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Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18–60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43–1·74; 75 mg, 0·79, 0·40–1·58; 150 mg, 0·98, 0·52–1·81; placebo, 0·38, 0·17–0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97–5·27; 75 mg, 2·30, 1·08–4·92; 150 mg, 2·49, 1·18–5·27; placebo, 3·07, 1·40–6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely measures a user’s mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (‘active tests’). Levels of mobility of study participants (‘life-space measurement’) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

Background Upper limb dysfunction is a common debilitating feature of relapsing‐remitting multiple sclerosis (RRMS). We aimed to examine the longitudinal trajectory of the iPad®‐based Manual Dexterity Test (MDT) and predictors of change over time. Methods We prospectively enrolled RRMS patients (limited to Expanded Disability Status Scale (EDSS) < 4). Longitudinal data was analysed using mixed‐effect modelling and latent class mixed models. We then examined whether group membership in latent classes predicted confirmed slowing in MDT. Results Seven hundred and twenty‐one participants had complete data for analysis. At a population level, MDT remained stable over time. No practice effect was seen. Baseline disability and T2 lesion volume were the strongest predictors of longitudinal MDT performance. We identified two latent class trajectories of MDT. The slower latent class was typified by greater variability and a weak association with confirmed worsening of MDT and EDSS. When compared to trajectory analysis stratified by baseline MDT, latent class analysis (LCA) was able to identify those at greater risk of confirmed slowing, signifying the importance of latent processes in upper limb function in pwMS. Conclusion In this cohort of mild to moderate RRMS, MDT scores remained stable over time with no evidence of a practice effect at a population level. Trajectory analysis based on LCA identified a cohort with greater variability and risk of disability progression and domain specific worsening. Our findings demonstrate the importance of latent processes in determining upper limb function in pwMS.

Adherence to injectable disease-modifying treatments in patients with multiple sclerosis (MS) impacts outcomes and can be influenced by perceptions of treatment efficacy, side effects, injection frequency, and the duration of injection. This study aimed to quantify preferences for selected attributes of injectable treatments among individuals with MS in the United Kingdom and France. Respondents with a self-reported diagnosis of MS completed an online discrete-choice-experiment survey, consisting of a series of treatment-choice questions. Each choice question presented two hypothetical treatments, each with six attributes (years until disability progression, relapses in the next 4 years, injection time, injection frequency, flu-like symptoms (FLS), and injection-site reactions), each with various levels. Mixed-logit regression analysis was used to estimate preference weights for attribute levels and to calculate the relative importance of changes in treatment attributes (vertical distance between preference weights). Minimum acceptable efficacy estimates indicate improvement in efficacy that respondents would require in exchange for worsening injection frequency and FLS. In both countries, 100 respondents completed the survey. In the United Kingdom and France, respectively, improving the time until disability progression from 2 to 4 years, reducing injection frequency from \"daily\" to \"every 2 weeks\", and reducing FLS from 3 days after every injection to none had a relative importance of 2.9 and 2.6, 3.0 and 3.5, and 2.5 and 3.1. Given the ranges included in the study, changes in these attributes were more important than most changes in other attributes assessed. Reductions in the injection frequency of MS treatments and FLS can be as important to patients as improvements in treatment efficacy.

Objective To validate the smartphone sensor‐based Draw a Shape Test – a part of the Floodlight Proof‐of‐Concept app for remotely assessing multiple sclerosis‐related upper extremity impairment by tracing six different shapes. Methods People with multiple sclerosis, classified functionally normal/abnormal via their Nine‐Hole Peg Test time, and healthy controls participated in a 24‐week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross‐sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls. Results Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure‐of‐8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate‐to‐good correlation (|r| = 0.14–0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate‐to‐good correlation (|r| = 0.18–0.41) with Nine‐Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls. Interpretation The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis‐related upper extremity impairment characterization.

