Abstract and Introduction
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.
There are two main mechanisms by which patients with multiple sclerosis acquire disability: (i) step-wise accrual of impairment due to incomplete recovery from a relapse [i.e. relapse-associated worsening (RAW)]; and (ii) progression independent of relapse activity (PIRA). While the former is considered to be the main source of permanent disability in relapsing multiple sclerosis, the latter is thought to drive the insidious progression typical in primary and secondary progressive multiple sclerosis (PPMS and SPMS). The clinical distinction of relapsing and progressive forms of multiple sclerosis has recently been challenged: In a study by Kappos et al. including pooled data from two large phase 3 clinical trials in relapsing multiple sclerosis, most disability accumulation was not associated with overt relapses. The study used a composite end point of walking ability, hand coordination, and physical disability for the detection of PIRA events. The extent to which this finding reflects the pathophysiology of multiple sclerosis, rather than the particular definitions of relapse and progression used in the Kappos et al. study, warrants further exploration in a large independent dataset with more stringent definitions of PIRA.
While the role of clinical relapses in diagnosis is undisputed, and their impact on the patient's quality of life is undeniable, the involvement of clinical relapse in long-term prognosis has been questioned.[2,3] In natural history studies, patients with and without relapses progressed similarly and so a common mechanism of progression independent of relapses was suggested. However, more recent population-based studies have confirmed relapses play a role in the transition time from relapsing-remitting multiple sclerosis (RRMS) to SPMS (with poor recovery from relapses and high frequency of early relapses reducing the time to onset of progressive disease),[5,6] in the accumulation of disability both in early and later RRMS,[7–10] and even in progressive disease. The quantitative relevance of relapses and progression in driving the accumulation of disability in the different stages of multiple sclerosis therefore requires further study.
Relapses and focal inflammation are predominantly a feature of young patients with multiple sclerosis. Paediatric multiple sclerosis is almost exclusively of the relapsing subtype,[12,13] with relapse rates being two to three times higher in paediatric-onset than adult-onset multiple sclerosis. In adult patients with RRMS, relapse frequency is highest in the youngest patients and decreases with age, even in placebo-treated patients. Current therapies for multiple sclerosis primarily target focal inflammation, and consequently their relative effect is strongest in patients where inflammation is most prominent, i.e. in young patients with multiple sclerosis.[15,16] However, the extent to which disease-modifying therapies (DMTs) impact long-term outcomes and prolong the time to milestone disability levels is a question not fully answered.
The Novartis-Oxford multiple sclerosis (NO.MS) dataset is an ideal dataset in which to investigate the mechanisms of disability acquisition. It is currently the largest, most comprehensive clinical trial dataset in multiple sclerosis, spanning all phenotypes and containing data from ~35 000 patients with up to 15 years of follow-up, with regular monitoring of patients' neurological status by trained and certified raters and the inclusion of randomized placebo-controlled trials across all stages of multiple sclerosis. Here, using a large subset of NO.MS data with longitudinal evaluations of disability and relapses, we quantify all confirmed disability worsening (CDW) events, and we investigate the mechanisms of disability accrual, i.e. RAW versus PIRA, across all multiple sclerosis phenotypes. This study examines the role of clinical relapses in driving disease worsening and estimates the extent to which DMTs can alter the disease course and prolong the time to milestone disability levels.
Brain. 2022;145(9):3147-3161. © 2022 Oxford University Press