Search

ObjectiveTo directly compare the efficacy of natalizumab and fingolimod in patients with active relapsing-remitting multiple sclerosis.MethodsThis phase 4, randomised, rater- and sponsor-blinded, prospective, parallel-group, clinic-based head-to-head study was conducted at 43 sites in nine countries. Patients were randomised (1:1) to intravenous natalizumab 300 mg every 4 weeks or oral fingolimod 0.5 mg once daily for ≤52 weeks. Enrolment-related early study termination precluded assessment of the primary endpoint (evolution of new on-treatment gadolinium-enhancing (Gd+) lesions to persistent black holes). Unplanned exploratory analyses of secondary endpoints evaluated the effects of treatment on the development of new T1 Gd+ lesions and new/newly enlarging T2 lesions, lesion volumes and relapse outcomes.ResultsThe intent-to-treat population comprised 108 patients (natalizumab, n=54; fingolimod, n=54); 63 completed ≥24 weeks of treatment. Due to the limited numbers of events and patients at risk, MRI and relapse outcomes were reported over up to 24 and 36 weeks, respectively. The mean number of new T1 Gd+ lesions was numerically lower with natalizumab than with fingolimod by 4 weeks; accumulation rates were 0.02 and 0.09 per week, respectively, over 24 weeks (p=0.004). The cumulative probability of developing ≥1 lesion at 24 weeks was 40.7% with natalizumab versus 58.0% with fingolimod (HR=0.60; 95% CI 0.31–1.16; p=0.126); the corresponding probabilities for ≥2 lesions were 11.5% vs 48.5% (HR=0.25; 95% CI 0.09–0.68; p=0.007). No significant between-group differences were observed for the other MRI outcomes at 24 weeks. The cumulative probability of relapse over follow-up was 1.9% with natalizumab versus 22.3% with fingolimod (HR=0.08; 95% CI 0.01–0.64; p=0.017). Adverse events were consistent with known safety profiles.ConclusionsThese results suggest that natalizumab is more efficacious than fingolimod in reducing multiple sclerosis relapses and T1 Gd+ lesion accumulation in patients with active disease.Trial registration numbersNCT02342704; EUCTR2013-004622-29-IT; Post-results.

Objective To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. Methods A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. Results UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. Conclusions SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24. © 2014 by the BMJ Publishing Group Ltd.

IntroductionREVEAL was designed as a 1 year, multicentre, randomised, rater- and sponsor-blinded, prospective study comparing natalizumab and fingolimod in patients with active RRMS. Although the study closed early (for non-safety/non-efficacy reasons), data permitted comparison of effects occurring shortly after treatment initiation. This analysis compares onset of efficacy with natalizumab and fingolimod in REVEAL.MethodsPatients were randomised to open-label intravenous natalizumab 300 mg every 4 weeks (n=54) or oral fingolimod 0.5 mg once daily (n=54). Magnetic resonance imaging was scheduled every 4 weeks for the first 24 weeks and at weeks 36 and 52. Analyses included Kaplan-Meier and Cox regression, negative binomial regression (annualised relapse rate [ARR] and number of T1 gadolinium-enhancing [Gd+] lesions) and a negative binomial generalised estimating equation (cumulative Gd +lesions over time).ResultsAs expected for a randomised study, patient characteristics and follow-up time (median 39 weeks) were generally similar between groups. Natalizumab patients were less likely than fingolimod patients to develop new Gd +lesions (for ≥1 lesion, cumulative probability 40.68% vs 57.99%; hazard ratio [HR]=1.678 [95% CI: 0.865 to 3.255]; p=0.1258; for ≥2 lesions, cumulative probability 11.54% vs 48.48%; HR=4.053 [95% CI: 1.474 to 11.144]; p=0.007). Natalizumab patients consistently had 63%–72% fewer Gd +lesions than fingolimod patients, with between-group differences apparent within 4 weeks and reaching significance by 12 weeks (p=0.030). ARR was 83% lower with natalizumab than with fingolimod (0.05 vs 0.29; p=0.023), and cumulative probability of relapse was 1.85% with natalizumab vs 22.28% with fingolimod (HR=12.184 [95% CI: 1.552 to 95.634]; p=0.017). Adverse events were consistent with known safety profiles.ConclusionThese results suggest that natalizumab reduces disease activity more rapidly and to a greater extent than fingolimod in patients with active RRMS. Given the early study closure, available data did not permit primary endpoint evaluation, and interpretation of these results requires caution.Study SupportBiogen.

