Silent progression in disease activity–free relapsing multiple sclerosis

Abstract

Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation. Methods Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates. Results Relapses were associated with a transient increase in disability over 1‐year intervals ( p = 0.012) but not with confirmed disability progression ( p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable ( p < 0.05). Interpretation Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

“…In MS, besides tissue damage due to relapse, progression independent of relapse activity (PIRA) leads to ongoing accumulation of disability in progressive as well as in relapsing forms of the disease. This chronic condition is characterized by ongoing brain tissue damage, also regarded as faster aging [41][42][43]. Other pathological changes are mitochondrial dysfunction, oxidative stress, and slowly enlarging lesions (SELs) detected on the MRI.…”

Knowledge Is Power, but Is Ignorance Bliss? Optimising Conversations About Disease Progression in Multiple Sclerosis

“…By contrast, patients are more likely to see the worsening of invisible symptoms, for example extreme fatigue or a bad mood episode, as signifying progression. Since these changes are not picked up via magnetic resonance imaging (MRI) or the expanded disability status scale (EDSS), the HCP may not consider or discuss them as signs of progression [24], yet failure to recognise changes in these invisible symptoms causes significant problems with regard to both mutual understanding of progression and patient satisfaction [24,25]. In addition, the use of clinical terminology, coupled with the complexity and variability of MS progression, can make conversations around the topic difficult for patients to fully understand [26].…”

“…A potential solution to this may be to combine clinical assessment scales with parallel feed-in from subjective patient evaluations [57]. From the patient side, it is also helpful for discussions to focus on disability progression rather than disease progression-and for physicians to differentiate the subjective experience of MS from the concept of disease activity and MRI changes, which may not be synonymous [15,25,58]. These changes may help to alleviate difficulties for HCPs in distinguishing secondary progression from silent progression-which could, at times, represent an ageing effect [59]-and help PwMS to understand the difference between 'disease progression' and 'progressive MS', preventing distress that can arise from conflating these concepts.…”

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod

“…Out of these 96 patients presenting with stable RR-MS at initial blood sampling, 26 suffered from an acute exacerbation during the period of completion of recruitment into the study. Relapse was defined as the occurrence of a new neurological disturbance with a duration of at least 24 h [68].…”