ORCID Profile
0000-0003-4323-2453
Current Organisations
Flinders University
,
Southern Adelaide Local Health Network and Flinders University
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Publications
Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study
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.
Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation
Publisher: Frontiers Media SA
Date: 16-06-2020
Platelet-Rich Plasma for the Management of Hip and Knee Osteoarthritis
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1007/S11926-017-0652-X
Abstract: Knee and hip osteoarthritis (OA) are major public health problems worldwide causing pain, disability and impaired quality of life. This narrative paper discusses platelet-rich plasma (PRP) as a treatment for hip and knee OA, with a focus on evidence from randomised controlled trials (RCTs). Since the first RCT of PRP in 2012, there has been 15 RCTs in knee OA and three in hip OA, mostly comparing PRP to another intra-articular injection therapy, hyaluronic acid. All studies are of low to moderate methodological quality and use variable PRP protocols. In general, results showed that PRP is a safe treatment with potential to provide symptomatic benefit for OA at least in the short term (up to 12 months). Younger patients with less severe disease may be more responsive. There are no RCTs investigating the effects of PRP on OA structural changes. No definitive conclusions can be made about the effects of PRP in OA given methodological concerns and considerable heterogeneity between studies. Further high-quality research is needed to establish the clinical and cost-effectiveness of PRP, the patients most likely to benefit and the optimal PRP protocol.
Functional Characterisation of the Circular RNA, circHTT(2-6), in Huntington’s Disease
Publisher: MDPI AG
Date: 07-05-2023
Abstract: Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease (HD), results from expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Since non-coding RNAs have been implicated in the initiation and progression of many diseases, herein we focused on a circular RNA (circRNA) molecule arising from non-canonical splicing (backsplicing) of HTT pre-mRNA. The most abundant circRNA from HTT, circHTT(2-6), was found to be more highly expressed in the frontal cortex of HD patients, compared with healthy controls, and positively correlated with CAG repeat tract length. Furthermore, the mouse orthologue (mmu_circHTT(2-6)) was found to be enriched within the brain and specifically the striatum, a region enriched for medium spiny neurons that are preferentially lost in HD. Transgenic overexpression of circHTT(2-6) in two human cell lines—SH-SY5Y and HEK293—reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within HTT. CircHTT(2-6) overexpression did not alter total HTT protein levels, but reduced its nuclear localisation. As these phenotypic and genotypic changes resemble those observed in HD patients, our results suggest that circHTT(2-6) may play a functional role in the pathophysiology of this disease.
Fluctuations of MS births and UV-light exposure
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.
The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease.
Publisher: Elsevier BV
Date: 03-0003
DOI: 10.1016/J.CLIM.2014.01.003
Abstract: We have identified a marked over-representation of transcription factors controlling differentiation of T, B, myeloid and NK cells among the 110 MS genes now known to be associated with multiple sclerosis (MS). To test if the expression of these genes might define molecular subtypes of MS, we interrogated their expression in blood in three independent cohorts of untreated MS (from Sydney and Adelaide) or clinically isolated syndrome (CIS, from San Francisco) patients. Expression of the transcription factors (TF) controlling T and NK cell differentiation, EOMES, TBX21 and other TFs was significantly lower in MS/CIS compared to healthy controls in all three cohorts. Expression was tightly correlated between these TFs, with other T/NK cell TFs, and to another downregulated gene, CCL5. Expression was stable over time, but did not predict disease phenotype. Optimal response to therapy might be indicated by normalization of expression of these genes in blood.
Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis
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.
Oral Presentations
Publisher: SAGE Publications
Date: 09-2016
An apparently non-maternally inherited syndrome of seizures, ataxia and phthalmoplegia, with distinctive cerebellar lesions, in an Irish pedigree
Publisher: Wiley
Date: 09-2005
Genetic variants are major determinants of CSF antibody levels in multiple sclerosis
Publisher: Oxford University Press (OUP)
Date: 22-01-2015
DOI: 10.1093/BRAIN/AWU405
Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing–remitting multiple sclerosis
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.
Persistence on Therapy and Propensity Matched Outcome Comparison of Two Subcutaneous Interferon Beta 1a Dosages for Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 21-05-2013
The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis
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.
Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation
Publisher: American Medical Association (AMA)
Date: 07-2023
DOI: 10.1001/JAMANEUROL.2023.1542
Abstract: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Dimethyl fumarate, fingolimod, and ocrelizumab. Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08) fingolimod, 0.26 (95% CI, 0.12-0.48) and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
The Amount of BCL6 in B Cells Shortly after Antigen Engagement Determines Their Representation in Subsequent Germinal Centers
Publisher: Elsevier BV
Date: 02-2020
Multiple sclerosis in Latin America: A different disease course severity? A collaborative study from the MSBase Registry
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.