The first publications about in vivo application of ultra-high field MRI in multiple sclerosis (MS) appeared in 2008. From then on, the number of studies performed at 7 Tesla (T) has rapidly increased. The main advantage of ultra-high field MRI is its higher signal-to-noise ratio, which can be used to increase spatial resolution greatly. This has led to improved detection of subtle MS pathology, particularly in clinically relevant regions like the grey matter (GM). Another advantage of 7 T MRI is its increased sensitivity to susceptibility effects. This has been used to image additional morphological characteristics of MS lesions.1 For example, susceptibility-weighted MRI at 7 T has confirmed that MS white matter (WM) lesions are consistently …

Objective A previous 1H-MR spectroscopy (MRS) study reported elevated levels of glutamate, an excitatory neurotransmitter, in acute lesions and normal-appearing white matter, which may relate to the presence of inflammatory cells and astrocytosis. We aim to assess whether glutamate levels (1) change in the grey matter (GM), and (2) relate to cognitive dysfunction. Methods Single-voxel MRS was performed at 3 T in 18 patients with relapsing-remitting MS [12 women, age 43.5 years, median EDSS 2.8] and 17 healthy subjects [11 women, age 39.7], using PRESS [TR6000, TE30, water suppression]. Voxels were located in the right cingulate and parietal cortices, right hippocampus and thalamus. Concentrations of metabolites were obtained using LCModel, scaled using the water signal amplitude, and corrected for fractions of different tissue compartments and their T1 and T2 relaxation times. Visual and verbal memory and speed of information processing were assessed. Results Patients showed significantly worse performance on the visual memory test (total errors p Discussion Glutamate neurotransmission is reduced in the cortical and hippocampal regions of people with MS and is linked to cognitive impairment. Reduced levels of glutamate and NAA in cortical GM agree with post-mortem findings of GM neuronal loss in MS. MR spectroscopy of cortical glutamate may provide a surrogate marker for assessing the efficacy of future therapies in reducing memory decline in people with MS.

We aim to assess whether the concentration of glutamate, an excitatory neurotransmitter, changes in the grey matter (GM) of patients with Multiple Sclerosis (MS), and whether it relates to cognitive dysfunction and disability. Single-voxel MRS was performed at 3T in 18 patients with relapsing-remitting MS [12 women, age 43.5 years, median EDSS 2.8] and 17 healthy subjects [11 women, age 39.7] in the right cingulate and parietal cortices, right hippocampus and thalamus. (Abstract 128 figure 1) Visual and verbal memory and speed of information processing were assessed. Patients showed significantly worse performance on the visual memory test, verbal learning, delayed verbal recall, and speed of information processing, compared to controls. Patients showed lower glutamate concentration in the cingulate and parietal cortices and in the hippocampus compared to controls. Patients showed significantly lower N-Acetyl-Aspartate levels in the thalamus and cortical GM, and reduced glutamate-glutamine, choline-containing compounds and creatine plus phosphocreatine levels in the cortical GM, compared to controls. Lower hippocampal glutamate levels correlated with worse visual memory. Reduced glutamate levels in the cingulate cortex and thalamus correlated with worse speed of processing and visual memory, respectively. We found reduced glutamate neurotransmission in the cortical and hippocampal regions, which was linked to cognitive impairment. Reduced levels of most of the metabolites in the cortical GM, together with normal Inositol, are in agreement with post-mortem findings of GM neuronal loss, modest glial proliferation, low degree of inflammation and energy metabolism.