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

Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed.OBJECTIVE To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set.

This is the first prospective, population-based IBD epidemiological study in a developed region of China. The incidence of IBD is similar to that in Japan and Hong Kong but lower than that in South Korea and Western countries.

Importance Disability measures in multiple sclerosis (MS) fail to capture potentially important variability in walking behavior. More sensitive and ecologically valid outcome measures are needed to advance MS research. Objectives To assess continuous step count activity remotely among individuals with MS for 1 year and determine how average daily step count is associated with other measures of MS disability. Design, Setting, and Participants In a prospective longitudinal observational cohort study, 95 adults with relapsing or progressive MS who were able to walk more than 2 minutes with or without an assistive device were recruited between June 15, 2015, and August 8, 2016, and remotely monitored in their natural environment for 1 year. Patients were excluded if they had a clinical relapse within 30 days or comorbidity contributing to ambulatory impairment. Longitudinal analysis was performed from October 2017 to March 2018. Revised analysis was performed in December 2018. Intervention Activity monitoring of step count using a wrist-worn accelerometer. Main Outcomes and Measures Average daily step count compared with in-clinic assessments and patient-reported outcomes. Results Of the 95 participants recruited (59 women and 36 men; mean [SD] age, 49.6 [13.6] years [range, 22.0-74.0 years]), 35 (37%) had progressive MS, and the median baseline Expanded Disability Status Scale score was 4.0 (range, 0-6.5). At 1 year, 79 participants completed follow-up (83% retention). There was a modest reduction in accelerometer use during the 1 year of the study. A decreasing average daily step count during the study was associated with worsening of clinic-based outcomes (Timed 25-Foot Walk, β = −13.09; P < .001; Timed-Up-and-Go, β = −9.25; P < .001) and patient-reported outcomes (12-item Multiple Sclerosis Walking Scale, β = −17.96; P < .001). A decreasing average daily step count occurred even when the Expanded Disability Status Scale score remained stable, and 12 of 25 participants (48%) with a significant decrease in average daily step count during the study did not have a reduction on other standard clinic-based metrics. Participants with a baseline average daily step count below 4766 (cohort median) had higher odds of clinically meaningful disability (Expanded Disability Status Scale score) worsening at 1 year, adjusting for age, sex, and disease duration (odds ratio, 4.01; 95% CI, 1.17-13.78; P = .03). Conclusions and Relevance Continuous remote activity monitoring of individuals with MS for 1 year appears to be feasible. In this study, a decreasing average daily step count during a 1-year period was associated with worsening of standard ambulatory measures but could also occur even when traditional disability measures remained sta...

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm 3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression.