ORCID Profile
0000-0002-3850-447X
Current Organisations
John Hunter Hospital
,
Hunter New England Local Health District
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Frontiers Media SA
Date: 16-06-2020
Publisher: Elsevier BV
Date: 04-2021
Publisher: Hindawi Limited
Date: 12-09-2012
DOI: 10.1111/ANE.12007
Abstract: Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. To assess the correlation between fluctuation of sunlight and birth season in persons with MS. For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P < 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.
Publisher: JMIR Publications Inc.
Date: 12-10-2020
Abstract: ladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied. his study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3. his will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance. his study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021. his will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS. his study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165). ERR1-10.2196/24969
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1186/S13148-021-01200-8
Abstract: The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors in idually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.
Publisher: ACM
Date: 29-12-2018
Publisher: Elsevier BV
Date: 06-2019
Publisher: Elsevier BV
Date: 02-2020
Publisher: Wiley
Date: 10-01-2019
DOI: 10.1002/JMRI.26642
Abstract: Two-dimensional localized correlation spectroscopy (2D L-COSY) is a research tool that has been applied to evaluate in vivo metabolic activity in many neurological and oncological disorders. Circadian mediators such as brain temperature, hydration, and osmotic regulation have been claimed to change metabolic profiles. To evaluate the diurnal variability of neuro-metabolites with 2D L-COSY in healthy subjects using a 3 T scanner. Crossover. Ten healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino." Field Strength/Sequence: 3 T/2D L-COSY MRS. In vivo 2D L-COSY measurements were performed on ten healthy subjects (5 M/5F, mean age 36.1 ± 7.7 years) repeatedly at three timepoints (0700, 1200, and 1700) on the same day. in vitro evaluations were performed in a similar fashion as in vivo on Braino containing selected brain metabolites at physiological concentrations and pH. 2D L-COSY was acquired from a 27 cm One-way repeated measured analysis of variance with Bonferroni post-hoc adjustment using SPSS software. In vitro data showed no statistically significant differences between different scans (P > 0.12). in vivo results showed statistically significant diurnal variations (P ≤ 0.05, F > 3.88) for 22 resonances. Bonferroni post-hoc testing showed there was statistically significant increases in metabolite ratios between 0700 and 1700 and these include different moieties of N-acetylaspartate, creatine, choline, myo-inositol, lipids, fucose, glutathione, and homocarnosine. 2D L-COSY can detect diurnal physiological variability in neuro-metabolite levels. Thus, time of the day should be considered when planning MRS studies to avoid confounding results. 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019 :592-601.
Publisher: Springer Science and Business Media LLC
Date: 06-2010
DOI: 10.1038/NG0610-469
Publisher: SAGE Publications
Date: 17-08-2015
Abstract: Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions. Centers from 18 countries with cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of year and years at time of EDSS measurement were evaluated. The MS Severity Score (MSSS) was used as a measure of disease progression. Comparisons among regions (North America, Europe, Australia and LA), hemispheres and countries were performed. A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%) North America, 1609 (16.7%) Australia, 1119 (11.6%) and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres ( p = 0.68), regions ( p = 0.96) or countries ( p = 0.50). Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.018
Abstract: In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.
Publisher: SAGE Publications
Date: 27-07-2022
DOI: 10.1177/13524585221111677
Abstract: Patients with relapsing–remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. To determine predictors of relapse hazard when switching to cladribine. Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03–5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01–4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65–14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35–12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91–0.99). Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.017
Abstract: In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence in idual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing in idual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.
Publisher: Oxford University Press (OUP)
Date: 18-10-2013
DOI: 10.1093/BRAIN/AWT281
Abstract: 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.
Publisher: SAGE Publications
Date: 12-12-2014
Abstract: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk of developing MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation are recognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure and inherited genetic systems. To identify methylation changes associated with MS, we performed a genome-wide DNA methylation analysis of CD4+ T cells from 30 patients with relapsing–remitting MS and 28 healthy controls using Illumina 450K methylation arrays. A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. After prioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of a major effect CpG island in DRB1 in MS cases ( p FDR 3 × 10 −3 ). In addition, we found 55 non-HLA CpGs that exhibited differential methylation, many of which localise to genes previously linked to MS. Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation to MS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.
Publisher: Oxford University Press (OUP)
Date: 27-02-2010
DOI: 10.1093/HMG/DDQ090
Abstract: Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these s les. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40 the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.016
Abstract: Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using in idual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.
Publisher: Frontiers Media SA
Date: 08-06-2018
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
Publisher: Public Library of Science (PLoS)
Date: 31-10-2018
Publisher: Oxford University Press (OUP)
Date: 09-2020
Abstract: In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
Publisher: SAGE Publications
Date: 06-04-2017
Abstract: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5–5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143 16.8%), moderate ( n = 378 44.3%), or severe ( n = 332 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.
Publisher: SAGE Publications
Date: 20-07-2016
Abstract: Patient-Reported Expanded Disability Status Scale (PREDSS) tools are an attractive alternative to the Expanded Disability Status Scale (EDSS) during long term or geographically challenging studies, or in pressured clinical service environments. Because the studies reporting these tools have used different metrics to compare the PREDSS and EDSS, we undertook an in idual patient data level analysis of all available tools. Spearman’s rho and the Bland–Altman method were used to assess correlation and agreement respectively. A systematic search for validated PREDSS tools covering the full EDSS range identified eight such tools. In idual patient data were available for five PREDSS tools. Excellent correlation was observed between EDSS and PREDSS with all tools. A higher level of agreement was observed with increasing levels of disability. In all tools, the 95% limits of agreement were greater than the minimum EDSS difference considered to be clinically significant. However, the intra-class coefficient was greater than that reported for EDSS raters of mixed seniority. The visual functional system was identified as the most significant predictor of the PREDSS–EDSS difference. This analysis will (1) enable researchers and service providers to make an informed choice of PREDSS tool, depending on their in idual requirements, and (2) facilitate improvement of current PREDSS tools.