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy
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.
Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-10-2022
DOI: 10.1212/WNL.0000000000201029
Abstract: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43–0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08–0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1–2 ARR: 0.80, 0.70–0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, −0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1–10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72–0.81) and disability accumulation (0.73, 0.65–0.80). The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 3 Treatment practicalities and recommendations
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.
Sex as a determinant of relapse incidence and progressive course of multiple sclerosis
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.
The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
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.
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies
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.
Incidence and Characteristics of Melanoma in Multiple Sclerosis Patients Treated With Fingolimod: A Systematic Review
Publisher: Springer Science and Business Media LLC
Date: 30-08-2023
Multifocal motor neuropathy: an observational study of the clinical, electrophysiological and self-reported disability outcomes in 54 patients
Publisher: No publisher found
Date: 2005
Late Breaking News
Publisher: SAGE Publications
Date: 09-2015
Delay from treatment start to full effect of immunotherapies for multiple sclerosis
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.
The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude
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.
Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis
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.
Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis
Publisher: American Medical Association (AMA)
Date: 11-2018
Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.CHOM.2017.06.009
Abstract: The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been h ered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.
The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells
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.
The Icepack Test in the Diagnosis of Myasthenia Gravis with Ocular Features: A Systematic Review of Diagnostic Accuracy, Technique, and Economic Utility
Publisher: Informa UK Limited
Date: 26-03-2023
Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study
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.
Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy
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.
A systematic review of the symptomatic management of Lhermitte’s phenomenon
Publisher: Elsevier BV
Date: 10-2023
The clinical profile of NMOSD in Australia and New Zealand
Publisher: Springer Science and Business Media LLC
Date: 31-01-2020
Poster Presentations
Publisher: SAGE Publications
Date: 09-2008
Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study
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
Iron budgets for three distinct biogeochemical sites around the Kerguelen Archipelago (Southern Ocean) during the natural fertilisation study, KEOPS-2
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.
Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis
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.
Poster Session 1
Publisher: SAGE Publications
Date: 09-2015
MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis
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.
Risk of secondary progressive multiple sclerosis: A longitudinal study
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.
Oral presentations
Publisher: SAGE Publications
Date: 09-2015
Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 30-05-2022
DOI: 10.1186/S12874-022-01623-8
Abstract: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered s le, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.
Pharmacogenomics of interferon beta and glatiramer acetate response in Australian MS Patients
Publisher: SAGE Publications
Date: 30-04-2012
ePoster Session 1
Publisher: SAGE Publications
Date: 09-2015
A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis
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.
Muscle-specific kinase antibody positive myaesthenia gravis and multiple sclerosis co-presentation: A case report and literature review
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JNEUROIM.2013.08.016
Abstract: We present the first case of simultaneous muscle-specific kinase antibody positive myaesthenia gravis and relapsing-remitting multiple sclerosis to be reported in the English literature along with the inherent diagnostic and treatment challenges. There may be an association between myaesthenia and central nervous system demyelination. We identified 72 previously published cases of myaesthenia with central nervous system demyelination. Of 19 cases of myaesthenia with relapsing-remitting multiple sclerosis, nine (47%) were acetylcholine receptor antibody negative, but there were no previously published cases with muscle-specific kinase antibody. Further research is required to clarify this association and optimal treatment in such cases.
Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
Publisher: Public Library of Science (PLoS)
Date: 18-03-2016
IVIG efficacy in CIDP patients is not associated with terminal complement inhibition
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JNEUROIM.2019.02.001
Abstract: Patients with acute and chronic inflammatory demyelinating neuropathies exhibit elevated serum and cerebrospinal fluid (CSF) levels of terminal complement activation products and therapeutic inhibition of complement activation is currently tested for its safety and efficacy in patients with Guillain-Barré syndrome (GBS). Here, we determined serum levels of the complement activation products C3a, C5a and the soluble terminal complement complex (sTCC) in 39 in iduals with chronic inflammatory demyelinating polyneuropathy (CIDP) who participated in one of the largest ever conducted clinical trial in patients with CIDP (ICE trial) and received Intravenous Immunoglobulin (IVIG) or placebo (albumin) in 3 week intervals for up to 24 weeks. In placebo-treated patients with spontaneous disease remission, serum sTCC levels moderately decreased over time. Levels of complement activation products were, however, not modulated by IVIG and remained unchanged in patients with a beneficial response to IVIG therapy as compared to those with steady or worsened disease. These results suggest that the therapeutic efficacy of IVIG in CIDP is based on immunomodulatory mechanisms different from complement inhibition. Terminal complement activation merits further investigation as a surrogate marker for disease progression and therapeutic target in patients with CIDP.
NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand
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.
The composition of the Earth
Publisher: Elsevier BV
Date: 03-1995
Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis.
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.
A case of valproate induced hyperammonemic encephalopathy
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/969505
Abstract: A 36-years-old man on phenytoin, levetiracetam, and sodium valproate presented with acute confusion. Routine investigations including serum valproate and phenytoin concentration were normal. His serum ammonia concentration was raised. His valproate was held and 2 days later he recovered with concordant normalisation of serum ammonia concentration. Urea acid cycle disorder was ruled out, and a diagnosis of valproate induced hyperammonemic encephalopathy (VHE) was made. Asymptomatic hyperammonemia occurs in 15–50% of valproate-treated patients, and while the true incidence of VHE is not known, it is a recognized complication of sodium valproate treatment. VHE typically presents acutely with impaired consciousness, lethargy, and vomiting. Valproate concentrations may be in the therapeutic range, and liver function tests are typically “normal.” Treatment for VHE consists of ceasing valproate and providing supportive care. Some have advocated carnitine replacement.
Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis
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.
Fingolimod after natalizumab and the risk of short-term relapse
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2014
Defining progression independent of relapse activity (PIRA) in adult patients with relapsing multiple sclerosis: A systematic review✰
Publisher: Elsevier BV
Date: 10-2023
Risk of relapse phenotype recurrence in multiple sclerosis
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.
Evaluating the Ability of Open-Source Artificial Intelligence to Predict Accepting-Journal Impact Factor and Eigenfactor Score Using Academic Article Abstracts: Cross-sectional Machine Learning Analys
Publisher: JMIR Publications Inc.
Date: 20-09-2022
Abstract: trategies to improve the selection of appropriate target journals may reduce delays in disseminating research results. Machine learning is increasingly used in content-based recommender algorithms to guide journal submissions for academic articles. e sought to evaluate the performance of open-source artificial intelligence to predict the impact factor or Eigenfactor score tertile using academic article abstracts. ubMed-indexed articles published between 2016 and 2021 were identified with the Medical Subject Headings (MeSH) terms “ophthalmology,” “radiology,” and “neurology.” Journals, titles, abstracts, author lists, and MeSH terms were collected. Journal impact factor and Eigenfactor scores were sourced from the 2020 Clarivate Journal Citation Report. The journals included in the study were allocated percentile ranks based on impact factor and Eigenfactor scores, compared with other journals that released publications in the same year. All abstracts were preprocessed, which included the removal of the abstract structure, and combined with titles, authors, and MeSH terms as a single input. The input data underwent preprocessing with the inbuilt ktrain Bidirectional Encoder Representations from Transformers (BERT) preprocessing library before analysis with BERT. Before use for logistic regression and XGBoost models, the input data underwent punctuation removal, negation detection, stemming, and conversion into a term frequency-inverse document frequency array. Following this preprocessing, data were randomly split into training and testing data sets with a 3:1 train:test ratio. Models were developed to predict whether a given article would be published in a first, second, or third tertile journal (0-33rd centile, 34th-66th centile, or 67th-100th centile), as ranked either by impact factor or Eigenfactor score. BERT, XGBoost, and logistic regression models were developed on the training data set before evaluation on the hold-out test data set. The primary outcome was overall classification accuracy for the best-performing model in the prediction of accepting journal impact factor tertile. here were 10,813 articles from 382 unique journals. The median impact factor and Eigenfactor score were 2.117 (IQR 1.102-2.622) and 0.00247 (IQR 0.00105-0.03), respectively. The BERT model achieved the highest impact factor tertile classification accuracy of 75.0%, followed by an accuracy of 71.6% for XGBoost and 65.4% for logistic regression. Similarly, BERT achieved the highest Eigenfactor score tertile classification accuracy of 73.6%, followed by an accuracy of 71.8% for XGBoost and 65.3% for logistic regression. pen-source artificial intelligence can predict the impact factor and Eigenfactor score of accepting peer-reviewed journals. Further studies are required to examine the effect on publication success and the time-to-publication of such recommender systems.
A Neuroethics Framework for the Australian Brain Initiative
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEURON.2019.01.004
Abstract: Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.
Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts
Publisher: Springer Science and Business Media LLC
Date: 18-09-2021
Late Breaker News
Publisher: SAGE Publications
Date: 09-2016
Response to treatment in NMOSD: the Australasian experience
Publisher: Elsevier BV
Date: 02-2021
Relapsing necrotising encephalomyelopathy due to RANBP2 mutation
Publisher: BMJ
Date: 22-02-2019
DOI: 10.1136/PRACTNEUROL-2018-002063
Abstract: A young woman with a history of previously undiagnosed episodic neurological deterioration since early childhood associated with viral illnesses developed fulminant encephalitis. Standard investigations gave no diagnosis. Next-generation sequencing identified a heterozygous mutation c.1754C T (p.Thr585Met) in the RANBP2 gene, giving the diagnosis of recurrent acute necrotising encephalopathy type 1. This condition is probably underdiagnosed, especially in adults, and should be considered in patients with recurrent encephalopathy.
Disability accrual in primary and secondary progressive multiple sclerosis
Publisher: BMJ
Date: 17-04-2023
Abstract: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Included patients comprised 1872 with PPMS (47% men 50% with activity) and 2575 with SPMS (32% men 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2–47.3) vs 43.9 (43.3–44.4) p .001), greater baseline disability, slower disability accrual (HR 0.86 (0.78–0.94) p .001) and similar age at wheelchair dependence. We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
Poster Session 1
Publisher: SAGE Publications
Date: 09-2016
Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
CSF hypotension: A review of its manifestations, investigation and management
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.JOCN.2016.07.002
Abstract: Intracranial cerebrospinal fluid (CSF) hypotension usually arises in the context of known or suspected leak of CSF. This can be spontaneous, or due to central nervous system trauma or dural defects created during lumbar puncture or epidural anaesthesia. Spontaneous intracranial hypotension (SIH) is increasingly being recognised as a cause for orthostatic headache or spontaneous subdural haematoma where no other obvious cause is found. We review CSF physiology, the mechanism of symptom generation in CSF hypotension and the investigation and management of the syndrome. Whilst commonly mild and self-limiting, CSF hypotension may result in life threatening complications and is most often treatable. When the syndrome is severe, prolonged or complicated, epidural blood patching (EBP) is the mainstay of treatment.
Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))
Publisher: Elsevier BV
Date: 2020
The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function
Publisher: Public Library of Science (PLoS)
Date: 11-06-2015
Equilibrium Modeling of Sorption-Enhanced Cogasification of Sewage Sludge and Wood for Hydrogen-Rich Gas Production with in Situ Carbon Dioxide Capture
Publisher: American Chemical Society (ACS)
Date: 05-05-2017
Poster Session 2
Publisher: SAGE Publications
Date: 09-2016
Incidence and prevalence of NMOSD in Australia and New Zealand.
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.
Late effects of oxaliplatin-induced peripheral neuropathy (LEON)—cross-sectional cohort study of patients with colorectal cancer surviving at least 2 years
Publisher: Springer Science and Business Media LLC
Date: 16-09-2015
DOI: 10.1007/S00520-014-2423-9
Abstract: Oxaliplatin accumulates in dorsal root ganglia, causing an axonal neuronopathy. Symptoms include numbness, pain and gait disturbance which may persist and impact on quality of life (QOL). Despite widespread use of this drug, its late effects and patient satisfaction outcomes have not been widely reported. Furthermore, there has been limited qualitative research published in this area. The objectives of this study were to establish the incidence and clinical impact of chronic peripheral neuropathy. We conducted a cross-sectional observational study of patients who started oxaliplatin treatment at least 2 years prior to study commencement. Patients were assessed in three ways: clinical assessment encompassing neurological examination and nerve conduction studies to calculate a total neuropathy score (TNS) self-reported assessment via validated questionnaires and assessment by recorded interview. The clinical and questionnaire-based assessments were analysed quantitatively and the interview data used for qualitative assessment. Twenty-five patients consented to participate. The mean starting dose of oxaliplatin given was 92 mg/m(2). The cumulative dose received ranged from 375 to 2,400 mg, with a mean cumulative dose of 1,515 mg. Oxaliplatin was ceased due to neuropathy in six patients (24 %), after a mean of 9 cycles of treatment. Modified TNS ranged from 1 to 15 with a mean of 9.5. There was a statistically significant correlation between cumulative oxaliplatin dose and TNS. Quality of life and functional impact questionnaires showed mildly lower physical quality of life, higher pain scores and functional impairment secondary to sensory deficit. Qualitative analysis demonstrated variable bio-psycho-social effects of chronic neuropathy but, importantly, highlighted that many patients felt they had been insufficiently warned of the risk of neuropathy. Despite this, the majority was satisfied with their decision to receive the drug. Many patients objectively demonstrated mild to moderate oxaliplatin neuropathy >2 years post-treatment. The majority of patients did not recall being warned of the risks of chronic peripheral neuropathy. Many of those who recall being warned did not feel sufficient emphasis was placed on the issue. Despite a varying burden of neuropathic symptoms, the majority of patients were highly satisfied with their decision to receive oxaliplatin.
ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 + T cell pathogenicity during CNS inflammation
Publisher: Proceedings of the National Academy of Sciences
Date: 12-12-2017
Abstract: How autoreactive CD4 + T cells recognize their target antigen and induce sustained inflammation in organ-specific autoimmune diseases is incompletely understood. In an experimental model of multiple sclerosis, we show that accumulation of myelin-specific CD4 + T cells within the CNS and subsequent clinical disease development requires autophagy protein (ATG)-dependent phagocytosis in dendritic cells (DCs). Absence of ATG-dependent phagocytosis in DCs abrogates myelin presentation to CD4 + T cells following phagocytosis of oligodendroglial cells, and its pharmacological inhibition delays the onset and reduces the clinical severity of experimental autoimmune encephalomyelitis. Thus, DCs use ATG-dependent phagocytosis for enhanced presentation of myelin antigen during autoimmune CNS inflammation, thereby linking oligodendrocyte injury with antigen processing and autoimmune T cell pathogenicity.
Physical examination in functional unresponsiveness
Publisher: BMJ
Date: 09-0010
Abstract: Functional unresponsiveness can present a diagnostic challenge, but there are many positive physical examination findings that may help to confirm this diagnosis. Some of these are associated with pain or potential tissue damage for the patient, and potentially ethical and legal risk for the practitioner, but several lesser-known physical examination techniques do not carry these risks. Such examination techniques include non-damaging irritative stimuli, a modification to the conventional hand drop test and evaluation of eyelid opening.
Closing the case of APOE in multiple sclerosis: No association with disease risk in over 29 000 subjects
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.
Seasonal variation of relapse rate in multiple sclerosis is latitude dependent
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.
Anti‐inflammatory disease‐modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study
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.
Utilisation of disease modifying treatment and diversity of treatment pathways in relapsing remitting multiple sclerosis
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.MSARD.2021.103412
Abstract: There is minimal information on the utilisation of Disease Modifying Treatment (DMTs) for multiple sclerosis. The appropriate and safe use of medicines is informed by utilisation studies. Outcomes can inform health interventions to improve appropriate use of medicines and post marketing surveillance activities to improve safety. To evaluate utilisation and treatment patterns of disease modifying treatments (DMTs) for relapsing remitting multiple sclerosis (RRMS). A representative s le of the Australian pharmaceutical benefits scheme data were analysed (2006-2016). Demographics of incident users and trends in incident and prevalent users were determined. In idual patient treatment pathways were determined by sequential initiation of medicines in two different periods (2006-2013 and 2014-2019). There were 20,660 patients with at least one dispensing of a DMT for RRMS during the study period (median age 41 years, 75% female). Incident and prevalent use increased by 20% and 88%, respectively. The market was responsive to 13 new listings of DMTs over the study period. Sequential treatment was found for 66% of initiators in 2006-2013 and 28.5% of initiators in 2014-2019. Diverse treatment pathways were found, with 278 and 93 unique sequences in 2006-2013 and 2014-2019, respectively. The availability of new DMTs has influenced both initial treatment choice and prevalence of users. In idualised treatment patterns and exposure to multiple medicines over time will challenge traditional pharmacovigilance systems.
Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis
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.
Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.
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.
ACTRIMS Forum 2016
Publisher: SAGE Publications
Date: 02-2016
Fc-galactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity
Publisher: Frontiers Media SA
Date: 06-06-2017
The Australian Multiple Sclerosis (MS) immunotherapy study: a prospective, multicentre study of drug utilisation using the MSBase platform
Publisher: Public Library of Science (PLoS)
Date: 19-03-2013
Speech-activated myoclonus: an uncommon form of action myoclonus
Publisher: Wiley
Date: 13-05-2005
DOI: 10.1002/MDS.20505
Abstract: We describe an unusual form of facial myoclonus activated by speech in 3 patients with different underlying neurological diseases and present the electrophysiological investigations and results of structural and functional imaging. In 1 of 2 patients in whom jerk-locked electroencephalogram (EEG) back-averaging was done, a cortical potential clearly preceded the facial jerks. In the second patient, a cortical potential preceding the jerk was not certain. In the third patient, the resting EEG contained outbursts of symmetric, slower frequencies of indeterminate significance. An epileptiform disorder was suspected in this patient.
