Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.
Objective In multiple sclerosis (MS) cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SCGM atrophy. Using phase sensitive inversion recovery (PSIR) MRI, we determined the association of the SCGM and SCWM areas with MS disability and disease type. Methods 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disc level. Two independent, clinically-masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results Relapsing (R) MS patients showed smaller SCGM areas than age and sex matched controls (p=0.008) without significant differences in SCWM areas. Progressive MS patients showed smaller SCGM and SCWM areas compared to RMS patients (all p≤0.004). SCGM, SCWM, and whole cord areas inversely correlated with EDSS (rho: −0.60, −0.32, −0.42, respectively; all p≤0.001). SCGM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, FLAIR lesion load, T1-lesion load, SCWM area, number of spinal cord T2 lesions, age, sex, disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation SCGM atrophy is detectable in-vivo in absence of WM atrophy in RMS. It is more pronounced in progressive than RMS and contributes more to patient disability than spinal cord WM or brain GM atrophy.
Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk C2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p \ 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) (p \ 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097–7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.
ObjectiveTo evaluate the safety of rituximab treatment before and during pregnancy in women with MS and neuromyelitis optica spectrum disorders (NMOSDs) who may be at risk of relapses by performing a systematic literature review combined with a retrospective single-center case series.MethodsStudies were systematically identified in the PubMed, Google Scholar, and EMBASE using the key terms “pregnancy” and “rituximab”; 22 articles were included for review (>17,000 screened). Then, patients with MS and NMOSD from 1 center (University of California, San Francisco) exposed to rituximab before conception were identified through medical record review.ResultsSystematic review: We identified 102 pregnancies with rituximab use within 6 months of conception: 78 resulted in live births and 12 in spontaneous abortions. Of 54 live births with reported gestational age, 31 occurred at term (37 weeks+) and 2 before 32 weeks. When checked, B-cell counts were low in 39% of newborns and normalized within 6 months. Case series: we identified 11 pregnancies (1 ongoing) in 10 women (7 MS and 3 NMOSD) treated with rituximab within 6 months of conception. All completed pregnancies resulted in term live births of healthy newborns (1 lost to follow-up at term). No maternal relapses occurred before/during pregnancy; 1 occurred postpartum (NMOSD).ConclusionNo major safety signal was observed with rituximab use within 6 months of conception. Beyond the need for monitoring neonatal B cells, these observations support prospectively monitoring a larger patient cohort to determine whether rituximab may safely protect women with MS and NMOSD who are planning a pregnancy against relapses.
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