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 11-2023
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 31-01-2020
Publisher: Copernicus GmbH
Date: 29-07-2015
Abstract: Abstract. Iron availability in the Southern Ocean controls phytoplankton growth, community composition and the uptake of atmospheric CO2 by the biological pump. The KEOPS-2 (KErguelen Ocean and Plateau compared Study 2) "process study", took place around the Kerguelen Plateau in the Indian sector of the Southern Ocean. This is a region naturally fertilised with iron on the scale of hundreds to thousands of square kilometres, producing a mosaic of spring blooms which show distinct biological and biogeochemical responses to fertilisation. This paper presents biogeochemical iron budgets (incorporating vertical and lateral supply, internal cycling, and sinks) for three contrasting sites: an upstream high-nutrient low-chlorophyll reference, over the plateau and in the offshore plume east of the Kerguelen Islands. These budgets show that distinct regional environments driven by complex circulation and transport pathways are responsible for differences in the mode and strength of iron supply, with vertical supply dominant on the plateau and lateral supply dominant in the plume. Iron supply from "new" sources (diffusion, upwelling, entrainment, lateral advection, atmospheric dust) to the surface waters of the plume was double that above the plateau and 20 times greater than at the reference site, whilst iron demand (measured by cellular uptake) in the plume was similar to that above the plateau but 40 times greater than at the reference site. "Recycled" iron supply by bacterial regeneration and zooplankton grazing was a relatively minor component at all sites ( 8 % of new supply), in contrast to earlier findings from other biogeochemical iron budgets in the Southern Ocean. Over the plateau, a particulate iron dissolution term of 2.5 % was invoked to balance the budget this approximately doubled the standing stock of dissolved iron in the mixed layer. The exchange of iron between dissolved, biogenic particulate and lithogenic particulate pools was highly dynamic in time and space, resulting in a decoupling of the iron supply and carbon export and, importantly, controlling the efficiency of fertilisation.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Public Library of Science (PLoS)
Date: 18-03-2016
Publisher: Elsevier BV
Date: 04-2021
Publisher: Oxford University Press (OUP)
Date: 12-01-2015
DOI: 10.1093/BRAIN/AWU388
Publisher: Springer Science and Business Media LLC
Date: 21-05-2018
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 09-03-2017
DOI: 10.1002/BRB3.670
Publisher: American Medical Association (AMA)
Date: 12-2020
Publisher: CSIRO Publishing
Date: 21-09-2021
DOI: 10.1071/AH21056
Abstract: Objective This study is the first to assess if the National Disability Insurance Scheme (NDIS) package allocated to people with multiple sclerosis (pwMS) is correlated with the disability level measured by standardised neurological assessment. Methods We aimed to recruit 10 pwMS per expanded disability status score (EDSS) step, including EDSS 0 (no disability) up to 9 (bedridden), and requested information about their NDIS application. Value of their packages was compared with mobility, cognition and psychological impact. Results Out of 186 pwMS, only 49% of all patients had an NDIS package approved. The mean values of the annual allowance were AU$30 318 for patients with mild disability, AU$38 361 for moderate disability and AU$115 113 for severe disability. There was a striking variability in packages approved, but restricted mobility seems to be the driving factor. Rejection rates were % in patients with mild and moderate disability and none in those with severe disability. The package value correlated with EDSS steps, cognitive impairment and physical impact, but not psychological impact. Conclusions This is the first study to assess if NDIS packages correlate with internationally accepted disability scales. The NDIS support was correlated with disability measured by EDSS steps and cognition, but not psychological impact of the disease. What is known about the topic? There are over 25 000 Australians living with multiple sclerosis, which is one of the most common neurological diseases leading to disability in early age. The National Disability Insurance Scheme has been introduced since 2013 to particularly assist young disabled Australians to participate in the community. Whether the approved package correlates with internationally accepted disability scores has not yet been assessed. What does this paper add? This study is the first to correlate disability, as assessed by the Expanded Disability Severity Scale (EDSS), with the approved package value. What are the implications for practitioners? Multiple sclerosis is a very variable disease affecting quality of life not only due to impairment of mobility, but also cognition and mental health. Although the NDIS package value was correlated with an EDSS and cognition, the psychological impact of the disease is often neglected.
Publisher: American Psychiatric Association Publishing
Date: 04-2017
DOI: 10.1176/APPI.NEUROPSYCH.16050085
Abstract: Neurological and psychological symptoms in multiple sclerosis can affect cognitive function. The objective of this study was to explore the relationship between psychological measures and cognitive performance in a patient cohort. In 322 multiple sclerosis patients, psychological symptoms were measured using the Depression Anxiety and Stress Scale, and cognitive function was evaluated using Audio Recorded Cognitive Screen. Multifactor linear regression analysis, accounting for all clinical covariates, found that anxiety was the only psychological measure to remain a significant predictor of cognitive performance (p<0.001), particularly memory function (p<0.001). Further prospective studies are required to determine whether treatment of anxiety improves cognitive impairment.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2021
Publisher: Elsevier BV
Date: 02-2021
Publisher: SAGE Publications
Date: 28-09-2016
Abstract: Since 1959, multiple sclerosis (MS) prevalence has been estimated for the east coast Australian city of Newcastle. Previous surveys, conducted in 1988 and 2003, have described an increase in the prevalence and incidence of MS. In this study, we evaluated whether these trends continue and provide 50 years of MS epidemiological follow-up for this southern hemisphere city. Expressed per 100,000 people, prevalence of MS in Newcastle was calculated for those with a confirmed diagnosis of MS on 9 August 2011 and incidence based on the number of cases with MS diagnosis made during the preceding decade. Data were age-standardised to the total Australian population. Statistical comparisons were undertaken using Poisson regression analysis. In 2011, the estimate of MS prevalence was 124.2, with female-to-male ratio reaching 3.1, a 53% increase in female predominance since 1996. MS incidence increased to 6.7, with a significantly higher proportion of new female cases since the previous survey. Prevalence of MS in Newcastle has risen linearly and is contributed to by a substantial increase in new cases over the preceding decade. Female predominance of MS cases continues to increase with a new diagnosis three times more likely in women.
Publisher: S. Karger AG
Date: 05-05-2017
DOI: 10.1159/000472706
Abstract: b i Background: /i /b Acute haemorrhagic leukoencephalitis (AHLE) is a rare and rapidly fatal disease of unknown aetiology. There is a paucity of literature on the presentation and management of this rare disease. b i Case Description: /i /b We report the case of a 33-year-old female presenting with headache and left-sided apraxia. Imaging revealed a right-sided white matter lesion with extensive cytotoxic oedema. Pathology was suggestive of AHLE. She underwent an open excisional biopsy and was treated with high-dose corticosteroids. Three months since symptom onset she remains clinically well with resolving apraxia and radiological appearance. b i Conclusion: /i /b This case may represent a milder spectrum of AHLE, which responded favourably to corticosteroids.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2017
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.MSARD.2019.101486
Abstract: Due to the considerable burden of multiple sclerosis (MS)-related symptoms and the need to identify effective interventions to prevent disease progression, various nutraceutical interventions have been trialed as adjunctive treatments. The aim of this review was to investigate the efficacy and safety of nutraceutical interventions for clinical and biological outcomes in people with MS. In accordance with PRISMA reporting guidelines, a systematic literature search was conducted using three electronic literature databases. Risk of bias was assessed using the Jadad scale. Thirty-seven randomized controlled trials, investigating fourteen nutraceuticals, were included in the review. Trials that investigated alpha lipoic acid (n = 4/6), ginkgo biloba (n = 3/5), vitamin A (n = 2/2), biotin (n = 1/2), carnitine (n = 1/2), green tea (n = 1/2), coenzyme Q10 (n = 1/1), probiotics (n = 1/1), curcumin (n = 1/1), Andrographis paniculata (n = 1/1), ginseng (n = 1/1), and lemon verbena (n = 1/1) were reported to improve biological (e.g. MRI brain volume change, antioxidant capacity) and/or clinical (e.g. fatigue, depression, Expanded Disability Status Scale) outcomes in multiple sclerosis compared to control. However, most trials were relatively small (average study s le size across included studies, n = 55) and there were few replicate studies per nutraceutical to validate the reported results. Furthermore, some nutraceuticals (e.g. green tea and inosine) should be used with caution due to reported adverse events. Risk of bias across most studies was low, with 31 studies receiving a score between 4 and 5 (out of 5) on the Jadad Scale. The existing literature provides preliminary support for the use of a number of nutraceutical interventions in MS. However, sufficiently powered long-term trials are required to expand the currently limited literature and to investigate unexplored nutraceuticals that may target relevant pathways involved in MS such as the gut microbiome and mitochondrial dysfunction. Prospero ID: CRD42018111736.
Publisher: Wiley
Date: 06-2016
DOI: 10.1002/ANA.24682
Abstract: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009). We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016 :89-100.
