Background: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an ␣4 1 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.Objective: To test the effect of natalizumab treatment on the CD4 ϩ /CD8 ϩ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.Design: Prospective longitudinal study.Setting: Academic and private multiple sclerosis centers.Patients: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients.Main Outcome Measures: CD4 ϩ and CD8 ϩ T cells were enumerated in CSF and peripheral blood.The mean fluorescence intensity of unbound ␣4 integrin on pe-ripheral blood CD4 ϩ and CD8 ϩ T cells was analyzed before and after natalizumab therapy.Results: Natalizumab therapy decreased the CSF CD4 ϩ / CD8 ϩ ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients.CD4 ϩ /CD8 ϩ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits.Six months after the cessation of natalizumab therapy, CSF CD4 ϩ /CD8 ϩ ratios normalized.The expression of unbound ␣4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4 ϩ vs CD8 ϩ T cells.Conclusions: Natalizumab treatment alters the CSF CD4 ϩ /CD8 ϩ ratio.Lower expression of unbound ␣4 integrin on CD4 ϩ T cells is one possible mechanism.These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.
To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets.Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]).Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch.Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.
The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10−12). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10−12). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
Compare time to first relapse (TTFR), annualized relapse rate (ARR), and discontinuation outcomes in patients initiating dimethyl fumarate (DMF) pair-wise versus a propensity-matched cohort of fingolimod (FTY), teriflunomide (TERI), interferons (IFN), or glatiramer acetate (GA).
To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments.
OBJECTIVE: This phase III double-blind, randomized clinical trial (NCT00666887) aims to demonstrate that minocycline reduces the conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS) by 25% compared to placebo within 6 months. Follow-up continues to 2 years. We describe the trial design, participant characteristics and recruitment challenges.
BACKGROUND: Minocycline is a widely available oral drug that appears promising for relapsing remitting MS.
DESIGN/METHODS: Patients from 12 Canadian MS clinics, aged 18 to 60 years who had a first focal episode of demyelination within the previous 180 days, and at least two lesions on T2-weighted brain screening magnetic resonance imaging (MRI), were randomized (1:1) to minocycline 100 mg twice daily or matching placebo. After the screening and baseline visits, follow-up occurred at 1, 3, 6, 12, 18, and 24 months. MRI scans were obtained at screening, 3, 6, 12, and 24 months.
RESULTS: This trial began in 2008 and will be completed in December 2014. Over 55 months, 236 patients were screened and 143 randomized. This was 92% of the recruitment target. The majority of screen failures were due to fewer than 2 lesions on cranial MRI (57%) or reaching the 2005 McDonald criteria for MS (the study endpoint) before randomization (24%). Mean age of the randomized group was 36 years (range: 18-56), 69% were women, mean CIS duration was 65 days (range: 4-183), median EDSS was 1.5 (range: 0-4.5), and 59% were randomized to the high risk strata (2 or more enhancing lesions or dissemination in space based on 2005 McDonald criteria). These characteristics did not change over time. Ten patients remain in follow-up to month 6. Only 12 patients (8.4%) discontinued participation before reaching month 6 indicating excellent retention.
CONCLUSIONS: Recruitment was challenging as the diagnostic criteria for MS changed and new therapies became available. Despite the length of the trial, participant characteristics remained comparable over the enrolment period.
StudySupported by: Multiple Sclerosis Society of Canada Disclosure: Dr. Metz has received personal compensation for activities with Teva Neuroscience as a consultant, and Novartis as a scientific advisory board member. Dr. Metz has received research support from EMD Serono. Dr. Traboulsee has received personal compensation for activities with Roche Diagnostics Corp., EMD Serono, Teva Neuroscience, and Biogen Idec. Dr. Traboulsee has received research support from Bayer Pharmaceuticals Corp., and Roche Diagnostics Corp. Dr. Li has received personal compensation for activities with Opexa, Nuron, Genzyme Corp., Roche Diagnostics Corp., and Novartis. Dr. Li has received research support from EMD Serono, Genzyme Corp., and Roche Diagnostics Corp. Dr. Duquette has received personal compensation for activities with Berlex, Biogen Idec, Serono, Novartis, and Teva Neuroscience. Dr. Kremenchutzky has received research support from Bayer Pharmaceuticals Corp., Biogen Idec, EMD Serono, Genzyme Corp., Novartis, Roche Diagnostics Corp., Sanofi-Aventis Pharmaceuticals Inc., and Teva Neuroscience. Dr. Vorobeychik has received personal compensation for activities with Berlex, Biogen Idec, EMD Serono, Teva Neuroscience, Pfizer Inc., and Novartis as a member of advisory boards. Dr. Vorobeychik has received research support from Biogen Idec. Dr. Freedman has received personal compensation for activities with Actelion, Bayer, Biogen Idec, EMD Canada, Genzyme Corporation, Novartis, Opexa, Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Freedman has received research support from Bayer and Genzyme. Dr. Bhan has received personal compensation for activities with Biogen Idec, Serono Inc., Genzyme Corporation, Novartis and Teva Neuroscience. Dr. Blevinshas received personal compensation for activities with Biogen Idec, Teva Neuroscience, Serono Inc., Novartis and GlaxoSmithKline, Inc. Dr. Marriott has received personal compensation for activities with Roche Diagnostics Corp. Dr. Marriott has received research support from Roche Diagnostics Corp. Dr. Grand-Maison has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Bayer Pharmaceuticals Corp., Serono Inc., Biogen Idec, Genzyme Corp., and Novartis. Dr. Grand-Maison has received research support from Sanofi-Aventis Pharmaceuticals Inc., Bayer Pharmaceuticals Corp., Serono Inc., Biogen Idec, Genzyme Corp., and Novartis. Dr. Lee has received personal compensation for activities with Novartis, Serono Inc., and Biogen Idec as a consultant and advisory board member. Dr. Lee has received research support from Serono Inc. Dr. Thibault has nothing to disclose. Dr. Eliasziw has nothing to disclose. Dr. Yong has received personal compensation for activities with Teva Neuroscience. Dr. Yong has received research support from Teva Neuroscience and Novartis. Dr. Cerchiaro has nothing to disclose. Dr. Wiebe has nothing to disclose. Dr. Cheng has nothing to disclose. Dr. Zhao has nothing to disclose. Dr. Greenfield has nothing to disclose. Dr. Topor has nothing to disclose. Dr. Riddehough has nothing to disclose.
ABSTRACT: Anosognosia is a well-known manifestation of non-dominant parietal lobe lesions and typically lasts a few days. That anosognosia may last only a few minutes to a few hours, as observed in six patients, has not been reported. In five patients, transient anosognosia for equally brief left-sided hemiparesis was a manifestation of transient ischemic attacks (TIAs). In the sixth patient, anosognosia for both a left-sided motor seizure and a subsequent brief left hemiparesis could best be explained by an epileptic ictal and post-ictal transient dysfunction of the non-dominant parietotemporal cortex. Prompt recognition of transient anosognosia, whether ischemic or epileptic, is mandatory for proper diagnosis and for rapid initiation of specific therapy.
We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.
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