BackgroundPatient Determined Disease Steps(PDDS) is a common patient-reported outcome(PRO) in multiple sclerosis(MS). However, concerns remain over its validity and reliability in mild to moderate disability, longitudinal performance and confounding due to mood disorders.ObjectivesWe aimed to examine the psychometric properties of the PDDS in people with MS(pwMS), to explore longitudinal associations between expanded disability status scale(EDSS) and PDDS, and examine the impact of mood on PDDS.MethodsWe prospectively enrolled relapsing-remitting multiple sclerosis(RRMS) patients with mild to moderate disability. Participants completed an iPad-based version of the PDDS, other PROs and EDSS 6-monthly. Test-retest reliability and validity was assessed. Longitudinal data was examined with mixed effect modelling.ResultsWe enrolled 904 RRMS patients with a median age of 40.9years, median EDSS of 1.5 and median PDDS of 0. The baseline correlation between PDDS and EDSS was weak. Correlations between functional systems(FS), age, disease duration and processing speed test(PST) and EDSS were stronger compared to PDDS. Conversely, correlations between PROs and PDDS were stronger. PDDS test-retest reliability was good to excellent. Longitudinally, PDDS was weakly associated with EDSS, depression and quality-of-life scores. Higher EDSS was associated with greater progression in PDSS. The magnitude of these associations were small.ConclusionThe PDDS differs from the EDSS in its psychometric properties, and should not be used interchangeably. The discordance in the aspects of disability that the PDDS measures may explain the small magnitude of longitudinal and cross-sectional associations. Modifying the PDDS to better detect under-reported symptoms such as bladder and bowel dysfunction may improve its validity.

Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.

BackgroundCognitive impairment is one of the most common and debilitating symptoms of relapsing remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad-based Processing Speed Test (PST) and predictors of change over time.MethodsWe prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients with an EDSS score of less than four. Longitudinal data was analysed with mixed effect modelling and latent class mixed models.ResultsAt a population level, PST trajectory was stable. A small practice effect was present up to the 4th visit. Age, baseline disability, T2 lesion volume, male gender and depression were associated with less correct PST responses, whilst years of education and full/part-time employment were associated with more correct PST responses.We identified four trajectories of processing speed with latent class analysis. The lowest latent class was typified by the lack of a practice effect and was associated with a greater hazard of time to sustained 5% decrease in PST (HR 2.84, 95%CI 1.16–6.94, p=0.02).ConclusionIn this cohort of mild to moderate RRMS, PST scores remained largely stable over time. Membership in the worst latent class trajectory was associated with a sustained 5% PST decrease. Poor cognitive performance at baseline and the lack of a practice effect is a predictor of future cognitive decline and should prompt early intervention for maximising cognitive function such as treatment escalation.

BackgroundUpper limb dysfunction is a common debilitating feature of relapsing remitting multiple sclerosis (RRMS). We aimed to examine the longitudinal trajectory of the iPad-based Manual Dexterity Test (MDT) and predictors of change over time.MethodsWe prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients with an EDSS score of less than four. Longitudinal data was analysed with mixed effect modelling and latent class mixed models. We examined whether group membership in latent classes were predictive of a confirmed decrease in MDT.ResultsAt a population level, MDT remained stable over time. No practice effect was seen. Baseline disability and T2 lesion volume were the strongest predictors of longitudinal MDT performance.Latent class analysis identified 2 classes of MDT trajectories. In the slower trajectory, greater variability and a weak association with sustained worsening of MDT was present. Group trajectory based on latent class analysis and baseline MDT was different, signifying the importance of latent processes in upper limb function in pwMS.ConclusionIn this cohort of mild to moderate RRMS, MDT scores remained stable over time with no evidence of a practice effect at a population level. Trajectory analysis based on latent class identified a cohort with greater variability and risk of sustained worsening. Our findings show the importance of latent processes in determining upper limb function trajectories in pwMS.

Gestational disruption of neurodevelopment has been proposed to lead to pathophysiological changes similar to those underlying schizophrenia. We induced such disruption by treating pregnant rat dams with methylazoxymethanol acetate (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When locomotor activity was assessed in an open field, MAM-exposed rats were hyper-responsive to a mild stress and to amphetamine (2 mg/kg, s.c.). They also engaged in less social interaction than controls. We studied, by microdialysis, the effect of amphetamine on extracellular dopamine in the nucleus accumbens and the medial prefrontal cortex of freely moving control and MAM-exposed rats. Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no difference was seen in the medial prefrontal cortex. In controls, amphetamine infused into the medial prefrontal cortex (50 microM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAM-exposed rats, where a transient increase in nucleus accumbens dopamine levels was seen after amphetamine infusion. These results show that the late gestational disruption of neurogenesis in the rat leads to behavioral changes that mimic positive and negative schizophrenia symptoms, and also to a dysregulation of subcortical dopamine neurotransmission. This study contributes to the evaluation of the validity of the prenatal MAM GD17 treatment in rats as an animal model for schizophrenia.