Publisher: BMJ
Date: 09-2012
DOI: 10.1136/JMEDGENET-2012-101175
Abstract: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Given the large s le size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 07-2021
Publisher: SAGE Publications
Date: 25-11-2016
Abstract: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs). To examine determinants of second attack and validate a prognostic nomogram for in idualised risk assessment of clinical conversion. Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices. A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities. This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.
Publisher: Wiley
Date: 02-11-2018
DOI: 10.1111/ENE.13824
Abstract: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. Of the 1284 included patients, 533 were matched (treated, n = 195 untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1 95% CI, 0.7-1.6, P = 0.69). Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.
Publisher: SAGE Publications
Date: 15-06-2020
Abstract: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores. The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p 0.001) and EDSS (β = 0.16, p 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p = 0.01) and EDSS (β = −0.06, p 0.001). Neither presentation was associated with changes in relapse risk. Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JNS.2018.06.001
Abstract: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a erse group of patients exposed to different DMTs. Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria) age ≥ 18 at index DMT start ≥12 months on index DMT prior to discontinuation ≥24 months of follow-up post-discontinuation did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.
Publisher: Oxford University Press (OUP)
Date: 10-09-2015
DOI: 10.1093/BRAIN/AWV258
Abstract: Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.
Publisher: Elsevier BV
Date: 2021
Publisher: SAGE Publications
Date: 28-10-2020
Abstract: Computer-aided diagnosis can facilitate the early detection and diagnosis of multiple sclerosis (MS) thus enabling earlier interventions and a reduction in long-term MS-related disability. Recent advancements in the field of artificial intelligence (AI) have led to the improvements in the classification, quantification and identification of diagnostic patterns in medical images for a range of diseases, in particular, for MS. Importantly, data generated using AI techniques are analyzed automatically, which compares favourably with labour-intensive and time-consuming manual methods. The aim of this review is to assist MS researchers to understand current and future developments in the AI-based diagnosis and prognosis of MS. We will investigate a variety of AI approaches and various classifiers and compare the current state-of-the-art techniques in relation to lesion segmentation/detection and prognosis of disease. After briefly describing the magnetic resonance imaging (MRI) techniques commonly used, we will describe AI techniques used for the detection of lesions and MS prognosis. We then evaluate the clinical maturity of these AI techniques in relation to MS. Finally, future research challenges are identified in a bid to encourage further improvements of the methods.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Elsevier BV
Date: 11-2021
Publisher: SAGE Publications
Date: 31-08-2017
Abstract: This propensity score–matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab. We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score–matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results. Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.
Publisher: Informa UK Limited
Date: 04-10-2021
Publisher: Cold Spring Harbor Laboratory
Date: 06-02-2022
DOI: 10.1101/2022.02.04.22270362
Abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 in iduals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
Publisher: Wiley
Date: 27-03-2015
DOI: 10.1002/ACN3.187
Publisher: Springer Science and Business Media LLC
Date: 24-06-2010
DOI: 10.1038/GENE.2010.36
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2016
Publisher: Computers, Materials and Continua (Tech Science Press)
Date: 2020
Publisher: SAGE Publications
Date: 09-11-2017
Abstract: We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 06-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-08-2017
DOI: 10.1212/WNL.0000000000004330
Abstract: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS). Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates. Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2–3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7–1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4–1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8–1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = −0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results. Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years. This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JNS.2019.03.007
Abstract: Fatigue is a common and debilitating symptom in multiple sclerosis (MS). Over the past decade, a growing body of research has focussed on the pathophysiological mechanisms underlying central (cognitive and physical) fatigue in MS. The precise mechanisms causing fatigue in MS patients are complex and poorly understood, and may differ between patients. Advanced quantitative magnetic resonance imaging (MRI) techniques allow for objective assessment of disease pathology and have been used to characterise the pathophysiology of central fatigue in MS. To systematically review the existing literature of MRI-based studies assessing the pathophysiological mechanisms of MS-related central fatigue. A systematic literature search of four major databases (PubMed, Medline, Embase, Scopus and Google Scholar) was conducted to identify MRI-based studies of MS-related fatigue published in the past 20 years. Studies using the following MRI-based methods were included: structural (lesion load/atrophy), T1 relaxation time/magnetisation transfer ratio (MTR), diffusion tensor imaging (DTI), functional MRI (fMRI) and magnetic resonance spectroscopy (MRS). A total of 92 studies were identified as meeting the search criteria and included for review. Structurally, regional gray/white matter atrophy, cortical thinning, decreased T1 relaxation times and reduced fractional anisotropy were associated with central fatigue in MS. Functionally, hyperactivity and reduced functional connectivity in several regional areas of frontal, parietal, occipital, temporal and cerebellum were suggested as causes of central fatigue. Biochemically, a reduction in N-acetyl aspartate/creatine and increased (glutamine+glutamate)/creatine ratios were correlated with fatigue severity in MS. Several advanced quantitative MRI methods have been employed in the study of central fatigue in MS. Central fatigue in MS is associated with macro/microstructural and functional changes within specific brain regions (frontal, parietal, temporal and deep gray matter) and specific pathways/networks (cortico-cortical and cortico-subcortical). Alternations in the cortico-striatal-thalamocortical (CSTC) loop are correlated with the development of fatigue in MS patients.
Publisher: Public Library of Science (PLoS)
Date: 05-06-2015
Publisher: Public Library of Science (PLoS)
Date: 12-2010
Publisher: Frontiers Media SA
Date: 02-2018
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
DOI: 10.1038/S41598-020-78809-X
Abstract: The pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4 + T cells of relapsing–remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39 . This study aimed to investigate the DNA methylation profiles of the CD4 + T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A , SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 05-2019
Publisher: Elsevier BV
Date: 10-2021
Publisher: SAGE Publications
Date: 2019
Abstract: We have applied in vivo two-dimensional (2D) localized correlation spectroscopy (2D L-COSY), in treated relapsing relapsing-remitting multiple sclerosis (RRMS) to identify novel biomarkers in normal-appearing brain parenchyma. 2D L-COSY magnetic resonance spectroscopy (MRS) spectra were prospectively acquired from the posterior cingulate cortex (PCC) in 45 stable RRMS patients undergoing treatment with Fingolimod, and 40 age and sex-matched healthy control (HC) participants. Average metabolite ratios and clinical symptoms including, disability, cognition, fatigue, and mental health parameters were measured, and compared using parametric and nonparametric tests. Whole brain volume and MRS voxel morphometry were evaluated using SIENAX and the SPM LST toolbox. Despite the mean whole brain lesion volume being low in this RRMS group (6.8 ml) a significant reduction in PCC metabolite to tCr ratios were identified for multiple N-acetylaspartate (NAA) signatures, gamma-aminobutyric acid (GABA), glutamine and glutamate (Glx), threonine, and isoleucine/lipid. Of the clinical symptoms measured, visuospatial function, attention, and memory were correlated with NAA signatures, Glx, and isoleucine/lipid in the brain. 2D L-COSY has the potential to detect metabolic alterations in the normal-appearing MS brain. Despite examining only a localised region, we could detect metabolic variability associated with symptoms.
Publisher: SAGE Publications
Date: 26-11-2022
DOI: 10.1177/13524585221137502
Abstract: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch relapse outcomes included time to first relapse and annualized relapse rate (ARR). Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. In iduals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.
Publisher: Oxford University Press (OUP)
Date: 12-02-2013
DOI: 10.1093/HMG/DDT062
Abstract: Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in in iduals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 s les and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools this result has important implications for the design of future fine-mapping studies.
