Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis.
We conducted a randomized, double-blind, ...phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging.
Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%).
In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.).
This study explores default-mode network (DMN) abnormalities in patients with secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) and whether such abnormalities correlate ...with cognitive impairment and damage to selected white matter (WM) fiber bundles, quantified using diffusion tensor (DT) MRI tractography.
Resting state (RS) functional MRI and DT MRI data were acquired from 33 patients with SPMS, 24 patients with PPMS, and 24 controls. Independent component analysis (ICA) was used to identify the DMN. SPM5 was used to assess within- and between-group activations.
Between-group differences in DMN activity were found in the left medial prefrontal cortex (mPFC), left precentral gyrus (PcG), and anterior cingulate cortex (ACC). Compared to controls, patients with SPMS had reduced activity in the mPFC (p = 0.01) and PcG (p = 0.02), while patients with PPMS had reduced activity in the PcG (p = 0.008) and the ACC (p = 0.002). Compared to patients with PPMS, patients with SPMS had increased ACC activity (p = 0.04). Reduction of RS activity in the ACC was more pronounced in cognitively impaired vs cognitively preserved patients with MS (p = 0.02). In patients with MS, DMN abnormalities correlated with the PASAT and word list test scores (r values ranging from 0.35 to 0.45) and DT MRI changes in the corpus callosum and the cingulum (r values ranging from 0.82 to 0.87).
These results suggest that a dysfunction of the anterior components of the default-mode network may be among the factors responsible for the accumulation of cognitive deficits in patients with progressive multiple sclerosis.
Natalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in ...large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic.
A registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age.
101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months. During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 (p < 0.001) at last NA infusion. Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit (p < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58% of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded.
NA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course.
A relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58% of cases.
Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that ...soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.
In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons ...(OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express
Synaptotagmin 13 (SYT13)
compared to spinal motor neurons. In end-stage ALS patients,
SYT13
is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with
Syt13
prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.
Summary Background Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the ...efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. Methods In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov , number NCT00666224. Findings All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0·55, 95% CI 0·40–0·77; p=0·0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 56% glatiramer acetate vs 56 24% placebo) and immediate post-injection reactions (47 19% vs 12 5%). Interpretation Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. Funding Teva Pharmaceutical Industries, Israel.
To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS).
The percent brain volume change (PBVC) was computed on existing longitudinal (2 time ...points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68).
There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.
This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.
Background and purpose
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid ...professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.
Methods
This guideline has been developed using the GRADE methodology and following the updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. Literature searches up to December 2016 were performed and the evidence is presented narratively and, when possible, combined in a meta‐analysis. The quality of evidence was rated into four categories – very high, high, low and very low − according to the risk of bias. The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results
A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 21 recommendations were agreed by the guideline working group members after three rounds of consensus.
Conclusion
The present guideline, which includes descriptions of the evidence together with recommendations, will enable homogeneity of treatment decisions across Europe.
Objectives
To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
Methods
Twelve ...months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test–retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.
Results
At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.
Conclusions
PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.
Objective:
To assess the long-term benefit-risk profile of repeated courses of rituximab in Caucasian patients affected by neuromyelitis optica (NMO) and related disorders, in everyday clinical ...practice.
Methods:
This is a prospective observational study performed at San Raffaele Hospital, Milan, Italy. From February 2006, we recruited 21 patients affected by NMO and NMO spectrum of disorders (NMOSD) whom underwent at least one cycle of intravenous (i.v.) rituximab and then were followed for at least 2 years.
Results:
At a mean follow-up time of 48 months, we observed a significant reduction of the annualized relapse rate (ARR), from 2.0 to 0.16 (p < 0.01); and of the median Expanded Disability Status Scale (EDSS), from 5.5 to 4.0 (p < 0.013). There were 12 patients (57%) who remained disease free during the follow-up period. Five patients (24%) reported mild hematological adverse events. Serious infectious adverse events were reported by another four patients: These were all wheelchair bound at the beginning of their rituximab treatment.
Conclusions:
A fixed treatment scheme of rituximab, with re-treatment every 6 months, was efficacious for NMO and NMOSD, with a good safety profile; however, to obtain an even better benefit-risk ratio, close monitoring of CD19+ B cells should be performed before the re-treatment of patients with high-level disability, concomitant leukopenia and hypogammaglobulinemia.