Flow Cytometry Identifies an Early Stage of Platelet Apoptosis Produced by Agonists of the P2X1 and P2X7 Receptors
Publisher: Informa UK Limited
Date: 18-01-2022
DOI: 10.1080/09537104.2021.1981844
Abstract: Platelets express P2X1 receptors and our data also show the expression of P2X7 receptors. We studied the role of both receptors in platelet apoptosis by incubation of PRP with P2X agonists, then centrifuged to remove viable platelets, and analyzed the supernatant by flow cytometry to identify a sparse platelet-derived population that stained with MitoTracker dyes and CD41. BzATP, a potent agonist of P2X receptors, and ABT737, an activator of intrinsic apoptosis, produced altered platelets that stained moderately for annexin V and corresponded to an early stage apoptotic platelet (ESAP). Over a range of BzATP concentrations, we observed a dose-dependent formation of ESAPs between 5 and 500 uM BzATP, together with a variable formation of ESAPs at nanomolar ATP or BzATP (50-200 nM). Production of ESAPs occurred with αβ-meATP, while responses with either BzATP or αβ-meATP showed desensitization at a higher agonist concentration. Formation of ESAPs by either 100 nM or 0.5 mM BzATP was inhibited by preincubation of platelets with latrunculin A, an inhibitor of the actin cytoskeleton that prevents apoptosis. ESAP production was totally inhibited by preincubation of platelets with methyl-beta-cyclodextrin, which removes cholesterol from lipid rafts. Our data show that both P2X1 and P2X7 receptors are localized in platelet lipid rafts where P2X-agonists act to produce early stage apoptotic platelets.
Switch to natalizumab versus fingolimod in active relapsing–remitting multiple sclerosis
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.
Defining reliable disability outcomes in multiple sclerosis
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.
A critical review on biomass pyrolysis: Reaction mechanisms, process modeling and potential challenges
Publisher: Elsevier BV
Date: 06-2023
DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes
Publisher: MDPI AG
Date: 08-08-2023
Abstract: Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.
Neuromyelitis optica (Devic's disease) in a patient with syphilis
Publisher: SAGE Publications
Date: 17-10-2008
Abstract: The patient initially presented with bilateral optic neuritis and periventricular cranial MRI abnormalities in the context of syphilis. Blood was positive but cerebrospinal fluid testing was negative for specific syphilis markers and he was oligoclonal cerebrospinal fluid (CSF) band negative. He initially responded well to penicillin and corticosteriod treatment, but went on to develop the clinical syndrome of neuromyelitis optica (NMO). Testing for the presence of the serum autoantibody for aquaporin-4 was negative. This patient appears to represent another case of post-infectious NMO. Possible pathogenesis of this post-syphilis NMO syndrome in the patient is discussed. Multiple Sclerosis 2008 14: 268—271. msj.sagepub.com
Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis
Publisher: American Medical Association (AMA)
Date: 07-2023
DOI: 10.1001/JAMANEUROL.2023.1184
Abstract: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. AHSCT vs fingolimod, natalizumab, or ocrelizumab. Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Of 4915 in iduals, 167 were treated with AHSCT 2558, fingolimod 1490, natalizumab and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77 95% CI, 0.61-5.08), and disability improvement (HR, 1.37 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.
The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies
Publisher: Elsevier BV
Date: 08-2021
Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.
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.
Prediction of multiple sclerosis outcomes when switching to ocrelizumab.
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.
Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis
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.
Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement
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.
Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.
Publisher: Oxford University Press (OUP)
Date: 30-11-2022
Abstract: Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis 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 multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 in iduals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273 βfemale =0.8289, P = 3.52 × 10-08), the other in males (rs698805 βmale = -1.5395, P = 4.35 × 10-08), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
Predictors of disability worsening in clinically isolated syndrome
Publisher: Wiley
Date: 27-03-2015
DOI: 10.1002/ACN3.187
Treatment utilisation and persistence in the Australian relapsing-remitting MS population: results from the MSBase Registry
Publisher: SAGE Publications
Date: 10-2011
Parkinsonism and dementia due to gliomatosis cerebri mimicking sporadic Creutzfeldt-Jakob disease (CJD)
Publisher: BMJ
Date: 04-2033
Contribution of different relapse phenotypes to disability in multiple sclerosis
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.
2014 Joint ACTRIMS-ECTRIMS Meeting (MSBoston 2014) MS Journal Online: Poster Session 1
Publisher: SAGE Publications
Date: 09-2014
Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
The Northern Territory Medical Program – growing our own in the NT
Publisher: Rural and Remote Health
Date: 27-05-2019
DOI: 10.22605/RRH4671
Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis.
Publisher: BMJ
Date: 19-10-2022
Abstract: To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing-remitting multiple sclerosis switching from fingolimod. Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab. Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation. After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences.
The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry
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.
Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 10-02-2023
DOI: 10.1186/S13148-023-01438-4
Abstract: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4 + and eight in CD8 + T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ‘CNS signature’ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis
Publisher: Wiley
Date: 16-02-2023
DOI: 10.1111/ENE.15706
Abstract: This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
Data quality evaluation for observational multiple sclerosis registries
Publisher: SAGE Publications
Date: 08-2016
Abstract: Objective and reproducible evaluation of data quality is of paramount importance for studies of ‘real-world’ observational data. Here, we summarise a standardised data quality, density and generalisability process implemented by MSBase, a global multiple sclerosis (MS) cohort study. Error rate, data density score and generalisability score were developed using all 35,869 patients enrolled in MSBase as of November 2015. The data density score was calculated across six domains (follow-up, demography, visits, MS relapses, paraclinical data and therapy) and emphasised data completeness. The error rate evaluated syntactic accuracy and consistency of data. The generalisability score evaluated believability of the demographic and treatment information. Correlations among the three scores and the number of patients per centre were evaluated. Errors were identified at the median rate of 3 per 100 patient-years. The generalisability score indicated the s les’ representativeness of the known MS epidemiology. Moderate correlation between the density and generalisability scores (ρ = 0.58) and a weak correlation between the error rate and the other two scores (ρ = −0.32 to −0.33) were observed. The generalisability score was strongly correlated with centre size (ρ = 0.79). The implemented scores enable objective evaluation of the quality of observational MS data, with an impact on the design of future analyses.
OPL043 Multifocal motor neuropathy: an observational study of the clinical, electrophysiological and self-reported disability outcomes in 54 patients
Publisher: Elsevier BV
Date: 2005
Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis
Publisher: American Medical Association (AMA)
Date: 15-01-2019
Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial
Publisher: Elsevier BV
Date: 03-2014
Toward a common clinical lexicon of consciousness
Publisher: Springer Science and Business Media LLC
Date: 08-07-2023
Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-06-2022
DOI: 10.1212/WNL.0000000000200545
Abstract: The severity of multiple sclerosis (MS) varies widely among in iduals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration’s Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35′ and 56°16′) were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes °, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04–0.12). For ex le, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes ° (β = −0.02, 95% CI −0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = − 0.5, 95% CI −0.6 to 0.4) and 18 years (β = − 0.6, 95% CI −0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = −1.0, 95% CI −1.1 to 0.9). In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS
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.
Conditional deletion of β-catenin leads to precocious oligodendrocyte precursor cell cycle exit and subsequent differentiation in vivo
Publisher: SAGE Publications
Date: 06-11-2015
Neurophysiological Findings in Multifocal Motor Neuropathy
Publisher: Wiley
Date: 16-06-2005
Multifocal motor neuropathy: The diagnostic spectrum and response to treatment
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-10-2007
DOI: 10.1212/01.WNL.0000277697.55288.D0
Abstract: To define the clinical spectrum in a large cohort of patients with multifocal motor neuropathy (MMN) and the effectiveness of IVIg treatment. We also test two neurophysiologic criteria for conduction block (CB) for relevance to treatment responsiveness. Retrospective case cohort analysis of 47 patients with MMN followed for up to 12 years. A total of 32 (70%) had an upper-limb onset with most showing clinical features of conduction block: weakened but non-wasted muscles (67%) and differential weakness across muscles supplied by a common terminal motor nerve (54%). Differential weakness of finger extension was a characteristic early sign. Application of consensus criteria for definite CB would have denied a trial of treatment to 6 patients with a typical phenotype compared with new criteria. No association was found between CB and presence of anti-GM1 ganglioside antibody. A total of 24 (51%) patients were treated with IVIg, which was associated with a marked initial improvement in self-reported disability in most patients. The magnitude of initial disability improvement was not sustained in all patients over time. However, the majority of treated patients reported significantly less disability at last follow-up than prior to treatment. Patients converted to a domiciliary IVIg program maintained function at least as well as hospital treated patients. The importance of the clinical phenotype of multifocal motor neuropathy (MMN) is emphasized. Neither conduction block (CB) nor antibody status is a reliable predictor of treatment responsiveness. Over-reliance upon consensus CB criteria can deny IVIg to patients with MMN who are treatment responsive.
No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis
Publisher: Oxford University Press (OUP)
Date: 13-11-2013
DOI: 10.1093/HMG/DDT574
Abstract: Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within in iduals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control in iduals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.
Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS
Publisher: Public Library of Science (PLoS)
Date: 05-06-2015
Exposure to Interferon-b Therapy in Early Pregnancy: A Literature Review of Pregnancy Outcomes in Women with Multiple Sclerosis
Publisher: BMJ
Date: 11-2012
A Transcription Factor Map as Revealed by a Genome- Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 12-2010
Predictors and dynamics of postpartum relapses in women with multiple sclerosis
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.
A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.JOCN.2011.02.019
Abstract: We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.
Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season
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.
A new era in the treatment of multiple sclerosis
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.
Relapsing encephalopathy with headache: An unusual presentation of isolated intracranial neurosarcoidosis
Publisher: BMJ
Date: 18-12-2007
PACTRIMS abstracts
Publisher: SAGE Publications
Date: 22-01-2016
The effects of chronic psychological stress on the immune response to lymphoma (#2098)
Publisher: Wiley
Date: 08-2016
Towards personalized therapy for multiple sclerosis: prediction of individual treatment response
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.
Chemical compositions and α-glucosidase inhibitory effects of anthocyanidins from blueberry, blackcurrant and blue honeysuckle fruits
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
Increasing age at disability milestones among MS patients in the MSBase Registry
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.
Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes
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.
Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study
Publisher: Elsevier BV
Date: 04-2017
Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
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.
Biomass-based chemical looping technologies: the good, the bad and the future
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6EE03718F
Abstract: This review article focuses on the challenges and opportunities of biomass-based chemical looping technologies and explores fundamentals, recent developments and future perspectives.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 29-09-2013
DOI: 10.1038/NG.2770
Evaluating the Ability of Open-Source Artificial Intelligence to Predict Accepting-Journal Impact Factor and Eigenfactor Score Using Academic Article Abstracts: Cross-sectional Machine Learning Analys
Publisher: JMIR Publications Inc.
Date: 23-12-2023
DOI: 10.2196/42789
Abstract: Strategies to improve the selection of appropriate target journals may reduce delays in disseminating research results. Machine learning is increasingly used in content-based recommender algorithms to guide journal submissions for academic articles. We sought to evaluate the performance of open-source artificial intelligence to predict the impact factor or Eigenfactor score tertile using academic article abstracts. PubMed-indexed articles published between 2016 and 2021 were identified with the Medical Subject Headings (MeSH) terms “ophthalmology,” “radiology,” and “neurology.” Journals, titles, abstracts, author lists, and MeSH terms were collected. Journal impact factor and Eigenfactor scores were sourced from the 2020 Clarivate Journal Citation Report. The journals included in the study were allocated percentile ranks based on impact factor and Eigenfactor scores, compared with other journals that released publications in the same year. All abstracts were preprocessed, which included the removal of the abstract structure, and combined with titles, authors, and MeSH terms as a single input. The input data underwent preprocessing with the inbuilt ktrain Bidirectional Encoder Representations from Transformers (BERT) preprocessing library before analysis with BERT. Before use for logistic regression and XGBoost models, the input data underwent punctuation removal, negation detection, stemming, and conversion into a term frequency-inverse document frequency array. Following this preprocessing, data were randomly split into training and testing data sets with a 3:1 train:test ratio. Models were developed to predict whether a given article would be published in a first, second, or third tertile journal (0-33rd centile, 34th-66th centile, or 67th-100th centile), as ranked either by impact factor or Eigenfactor score. BERT, XGBoost, and logistic regression models were developed on the training data set before evaluation on the hold-out test data set. The primary outcome was overall classification accuracy for the best-performing model in the prediction of accepting journal impact factor tertile. There were 10,813 articles from 382 unique journals. The median impact factor and Eigenfactor score were 2.117 (IQR 1.102-2.622) and 0.00247 (IQR 0.00105-0.03), respectively. The BERT model achieved the highest impact factor tertile classification accuracy of 75.0%, followed by an accuracy of 71.6% for XGBoost and 65.4% for logistic regression. Similarly, BERT achieved the highest Eigenfactor score tertile classification accuracy of 73.6%, followed by an accuracy of 71.8% for XGBoost and 65.3% for logistic regression. Open-source artificial intelligence can predict the impact factor and Eigenfactor score of accepting peer-reviewed journals. Further studies are required to examine the effect on publication success and the time-to-publication of such recommender systems.
Confirmed disability progression as a marker of permanent disability in multiple sclerosis
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1111/ENE.15406
Abstract: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS) however, randomized clinical trials evaluate only short‐term treatment effects on disability. This study aimed to define criteria for 6‐month confirmed disability progression events of MS with a high probability of resulting in sustained long‐term disability worsening. In total, 14,802 6‐month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6‐month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long‐term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52 discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72% 2: 88% 3: 94% 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was % likely to be sustained (events with score ˃1.5). Clinicodemographic characteristics of 6‐month confirmed disability progression events identify those at high risk of sustained long‐term disability. This knowledge will allow future trials to better assess the effect of therapy on long‐term disability accrual.
Related Organisations
University Of Oxford And NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
Southern Adelaide Local Health Network And Flinders University
Location: Australia
Related Funding Activities
No related grants have been discovered for Mark Slee.