Publisher: SAGE Publications
Date: 23-10-2018
Abstract: Transition probabilities are the engine within many health economics decision models. However, the probabilities of progression of disability due to multiple sclerosis (MS) have not previously been estimated in Australia. To estimate annual probabilities of changing disability levels in Australians with relapsing-remitting MS (RRMS). Combining data from Ausimmune/Ausimmune Longitudinal (2003–2011) and Tasmanian MS Longitudinal (2002–2005) studies ( n = 330), annual transition probabilities were obtained between no/mild (Expanded Disability Status Scale (EDSS) levels 0–3.5), moderate (EDSS 4–6.0) and severe (EDSS 6.5–9.5) disability. From no/mild disability, 6.4% (95% confidence interval (CI): 4.7–8.4) and 0.1% (0.0–0.2) progressed to moderate and severe disability annually, respectively. From moderate disability, 6.9% (1.0–11.4) improved (to no/mild state) and 2.6% (1.1–4.5) worsened. From severe disability, 0.0% improved to moderate and no/mild disability. Male sex, age at onset, longer disease duration, not using immunotherapies greater than 3 months and a history of relapse were related to higher probabilities of worsening. We have estimated probabilities of changing disability levels in Australians with RRMS. Probabilities differed between various subgroups, but due to small s le sizes, results should be interpreted with caution. Our findings will be helpful in predicting long-term disease outcomes and in health economic evaluations of MS.
Publisher: Elsevier BV
Date: 08-2019
Publisher: SAGE Publications
Date: 11-01-2021
Abstract: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) 6 and ARR 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS 6 and ARR 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR 1 54.3 weeks (95% CI = 47.2–61.5). Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
Publisher: Wiley
Date: 23-04-2018
DOI: 10.1002/JMRI.26036
Abstract: Two-dimensional localized correlational spectroscopy (2D L-COSY) has been applied in vivo to investigate metabolic profiles in many disorders due to its ability to detect several metabolites simultaneously. Successful application of this technique depends on the reliability of the detection and understanding of the variability result from test-retest measurements. To evaluate the test-retest repeatability/reliability of 2D L-COSY in detecting brain metabolites in a phantom and healthy subjects in a 3T scanner. Test-retest. Six healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino". 3T/2D L-COSY MRS. Healthy subjects underwent eight weekly experiments over a period of 3 months with an intersession delay of 1 month after the first four measurements. Twenty-nine neurometabolite resonances (8 diagonal, 14 cross, and 7 composite resonances) were studied using a 27 cm Intra- and intersubject variability were measured. Test-retest repeatability was calculated using coefficient of variation (CV), and reliability was assessed with standard error measurement (SEM) and intraclass correlation coefficient (ICC), using SPSS software. The intra/inter CV for in vitro and in vivo data ranged from 0.01-0.23%/0.02-0.29% and 0.03-0.23%/0.04-0.39%, respectively. The major diagonal peaks showed ICC ranging from 0.31 to 0.93, while the ICC for cross peaks were 0.09-0.87. The SEM for in vivo data ranged from 0.0016 to 0.08. The interweek interval may have a positive effect on metabolite ratios (P = 0.08 F = 1.78). The low variability in metabolite concentration in this study shows a high level of reliability of 2D L-COSY in the human brain. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018 :1559-1569.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-11-2021
DOI: 10.1212/WNL.0000000000012850
Abstract: Longitudinal cognitive trajectories in multiple sclerosis are heterogeneous and difficult to measure. We aimed to identify discrete longitudinal reaction time trajectories in relapsing-remitting multiple sclerosis using a computerized cognitive battery and to assess the association between trajectories of reaction time and disability progression. All participants serially completed computerized reaction time tasks measuring psychomotor speed, visual attention, and working memory. Participants completed at least 3 testing sessions over a minimum of 180 days. Longitudinal reaction times were modeled with latent class mixed models to identify groups of in iduals sharing similar latent characteristics. Optimal models were validated for consistency and baseline associations with class membership tested using multinomial logistic regression. Interclass differences in the probability of reaction time worsening and the probability of 6-month confirmed disability progression were assessed with survival analysis. A total of 460 people with relapsing-remitting multiple sclerosis were included in the analysis. For each task of the MSReactor battery, the optimal model comprised 3 latent classes. All MSReactor tasks could identify a group with high probability of reaction time slowing. The visual attention and working memory tasks could identify a group of participants who were 3.7 and 2.6 times more likely to experience a 6-month confirmed disability progression, respectively. Participants could be classified into predicted cognitive trajectories after just 5 tests with 64% to 89% accuracy. Latent class modeling of longitudinal cognitive data collected by a computerized battery identified patients with worsening reaction times and increased risk of disability progression. Slower baseline reaction time, age, and disability increased assignment into this trajectory. Monitoring of cognition in clinical practice with computerized tests may enable detection of cognitive change trajectories and people with relapsing-remitting multiple sclerosis at risk of disability progression.
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Publisher: BMJ
Date: 13-06-2016
Abstract: Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry (2) To identify predictors of time to first relapse and disability progression in DMT stoppers. Inclusion criteria for DMT stoppers were: age ≥18 years no relapses for ≥5 years at DMT discontinuation follow-up for ≥3 years after stopping DMT not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model. Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37 p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period. Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-08-2023
DOI: 10.1212/WNL.0000000000207489
Abstract: In multiple sclerosis (MS), accelerated aging of the immune system (immunosenescence) may be associated with disease onset or drive progression. DNA methylation (DNAm) is an epigenetic factor that varies among lymphocyte subtypes, and cell-specific DNAm is associated with MS. DNAm varies across the life span and can be used to accurately estimate biological age acceleration, which has been linked to a range of morbidities. The objective of this study was to test for cell-specific epigenetic age acceleration (EAA) in people with MS. This was a case-control study of EAA using existing DNAm data from several independent previously published studies. Data were included if .idat files from Illumina 450K or EPIC arrays were available for both a case with MS and an age-matched and sex-matched control, from the same study. Multifactor statistical modeling was performed to assess the primary outcome of EAA. We explored the relationship of EAA and MS, including interaction terms to identify immune cell-specific effects. Cell-sorted DNA methylation data from 3 independent datasets were used to validate findings. We used whole blood DNA methylation data from 583 cases with MS and 643 non-MS controls to calculate EAA using the GrimAge algorithm. The MS group exhibited an increased EAA compared with controls (approximately 9 mths, 95% CI 3.6–14.4), p = 0.001). Statistical deconvolution showed that EAA is associated with MS in a B cell–dependent manner ( β int = 1.7, 95% CI 0.3–2.8), p = 0.002), irrespective of B-cell proportions. Validation analysis using 3 independent datasets enriched for B cells showed an EAA increase of 5.1 years in cases with MS compared with that in controls (95% CI 2.8–7.4, p = 5.5 × 10 −5 ). By comparison, there was no EAA difference in MS in a T cell–enriched dataset. We found that EAA was attributed to the DNAm surrogates for Beta-2-microglobulin (difference = 47,546, 95% CI 10,067–85,026 p = 7.2 × 10 −5 ), and smoking pack-years (difference = 8.1, 95% CI 1.9–14.2, p = 0.002). This study provides compelling evidence that B cells exhibit marked EAA in MS and supports the hypothesis that premature B-cell immune senescence plays a role in MS. Future MS studies should focus on age-related molecular mechanisms in B cells.
Publisher: Wiley
Date: 19-01-2016
DOI: 10.1111/ENE.12929
Abstract: Early relapse outcomes in long-term stable patients switching from interferon β/glatiramer acetate (IFNβ/GA) to oral therapy are unknown. The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNβ/GA, relative to a propensity-matched comparator of patients remaining on IFNβ/GA. The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNβ/GA ('stayers') using a Cox marginal model. Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.
Publisher: BMJ
Date: 15-11-2017
Abstract: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
Publisher: Oxford University Press (OUP)
Date: 22-01-2015
DOI: 10.1093/BRAIN/AWU405
Publisher: Elsevier BV
Date: 10-2020
Publisher: SAGE Publications
Date: 05-12-2014
Abstract: The results of head-to-head comparisons of injectable immunomodulators (interferon β, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed. We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted. Of the 3326 included patients, 345–1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated % of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon β-1a relative to intramuscular interferon β-1a and interferon β-1b ( p≤0.001). No differences in 12-month confirmed progression of disability were observed. Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.
Publisher: Public Library of Science (PLoS)
Date: 21-05-2013
Publisher: Elsevier BV
Date: 11-2020
Publisher: SAGE Publications
Date: 10-2018
Abstract: Despite evidence of perceived stress as a risk factor for multiple sclerosis activity, the evidence for managing stress is limited. Objective To evaluate a stress management programme on perceived stress and quality of life, over 6 months. One hundred people with multiple sclerosis were randomly assigned to either a stress management programme of mindfulness, meditation and progressive muscle relaxation, or wait list. Perceived stress and quality of life were assessed at three intervals across 6 months. Salivary cortisol levels were assessed at two intervals: baseline and first follow-up. The stress management programme did not significantly reduce perceived stress, when comparing mean scores. Secondary analysis using median scores found a significant improvement for quality of life, favouring the intervention group. Stress management had no significant effect on the primary outcome of perceived stress but did improve quality of life in a secondary analysis of median scores.
Publisher: SAGE Publications
Date: 21-07-2015
Abstract: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset ( n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p .001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies ( p .001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.
Publisher: BMJ
Date: 20-03-2017
Abstract: To investigate the prospective associations between adiposity and lipid-related variables and conversion to multiple sclerosis (MS), time to subsequent relapse and progression in disability. A cohort of 279 participants with a first clinical diagnosis of central nervous system demyelination was prospectively followed to 5-year review. Height, weight, waist and hip circumference were measured, and serum s les taken for measurement of lipids and apolipoproteins. Survival analysis was used for conversion to MS and time to relapse, and linear regression for annualised change in disability (Expanded Disability Status Scale). Higher body mass index (BMI adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m Higher levels of adiposity, non-HDL and TC/HDL ratio were prospectively associated with a higher rate of disability progression, and higher adiposity and triglycerides were associated with relapse but not with conversion to MS. Improving the lipid profile and losing weight into the healthy range could reduce the accumulation of disability.
Publisher: SAGE Publications
Date: 14-11-2016
Abstract: The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity. To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity. We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to ‘No Evidence of Disease Activity’ (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression. Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment ( p 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects ( p 0.05). The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.
Publisher: SAGE Publications
Date: 09-07-2010
Abstract: Background: Cognitive impairment is a common complication of multiple sclerosis, even in early stage disease, with significant impacts on life quality and social interaction. However, its detection is highly test-dependent. Objective: To validate a recently described screening tool, the ARCS, for detecting cognitive impairment in a multiple sclerosis population. Methods: The ARCS administers tests of executive function, memory, visual spatial construction and language via an audio device to unsupervised patients who write their responses for later scoring. Some 127 patients with a wide variety of disease course and severity were assessed by ARCS, of whom 87 also completed the Paced Auditory Serial Addition Test (PASAT) and 45 underwent formal (‘gold standard’) neuropsychological testing. Results: Compared with PASAT, we found that the ARCS showed better sensitivity (86% versus 68%) at equivalent specificity (71%) for detection of impairment in any cognitive domain, and superiority in the detection of memory and executive impairments. Acceptance and completion rates for the ARCS were as good or better than for the PASAT. Conclusions: ARCS is sensitive, well-tolerated, easy to administer and facilitates comprehensive cognitive assessment in less than 5 min of clinician time. It has several advantages over the PASAT for detecting cognitive impairment in patients with multiple sclerosis.
Publisher: Elsevier BV
Date: 2019
Publisher: SAGE Publications
Date: 23-07-2020
Abstract: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. This study included baseline food frequency questionnaire dietary intake (entry to the Ausimmune Study) and 5-year follow-up iterated principal factor analysis was applied. MS conversion and relapse risks were assessed by Cox proportional hazards models, adjusted for age, sex, study site, education, body mass index (BMI), smoking and omega-3 supplement use. In cases with a first clinical diagnosis of central nervous system (CNS) demyelination, we identified three major dietary patterns, ‘Prudent’, ‘High-Vegetable’ and ‘Mixed’, explaining 43%, 37% and 24% of diet variance in dietary intake, respectively. Fruits, vegetables, fish, wholegrains and nuts loaded highly on the Prudent pattern, starchy vegetables and legumes on the High-Vegetable pattern, and meats and alcohol on the Mixed pattern. Diet factor scores were not associated with MS conversion risk. Those with baseline Prudent scores above the median had significantly lower relapse risk (adjusted hazard ratio = 0.54, 95% confidence interval (CI) 0.37, 0.81) with some evidence of a plateau effect. Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 04-2020
Publisher: SAGE Publications
Date: 21-06-2019
Abstract: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients. To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. Survival analysis was applied in three MS cohorts from different countries ( n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. Rs7298096 AA patients show a shorter TTFR than rs7298096 G -carriers (P meta-analysis = 3 × 10 −4 , hazard ratio = 1.41). Moreover, rs7298096 AA is associated with a higher NINJ2 expression in blood ( p = 7.0 × 10 −6 ), which was confirmed in vitro ( p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.
Publisher: Elsevier BV
Date: 02-2019
Publisher: SAGE Publications
Date: 20-12-2011
Abstract: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) statusfor the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude ( p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change ( p 0.001). The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.
Publisher: Elsevier BV
Date: 10-2019
Publisher: American Medical Association (AMA)
Date: 11-2018
Publisher: Wiley
Date: 22-02-2021
DOI: 10.1111/JON.12836
Publisher: Oxford University Press (OUP)
Date: 08-04-2031
DOI: 10.1093/HMG/DDT529
Abstract: Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.MSARD.2019.01.003
Abstract: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing. To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS. We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed. Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010) but no differences in spontaneous abortions, term or preterm births. We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.
Publisher: SAGE Publications
Date: 12-06-2021
Abstract: Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS. A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment. Mean age on starting cladribine was 47 years mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years. These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2016
DOI: 10.1038/TPJ.2016.20
Abstract: Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad combined P-value 6.74 × 10
Publisher: American Medical Association (AMA)
Date: 04-2015
DOI: 10.1001/JAMANEUROL.2014.4147
Abstract: After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain. To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS. Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted. Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42 95% CI, 0.02-0.19 P=.009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74 95% CI, 0.56-0.98 P=.04), lower hazard of disability progression (HR, 0.53 95% CI, 0.31-0.91 P=.02), higher rate of disability regression (HR, 2.0 95% CI, 1.2-3.3 P=.005), and lower hazard of treatment discontinuation (HR, 0.55 P=.04) compared with the injectable group. Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.
