse recovery by phenotype (top row RRMS, bottom row SPMS), sex, pre-existing level of disability (categorized) and as a function of the patient’s age at the time of the relapse. Relapse recovery was analysed in a logistic regression model with adjustments for sex, age and EDSS score (prior to relapse). Data for the phase 3 trials and the placebo-controlled phase 3 trials are presented in Supplementary Fig. 4 and are broadly consistent.