How patients with multiple sclerosis acquire disability

Abstract

Patients with multiple sclerosis acquire disability either through: (1) Relapse-associated worsening (RAW), or (2) 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 MS (NO.MS) data pool spanning all multiple sclerosis phenotypes and pediatric multiple sclerosis, we evaluated ∼200,000 EDSS transitions from >27,000 patients with ≤15 years follow-up. We analyzed three datasets: (A) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (N = 27,328); (B) All phase 3 clinical trials (N = 8364); and (C) 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 (DMTs) on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in multiple sclerosis, 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 (vs 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 DMTs delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and by 3.09 years (2.60, 3.72), respectively. In relapsing-remitting multiple sclerosis (RRMS), patients who worsened exclusively due to RAW events took a similar 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 relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA starts already in RRMS 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. Using DMTs delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study

“…Although this finding might seem counterintuitive, as previous data support an amplified beneficial effect of cladribine tablets in highly active patients [ 9 , 30 ], the definition of “high activity” usually requires the occurrence of two relapses in the year prior to treatment start, and the relapse rate in our cohort was far from this cutoff (0.7 in the overall population, 0.9 in patients experiencing progression). Thus, our results are better interpreted in the light of a recent study that, analyzing more than 27,000 patients with ≤ 15.7 years of follow-up, has confirmed the major contribution of relapses to the accumulation of disability over the course of MS [ 31 ].…”

Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration

“…We recently developed a new rodent model of progressive MS, in which the focal lesions mimic histological features of the disease, including microglia activation, astrogliosis, demyelination, and B- and T-cell infiltration ( 33 ). Importantly, the lesions are clinically silent, which reflects the increased relevance of centrally compartmentalized demyelination/neurodegenerative pathophysiological processes and the reduction in acute inflammatory/relapse activity that is typical of the progressive phase of the disease ( 44 ), and further allows for longitudinal studies and assessment of treatment paradigms. Furthermore, the model features structured and long-term aggregates of B-cells in the meningeal-brain parenchymal interface, representing TLS.…”

MSProDiscuss™ Clinical Decision Support Tool for Identifying Multiple Sclerosis Progression

“…A consensus is growing that MS exists on a continuum, with an overlap between relapsing and progressive phenotypes [ 5 , 10 ]. Although it is widely recognized that relapses lead to disability (relapse-associated worsening), mounting evidence demonstrates progression independent of relapse activity [ 11 , 12 , 13 ]. Progressive neuroaxonal loss is responsible for the accumulation of disability and occurs from the outset; the pathology is thought to be driven by a primary ‘smoldering’ process, accompanied by concurrent inflammatory activity reflective of the patient’s immune response to various putative causative mechanisms, including axonal and synaptic loss; demyelination; macrophage/microglial activation; oxidative injury; age-related iron accumulation; mitochondrial damage; and infection [ 5 ].…”

“…The early identification of progression is vital to optimize long-term brain health, and the ability to consistently identify progression, with a high degree of sensitivity and specificity, is directly relevant to this aim. MS management with disease-modifying therapies (DMTs) can delay the accumulation of disability [ 11 , 27 , 28 ]; however, treatment should be adapted according to the phase of the disease and, in many regions, labels of DMTs restrict use to specific phenotypic descriptors (e.g., RRMS; active SPMS) [ 26 ]. Thus, the phenotypic classification of MS, partly based on progression, has implications for treatment decisions.…”