Publisher: SAGE Publications
Date: 09-08-2019
Abstract: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Patients with adult-onset relapsing–remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p 0.001), more rapid disability trajectory (HR = 2.82, p 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
Publisher: Frontiers Media SA
Date: 09-09-2021
DOI: 10.3389/FNEUR.2021.722237
Abstract: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), “bright spotty” (OR = 93.8), whole (axial OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2016
Publisher: Oxford University Press (OUP)
Date: 17-07-2015
DOI: 10.1093/HMG/DDV278
Abstract: Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2017
Publisher: Springer Science and Business Media LLC
Date: 02-07-2021
DOI: 10.1007/S00415-021-10665-9
Abstract: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Māori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. The prevalence of NMOSD in the Māori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.
Publisher: BMJ
Date: 28-09-2017
Abstract: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy. The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6 and 6-6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted. For the EDSS 3-6, 4-6 and 6-6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92-1.11) and postbaseline (2.15-2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58-3.07 p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72-0.91 per 25% p≤0.02). 3 sensitivity analyses confirmed these results. Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2021
Publisher: Elsevier BV
Date: 2020
Publisher: MDPI AG
Date: 22-10-2012
Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (−597 G A and −174 G C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (−572 G C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different −597 or −174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of in iduals with MS who carried a C allele at position −572, although this was not significant after correction for multiple comparisons. Interestingly, however, the −572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2014
Publisher: Elsevier BV
Date: 05-2020
Publisher: SAGE Publications
Date: 28-04-2014
Abstract: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10 -14 ). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
Publisher: Public Library of Science (PLoS)
Date: 11-06-2015
Publisher: Springer Science and Business Media LLC
Date: 14-02-2018
Publisher: BMJ
Date: 26-05-2017
Abstract: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2018
DOI: 10.1007/S10072-017-3177-1
Abstract: Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.1038/NATURE10251
Publisher: Wiley
Date: 25-03-2015
DOI: 10.1111/ENE.12696
Abstract: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an in idual risk score calculated from demographic and clinical variables collected at disease onset. An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2018
DOI: 10.1038/S41598-018-35603-0
Abstract: Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. The inflammatory process in MS is driven by both T and B cells and current therapies are targeted to each of these cell types. Epigenetic mechanisms may provide a valuable link between genes and environment. DNA methylation is the best studied epigenetic mechanism and is recognized as a potential contributor to MS risk. The objective of this study was to identify DNA methylation changes associated with MS in CD19 + B-cells. We performed an epigenome-wide association analysis of DNA methylation in the CD19 + B-cells from 24 patients with relapsing-remitting MS on various treatments and 24 healthy controls using Illumina 450 K arrays. A large differentially methylated region (DMR) was observed at the lymphotoxin alpha ( LTA ) locus. This region was hypermethylated and contains 19 differentially methylated positions (DMPs) spanning 860 bp, all of which are located within the transcriptional start site. We also observed smaller DMRs at 4 MS-associated genes: SLC44A2 , LTBR , CARD11 and CXCR5 . These preliminary findings suggest that B-cell specific DNA-methylation may be associated with MS risk or response to therapy, specifically at the LTA locus. Development of B-cell specific epigenetic therapies is an attractive new avenue of research in MS treatment. Further studies are now required to validate these findings and understand their functional significance.
Publisher: Wiley
Date: 20-10-2014
DOI: 10.1002/ANA.24287
Abstract: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 20-12-2016
Abstract: Patients presenting with clinically isolated syndrome (CIS) may proceed to clinically definite multiple sclerosis (CDMS). Midsagittal corpus callosum area (CCA) is a surrogate marker for callosal atrophy, and can be obtained from a standard MRI study. This study explores the relationship between CCA measured at CIS presentation (baseline) and at 5 years post presentation, with conversion from CIS to CDMS. The association between CCA and markers of disability progression is explored. Corpus callosum area was measured on MRI scans at presentation and 5-year review following diagnosis of a first demyelinating event, or evidence of progressive MS, in 143 participants in the Ausimmune/AusLong Study. Relationships between CCA (at baseline and follow-up) and clinical outcomes were assessed. Mean CCA at baseline study was 6.63 cm Baseline CCA obtained from standard MRI protocols may be compared with subsequent MRI examinations as a surrogate for neurodegeneration and cerebral atrophy in patients with MS. This study demonstrates an association between CCA and disability in in iduals presenting with CIS who convert to MS.
Publisher: SAGE Publications
Date: 29-07-2014
Abstract: Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes in MS patients. Based on our gene expression results, we wanted to identify whether polymorphisms in the genes associated with the plasminogen pathway could predict MS risk. We genotyped 1153 trio families, 727 MS cases and 604 healthy controls for 17 polymorphisms in MMP9, plasminogen activator urokinase (PLAU), PLAU receptor (PLAUR) and serpin peptidase inhibitor/clade 2/member B2 (SERPINB2) genes. No associations were found between the 17 polymorphisms and MS. Also, gene expression levels were analysed according to genotype: no associations were observed. In conclusion despite the consistent evidence for the role of MMP9 and the plasminogen activation cascade in MS, we found no associations between genotype nor gene expression. This suggested there are other potentially modifiable factors influencing gene expression in MS.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.MSARD.2017.06.002
Abstract: Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a significant amount of conflicting evidence. Some of the evidence for EBV involvement in MS includes: almost 100% of MS patients showing past EBV infection, an association with Infectious Mononucleosis (acute EBV infection), higher titres of EBV antibodies associated with an increased risk of MS development, and an overall altered immune response to EBV found in peripheral blood and the CNS of MS patients. However, evidence for EBV presence in the CSF and T cell responses to EBV in MS have been particularly conflicting. Several hypotheses have been proposed for direct and indirect EBV involvement in MS such as 1) Molecular Mimicry 2) Mistaken Self 3) Bystander Damage and 4) Autoreactive B cells infected with EBV. More recently, an association between EBV and human endogenous retrovirus in MS has been shown, which may provide an alternative pathogenetic target for MS treatment. However, if EBV is not the major contributor to MS and is instead one of several viral or infectious agents able to elicit a similar altered immune response, MS development may be the result of a failure of viral clearance in general. This review aims to evaluate the evidence for the currently discussed theories of EBV involvement in MS pathogenesis.
Publisher: BMJ
Date: 03-11-2016
Abstract: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10 An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.
Publisher: Public Library of Science (PLoS)
Date: 19-03-2013
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.EJRAD.2018.09.020
Abstract: This study was designed to evaluate the diurnal stability and long-term repeatability and reliability of one-dimensional (1D) hydrogen magnetic resonance spectroscopy (1H-MRS) in vitro and in vivo at 3 T. A standard brain phantom was used for in vitro study. In vivo diurnal evaluation involved ten healthy subjects, while repeatability study involved six subjects. MRS was acquired from posterior cingulate gyrus (PCG), and processed with LCModel. Diurnal effects were assessed with repeated measures ANOVAs, repeatability was evaluated using coefficient of variation (CV), while reliability was assessed with standard error measurement (SEM) and intra-class correlation coefficient (ICC). Diurnal metabolic changes in vitro were non-significant. The intra/inter-in vitro CVs for the major metabolites N-acetylaspartate (NAA), creatine (Cr), myo-inositol (mI), glutamate + glutamine (Glx) and total choline (tCho) were 1-3%/2-6%, respectively. Statistically significant in vivo diurnal effects were only seen for glycerophosphocholine (GPC, +10%, F = 10.6, p = 0.001) and Glx (+6%, F = 5.1, p = 0.018). The intra/inter-subject CVs for the major metabolites ranged from 2-5%/ 5-9%, respectively. The major metabolites displayed ICC ranging from 0.5-0.7 and low SEM (0.001-0.078) reflecting high reliability in detecting neurometabolites. The inter-week interval for in vivo measurements had minimal effect on metabolite ratios (F = 1.4, p = 0.09). In vitro MRS showed no diurnal effects and minimal variation in metabolite levels. Most PCG metabolites are not altered diurnally. The low in vivo variability of metabolite concentration supports the use of localised MRS on clinical 3 T scanners for reliable neurometabolic profiling of the brain.
