No evidence for an association between alcohol consumption and Multiple Sclerosis risk: a UK Biobank study

Multiple Sclerosis (MS) has been linked to a variety of environmental risk factors, including smoking, Epstein-Barr Virus infection, and childhood obesity. There is some evidence to support a relationship between alcohol consumption and MS risk, but this finding has been inconsistent across cohorts. A protective link between alcohol consumption and MS risk is seen in Swedish and Danish cohorts, however evidence from other cohorts and mendelian randomisation studies have failed to support this relationship. We assessed the relationship between alcohol consumption (never vs. ever drinking) and MS in 409,228 individuals (2100 with MS) from UK Biobank (UKB). We used multivariable logistic regression models adjusted for age and sex. To determine whether there was evidence of statistical interaction between alcohol consumption and HLA-DRB1*15:01 genotype, we calculated interaction on the additive and multiplicative scales. We analysed data from 2100 individuals with MS (72.3% female, median age at recruitment 56) and 407,128 controls (53.9% female, median age at recruitment 58). We found no evidence for an association between alcohol consumption and MS risk (OR = 1.12, 95% CI 0.61–2.08, p = 0.314). As expected, the HLA-DRB1*15:01 allele was strongly associated with MS risk (OR = 2.72, 95% CI 2.72–2.72, p < 2 × 10(−16)). We found no evidence of statistical interaction between non-drinking and MS risk on either the multiplicative scale (p = 0.8) or on the additive scale (Attributable Proportion = 0.03, 95% CI − 0.43–0.29, P = 0.45). Empirical power calculations indicated reasonable statistical power (85%) to detect a protective effect of alcohol consumption of Relative Risk ≤ 0.7. We were thus unable to replicate findings from other cohorts within UK Biobank. The inconsistent association seen between studies may reflect limited statistical power to detect a weak effect, differences in population characteristics, or the lack of a true causal association

Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

Multiple sclerosis (MS) is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC) to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4) and FCAR (Fc fragment of IgA, CD89) that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Alemtuzumab; Disease-modifying therapy; Multiple sclerosisAlemtuzumab; Teràpia modificadora de la malaltia; Esclerosi múltipleAlemtuzumab; Terapia modificadora de la enfermedad; Esclerosis múltipleBackground and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course.The TOPAZ study as well as writing and editorial support for this article were funded by Sanofi

Cerebellar volume as imaging outcome in progressive multiple sclerosis

Background and purpose: To assess whether cerebellar volumes changes could represent a sensitive outcome measure in primary-progressive MS. Material and methods: Changes in cerebellar volumes over one-year follow-up, estimated in 26 primary-progressive MS patients and 20 controls with Freesurfer longitudinal pipeline, were assessed using Wilcoxon test and tested for their correlation with disability worsening by a logistic regression. Clinical worsening was defined as EDSS score increase or change of &gt;20% for 25-foot walk test or 9-hole peg test scores at follow-up. Sample sizes for given treatment effects and power were calculated. The findings were validated in an independent cohort of 20 primary-progressive MS patients. Results: Significant changes were detected in brain T1 lesion volume (p&lt;0.01), cerebellar T2 and T1 lesion volume (p&lt;0.01 and p&lt;0.05), cerebellar volume, cerebellar cortex volume, and cerebellar WM volume (p&lt;0.001). Only cerebellar volume and cerebellar cortex volume percentage change were significantly reduced in clinically progressed patients when compared to patients who did not progress (p&lt;0.01; respectively AUC of 0.91 and 0.96). Cerebellar volume percentage changes were consistent in the exploration and validation cohorts (cerebellar volume -1.90±1.11% vs -1.47±2.30%; cerebellar cortex volume -1.68±1.41% vs -1.56±2.23%). Based on our results the numbers of patients required to detect a 30% effect are 81 per arm for cerebellar volume and 162 per arm for cerebellar cortex volume (90% power, type 1 error alpha = 0.05). Conclusions: Our results suggest a role for cerebellar cortex volume and cerebellar volume as potential short-term imaging metrics to monitor treatment effect in primary-progressive MS clinical trials

Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis MAGNIFY-MS

BACKGROUND AND OBJECTIVES The onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an important parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS. METHODS MRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium-enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed. RESULTS Included in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (-1.193 between month 1 and month 6, -1.500 between month 2 and month 6, and -1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (-0.857 at month 2, -1.355 at month 3, and -1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6. DISCUSSION Findings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time. TRIAL REGISTRATION INFORMATION NCT03364036; Date registered: December 06, 2017. CLASSIFICATION OF EVIDENCE Using frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time

Eleven fetal echocardiographic planes using 4-dimensional ultrasound with spatio-temporal image correlation (STIC): a logical approach to fetal heart volume analysis

<p>Abstract</p> <p>Background</p> <p>Theoretically, a cross-sectional image of any cardiac planes can be obtained from a STIC fetal heart volume dataset. We described a method to display 11 fetal echocardiographic planes from STIC volumes.</p> <p>Methods</p> <p>Fetal heart volume datasets were acquired by transverse acquisition from 200 normal fetuses at 15 to 40 weeks of gestation. Analysis of the volume datasets using the described technique to display 11 echocardiographic planes in the multiplanar display mode were performed offline.</p> <p>Results</p> <p>Volume datasets from 18 fetuses were excluded due to poor image resolution. The mean visualization rates for all echocardiographic planes at 15-17, 18-22, 23-27, 28-32 and 33-40 weeks of gestation fetuses were 85.6% (range 45.2-96.8%, N = 31), 92.9% (range 64.0-100%, N = 64), 93.4% (range 51.4-100%, N = 37), 88.7%(range 54.5-100%, N = 33) and 81.8% (range 23.5-100%, N = 17) respectively.</p> <p>Conclusions</p> <p>Overall, the applied technique can favorably display the pertinent echocardiographic planes. Description of the presented method provides a logical approach to explore the fetal heart volumes.</p

Longitudinal Assessment of Antisaccades in Patients with Multiple Sclerosis

We have previously demonstrated that assessment of antisaccades (AS) provides not only measures of motor function in multiple sclerosis (MS), but measures of cognitive control processes in particular, attention and working memory. This study sought to demonstrate the potential for AS measures to sensitively reflect change in functional status in MS. Twenty-four patients with relapsing-remitting MS and 12 age-matched controls were evaluated longitudinally using an AS saccade task. Compared to control subjects, a number of saccade parameters changed significantly over a two year period for MS patients. These included saccade error rates, latencies, and accuracy measures. Further, for MS patients, correlations were retained between OM measures and scores on the PASAT, which is considered the reference task for the cognitive evaluation of MS patients. Notably, EDSS scores for these patients did not change significantly over this period. These results demonstrate that OM measures may reflect disease evolution in MS, in the absence of clinically evident changes as measured using conventional techniques. With replication, these markers could ultimately be developed into a cost-effective, non-invasive, and well tolerated assessment tool to assist in confirming progression early in the disease process, and in measuring and predicting response to therapy

Is the Concept of Quality of Life Relevant for Multiple Sclerosis Patients with Cognitive Impairment? Preliminary Results of a Cross-Sectional Study

Background: Cognitive impairment occurs in about 50 % of multiple sclerosis (MS) patients, and the use of self-reported outcomes for evaluating treatment and managing care among subjects with cognitive dysfunction has been questioned. The aim of this study was to provide new evidence about the suitability of self-reported outcomes for use in this specific population by exploring the internal structure, reliability and external validity of a specific quality of life (QoL) instrument, the Multiple Sclerosis International Quality of Life questionnaire (MusiQoL). Methods: Design: cross-sectional study. Inclusion criteria: MS patients of any disease subtype. Data collection: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, Expanded Disability Status Scale, disease duration); QoL (MusiQoL and SF36); and neuropsychological performance (Stroop color-word test). Statistical analysis: confirmatory factor analysis, item-dimension correlations, Cronbach’s alpha coefficients, Rasch statistics, relationships between MusiQoL dimensions and other parameters. Principal Findings: One hundred and twenty-four consecutive patients were enrolled. QoL scores did not differ between the 69 cognitively non-impaired patients and the 55 cognitively impaired patients, except for the symptoms dimension. The confirmatory factor analysis performed among the impaired subjects showed that the structure of the questionnaire matched with the initial structure of the MusiQoL. The unidimensionality of the MusiQoL dimensions was preserved, and th