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Publisher: SAGE Publications
Date: 03-08-2012
Abstract: Background: The environmental influence of sun exposure and vitamin D in particular and its implication with multiple sclerosis (MS) has recently received considerable attention. Current evidence based on genetic and epidemiological studies indicate that vitamin D is implicated in the aetiology of this disease. Methods: We examined two common variants in the vitamin D receptor ( VDR) gene in 1153 trio families and 726 cases and 604 controls. We also examined epistatic interactions between the VDR SNPs rs731236 and rs2228570 with the tagging single nucleotide polymorphism (SNP) rs3135388 for the HLA-DRB*1501 locus containing a highly conserved vitamin D responsive element within its promoter region. Results: We found weak evidence for an association between the rs731236C allele and MS, while there was no direct association with rs2228570. When examining the interaction between the VDR gene variations and the DRB1*1501 tagging SNP a more complex relationship was observed. Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1). Conclusion: We have identified weak evidence of an association between a common variation within the VDR gene and MS, in the largest study reported to date of this candidate gene. There appears to be a relationship between polymorphisms in the VDR and the risk of MS, which is potentially modified by HLA-DRB1*1501.
Publisher: Wiley
Date: 17-01-2015
DOI: 10.1002/ANA.24339
Abstract: In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. Of the 792 included patients, 578 patients were matched (natalizumab, n = 407 fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p < 0.001). This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.
Publisher: SAGE Publications
Date: 07-2018
Abstract: Dimethyl fumarate is an oral treatment for multiple sclerosis, whose mechanism of action is not fully understood. To investigate the effects of dimethyl fumarate on DNA methylation in the CD4 + T cells of multiple sclerosis patients. We performed Illumina EPIC arrays to investigate the DNA methylation profiles of CD4 + T cells derived from multiple sclerosis patients before and after dimethyl fumarate treatment. Treatment with dimethyl fumarate resulted in 97% of differentially methylated positions showing hypermethylation. Four genes, SNORD1A, SHTN1, MZB1 and TNF had a differentially methylated region located within the transcriptional start site. This study investigates the effect of dimethyl fumarate on DNA methylation in multiple sclerosis patients.
Publisher: Elsevier BV
Date: 10-2020
Publisher: JMIR Publications Inc.
Date: 19-10-2021
DOI: 10.2196/24969
Abstract: Cladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied. This study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3. This will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance. This study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021. This will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS. This study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165). DERR1-10.2196/24969
Publisher: Springer Science and Business Media LLC
Date: 05-11-2015
Publisher: Wiley
Date: 05-03-2019
DOI: 10.1111/ENE.13932
Abstract: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been identified in both children and adults with demyelination, with a strong association with bilateral or recurrent optic neuritis (ON). However, the full clinical spectrum of this newly described condition is unknown. We sought to describe non-ON inflammatory ophthalmological presentations such as uveitis and optic perineuritis in the context of MOG antibody seropositivity. Using a live cell-based assay analysed by flow cytometry, we identified seropositive patients referred for MOG antibody testing in Australasia between 2014 and 2017. We identified four MOG antibody-positive patients with non-ON inflammatory ophthalmological presentations and present their detailed clinical information in this case series. Three patients had uveitis either in association with, or remote from, ON. One patient had optic perineuritis and peripheral ulcerative keratitis. We describe the presentation, examination, investigation findings and clinical course of these four patients. Recognition of these novel clinical associations may expand the clinical spectrum of MOG antibody-associated presentations. An expedited diagnosis may guide the management of these complex patients.
Publisher: BMJ
Date: 13-01-2019
Abstract: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring). The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24 p=0.05) and dimethyl fumarate (0.20 vs 0.26 p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22 p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68). The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
Publisher: Elsevier BV
Date: 08-2021
Publisher: SAGE Publications
Date: 11-02-2013
Abstract: Multiple sclerosis (MS) is an autoimmune disorder where a breakdown in the integrity of the blood-brain barrier is thought to allow lymphocytes to enter the central nervous system. The purpose of this study was to examine gene expression profiles between MS patients and healthy controls to identify genes intimately involved in the pathobiology of MS. Whole-genome gene expression analysis was performed using peripheral blood mononuclear cells from 39 healthy controls and 37 MS patients, 24 MS patients receiving no disease modifying therapy and 13 MS patients receiving interferon-beta (IFN-beta). Pathway analysis was performed to identify pathways dysregulated in MS. Gene expression profiling of MS identified a signature of predominately immune associated genes. The plasminogen activation pathway contained an over-representation of significantly differentially expressed genes, including matrix metallopeptidase 9 (MMP9). Treatment with IFN-beta ameliorated the over-expression of MMP9, however the expression of two genes, plasminogen activator urokinase (PLAU) and serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), forming part of the plasminogen activation pathway were not affected by IFN-beta therapy. High expression levels of MMP9 have been associated with MS and the breakdown of the blood-brain barrier, while IFN-beta therapy decreases MMP9 expression. We confirm altered MMP9 expression in MS, and identify dysregulation within the plasminogen activation cascade, a pathway involved in the activation of MMP9.
Publisher: Elsevier BV
Date: 10-2021
Publisher: SAGE Publications
Date: 08-10-2022
DOI: 10.1177/13524585211049986
Abstract: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
Publisher: SAGE Publications
Date: 19-02-2023
DOI: 10.1177/13524585231151394
Abstract: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80] marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43] marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.
Publisher: SAGE Publications
Date: 27-02-2023
DOI: 10.1177/13524585231151951
Abstract: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. To determine whether early non-disabling relapses predict disability accumulation in RRMS. We redefined mild relapses in MSBase as ‘non-disabling’, and moderate or severe relapses as ‘disabling’. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n = 285 vs 4717 hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00–1.68) or given platform DMTs ( n = 1074 vs 7262 HR = 1.33, 95% CI = 1.15–1.54), but not if given high-efficacy DMTs ( n = 572 vs 3534 HR = 0.90, 95% CI = 0.71–1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.
Publisher: SAGE Publications
Date: 11-07-2016
Abstract: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25–0.29)), cerebellar (β = 0.35 (0.30–0.39)) and bowel/bladder (β = 0.42 (0.35–0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains. Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
Publisher: SAGE Publications
Date: 12-04-2017
Abstract: The connection between ownership structure and firm performance has attracted significant attention especially in emerging markets, yet empirical evidence remains inconsistent. This article presents an analysis of the association among eight categories of ownership, Hirschman–Herfindahl index (HHI) index, Gini index, and firm performance in the emerging market of Pakistan. Some researchers argue that ownership concentration can improve firm performance by making the owners more willing or able to monitor agents. In contrast, others argue that in the presence of efficient markets, market monitoring will discipline the managers. Our results show that there is a significant positive association between ownership structure and both market-based performance measures and also economic profit. The ownership proportion of the institutional shareholding and foreign shareholding is also positively associated with firm performance.
Publisher: SAGE Publications
Date: 03-04-2022
DOI: 10.1177/13524585221084577
Abstract: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients’ demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years 72% female disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of in idual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the in idual accuracy of prognostics in MS.
Publisher: BMJ
Date: 28-12-2011
Abstract: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry. Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5-year EDSS scores. Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7-12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years one-point progression risk was greater for EDSS score of >2 than ≤2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4. EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5-year outcome in in iduals 4 years after disease onset.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.MSARD.2019.101868
Abstract: Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD. This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024). This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.MSARD.2021.103262
Abstract: The theory that multiple sclerosis is related to venous pressure has been discredited due to previous operator dependent diagnostic criteria and premature attempts at treatment. (1) An elevation in venous pressure may only be a component of the compliance changes found in MS. (2) The neck veins may only supply a component of the venous pressure elevation found intracranially. Although a more targeted approach towards neck angioplasty (both towards disease subtype and those with more favorable stenoses) may be beneficial, we would advocate caution. We encourage others to give the venous pressure theory a second chance and to replicate our work.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-08-2021
DOI: 10.1212/WNL.0000000000012354
Abstract: To compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag. Patients treated with high-efficacy (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon beta, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP), 2 large observational cohorts. Therapeutic lag was estimated for each patient from their demographic and clinical characteristics. Propensity score was used to match patients treated with high- and low-efficacy therapies. Outcomes after the period of therapeutic lag was disregarded were compared in paired, pairwise-censored analyses. One thousand patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7, p = 0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8, p = 0.39). No evidence for a difference in the risk of disability progression was observed. In treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active but not those with inactive SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group. This study provides Class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS, although we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.
Publisher: Elsevier BV
Date: 2022
Publisher: SAGE Publications
Date: 07-10-2015
Abstract: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients’ lives. ENABLE assessed the effect of long-term prolonged-release (PR) f ridine (dalf ridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment. ENABLE was a 48-week, open-label, Phase 4 study of PR-f ridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score. At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78) p 0.0001), week 24 (3.75 (3.23, 4.27) p 0.0001), week 36 (3.46 (2.95, 3.97) p 0.0001), and week 48 (3.24 (2.72, 3.77) p 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment. PR-f ridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.
Publisher: American Medical Association (AMA)
Date: 15-01-2019
Publisher: SAGE Publications
Date: 20-09-2018
Abstract: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.
Publisher: Elsevier BV
Date: 8
Publisher: SAGE Publications
Date: 20-03-2018
Abstract: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
Publisher: SAGE Publications
Date: 2016
Abstract: Multiple sclerosis (MS) is an autoimmune disease characterised by lymphocytic infiltration of the central nervous system and subsequent destruction of myelin and axons. On the background of a genetic predisposition to autoimmunity, environmental triggers are assumed to initiate the disease. The majority of MS research has focused on the pathological involvement of lymphocytes and other immune cells, yet a paucity of attention has been given to erythrocytes, which may play an important role in MS pathology. The following review briefly summarises how erythrocytes may contribute to MS pathology through impaired antioxidant capacity and altered haemorheological features. The effect of disease-modifying therapies on erythrocytes is also reviewed. It may be important to further investigate erythrocytes in MS, as this could broaden the understanding of the pathological mechanisms of the disease, as well as potentially lead to the discovery of novel and innovative targets for future therapies.
Publisher: SAGE Publications
Date: 09-10-2013
Abstract: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. An observational case–control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Hindawi Limited
Date: 12-01-2016
DOI: 10.1111/ANE.12554
Abstract: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.
Publisher: SAGE Publications
Date: 14-10-2013
Abstract: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system which responds to therapies targeting circulating immune cells. Our aim was to test if the T-cell activation gene expression pattern (TCAGE) we had previously described from whole blood was replicated in an independent cohort. We used RNA-seq to interrogate the whole blood transcriptomes of 72 in iduals (40 healthy controls, 32 untreated MS). A cohort of 862 control in iduals from the Brisbane Systems Genetics Study (BSGS) was used to assess heritability and seasonal expression. The effect of interferon beta (IFNB) therapy on expression was evaluated. The MS/TCAGE association was replicated and rationalized to a single marker, ribosomal protein S6 (RPS6). Expression of RPS6 was higher in MS than controls ( p .0004), and lower in winter than summer ( p .6E-06). The seasonal pattern correlated with monthly UV light index ( R=0.82, p .002), and was also identified in the BSGS cohort ( p .0016). Variation in expression of RPS6 was not strongly heritable. RPS6 expression was reduced by IFNB therapy. These data support investigation of RPS6 as a potential therapeutic target and candidate biomarker for measuring clinical response to IFNB and other MS therapies, and of MS disease heterogeneity.
Publisher: Elsevier BV
Date: 06-2021
Publisher: AMPCo
Date: 08-2015
DOI: 10.5694/MJA14.01218
Abstract: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.
Publisher: SAGE Publications
Date: 08-07-2020
Abstract: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. This RRMS MSBase cohort study ( n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Oxford University Press (OUP)
Date: 03-08-2017
DOI: 10.1093/BRAIN/AWX185
Abstract: Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis however, treatment response varies greatly among patients. Comprehensive predictive models of in idual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for in idual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of in idual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the in idual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict in idual response to disease-modifying therapies at the time of their commencement.
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2019
DOI: 10.1101/735662
Abstract: Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity. 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10 -9 ) and worsening of disability (0.81, 0.67-0.99, p=0.043). Continued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.FOODCHEM.2019.125102
Abstract: The chemical compositions and α-glucosidase inhibitory activities of anthocyanins extracted from blueberry, blackcurrant and blue honeysuckle fruits and their acid hydrolysates (anthocyanidins) were analysed. Those anthocyanins were glycosidic anthocyanins that converted to anthocyanidins during acid hydrolysis, leading to increases in their α-glucosidase inhibitory activities (expressed as IC
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JNS.2012.03.017
Abstract: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period. We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subs les of patients diagnosed according to Poser or McDonald criteria. The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets. The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.JNEUROIM.2011.08.004
Abstract: Recent studies have revealed an association between interleukin 28B (IL28B) and response to IFN-alpha treatment in hepatitis C patients. Here we investigated the influence of IL28B polymorphisms in the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. We genotyped two SNPs of the IL28B gene (rs8099917 and rs12979860) in 588 MS patients classified into responders (n=281) and non-responders (n=307) to IFNβ. Combined analysis of the study cohorts showed no significant associations between SNPs rs8099917 and rs12979860 and the response to treatment. These findings do not support a role of IL28B polymorphisms in the response to IFNβ in MS patients.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Springer Science and Business Media LLC
Date: 18-07-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-12-2020
DOI: 10.1212/WNL.0000000000011242
Abstract: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43–0.82, p = 0.0016), worsening of disability (0.56, 0.38–0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19–0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p = 10 −9 ) and worsening of disability (0.81, 0.67–0.99, p = 0.043). Continued treatment with MS immunotherapies reduces disability accrual by 19%–44% (95% CI 1%–62%), the risk of need of a walking aid by 67% (95% CI 41%–81%), and the frequency of relapses by 40–41% (95% CI 18%–57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
Publisher: BMJ
Date: 07-05-2011
Abstract: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2013
DOI: 10.1038/NG.2770
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 08-2020
No related grants have been discovered for Jeannette Lechner-Scott.