Conjoint Professor Jeannette Lechner-Scott

Background: Multiple sclerosis is characterised by acute and chronic inflammation in the CNS. Diet may influence inflammation, and therefore MS outcomes. Objective: To determine whether the Dietary Inflammatory Index (DII®)) is associated with depression, anxiety, and fatigue in a prospective cohort of people with MS. Methods: People with a first clinical diagnosis of demyelination were followed over 10 years (n=223). DII and energy-adjusted DII (E-DIITM) scores were calculated from the dietary intake in the preceding 12 months measured by food frequency questionnaire. Depression and anxiety were assessed by the Hospital Anxiety and Depression Scale (HADS-A and HADS-D, respectively), and fatigue by the Fatigue Severity Scale. Results: A higher E-DII score was associated with higher levels of depression and anxiety five years later (e.g., highest vs lowest E-DII quartile, HADS-D score: ß=2.23, 95%CI=0.98,3.48, p<0.001; HADS-A score: ß=1.90, 95%CI=0.59,3.21, p<0.001). A cumulative E-DII score was associated with depression (p<0.01) and anxiety (p=0.05) at the 10-year review. No associations were seen for fatigue. Conclusion: Our findings suggest that, in people with MS, a more pro-inflammatory diet may long-term adverse impact on depression and anxiety, but not fatigue.

Background and purpose: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). Methods: This prospective cohort study comprised adults (aged 18¿59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part-time, or full-time employed. A Markov multistate model was used to examine the rate of state-to-state transitions. Results: At the time of FCD, participants with full-time employment had an 89% chance of being in the same state over a 1-year period, but this decreased to 42% over the 10-year follow-up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow-up period were less likely to gain employment after being unemployed. Conclusions: In our FCD cohort, we found a considerable rate of employment transition during the early years post-diagnosis. Over more than a decade of follow-up post-FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment.

Cognitive impairment in multiple sclerosis (MS) affects approximately 40¿70% of patients and can have varying degrees of severity. Even mild cognitive impairment can impact on quality of life and productivity. Despite this, patients are not routinely screened or monitored for cognitive impairment in Australia due to a range of issues, with time and space being the main limiting factors. This Australian multidisciplinary perspective provides recommendations on cognition management in Australia. It gives a broad overview of cognition in MS, advice on the screening and monitoring tools available to clinicians, and strategies that can be implemented in clinics to help monitor for cognitive impairment in patients with MS. We suggest a routine baseline assessment and multidomain cognitive battery in regular intervals; a change should trigger a thorough investigation of the cause.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF¿ZNF638 locus, the risk allele of which is associated with a¿shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers¿and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3¿PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Background: Diet-dependent acid-base load has been associated with worsening in mental health, but to date no study has examined this in people with multiple sclerosis (PwMS). We examined the association between potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores and depression, anxiety, and fatigue in PwMS. Methods: Participants with a first clinical diagnosis of CNS demyelination were followed prospectively as part of the AusLong Study (aged 18-59 years at cohort entry). At baseline, 5- and 10-year reviews, PRAL and NEAP scores were calculated using dietary intake in the preceding 12 months calculated from a food frequency questionnaire. At 5- and 10-year reviews, the Hospital Anxiety and Depression Scale was used to assess depression and anxiety, and the Fatigue Severity Scale assessed fatigue. Results: Higher PRAL and NEAP scores were associated with increased subsequent absolute value and change in HADS depression scores over five years¿ follow-up (e.g., highest vs lowest PRAL quartile, 5-year change in HADS-D score: ß=+3.01, 95%CI= 1.54, 4.48, p<0.001). The level of depression at the 10-year review was determined by both the baseline dietary acid scores and baseline-5-year changes in dietary acid scores (e.g., PRAL change from baseline to 5-year review, 10-year review HADS-D score: ß=+0.09, 95%CI= 0.03, 0.15, p<0.001, NEAP change from baseline to 5-year review, 10-year review HADS-D score: ß=+0.07, 95%CI= 0.01, 0.14, p=0.03). Some associations were observed with anxiety and fatigue but were much weaker and less consistent. Conclusion: Our findings indicate that a higher dietary acid load potentially has a long-term influence on the level of depression in PwMS. The evidence is less convincing for anxiety and fatigue.

Background: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). Objective: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. Methods: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. Results: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1¿2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. Conclusions: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

Background: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, ¿BRACETD¿) often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after =1 relapse. Methods: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with =1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for =3 months after the switch. Results: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59¿0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60¿0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03¿1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. Conclusions: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod.

Background: 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. Results: 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. Conclusion: 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.

Background: Cladribine is a useful therapeutic option in RRMS with moderate to high disease activity. Its oral formulation and tolerability make it a useful alternative to infusion therapies. Cladribine is known to deplete CD19+ B lymphocytes, but its effect on immunoglobulin subsets is unclear. Objective: To identify whether cladribine therapy in pwMS reduces immunoglobulin subset levels as a surrogate marker of infection risk. Methods: A ¿real-world¿ retrospective analysis of 341 pwMS presenting to a single tertiary centre between March 2017 and July 2021. Differences in immunoglobulin levels between cladribine, other disease-modifying therapies and no active treatment were assessed using a univariate ANOVA. Results: Three hundred and forty-one patients had immunoglobulin levels assessed, with 29 patients treated with cladribine. The mean IgG, IgM and IgA levels on cladribine therapy were 10.44 ± 0.40, 0.99 ± 0.09 and 2.04 ± 0.18 g/L respectively. These were not significantly different from patients not on active treatment. There was a statistically significant reduction in IgG and IgM levels for patients treated with ocrelizumab (9.37 ± 0.19 and 0.68 ± 0.04 g/L) and natalizumab (8.72 ± 0.53 and 0.69 ± 0.12 g/L) compared to patients not on treatment. Conclusion: Cladribine therapy for RRMS was not associated with immunoglobulin subset deficiencies. This is contrasted to ocrelizumab and natalizumab which demonstrate significant reductions in both IgG and IgM levels.

Background: Cognitive impairment is a common symptom of multiple sclerosis (MS). The effect of cognitive impairment in people with MS on employment, quality of life and mental health is known, however, few studies have investigated if cognitive deficits contribute to the economic burden of MS. Objective: To investigate if cognitive impairment correlates with the economic burden of MS. Methods: The client service receipt inventory was used to determine cost to the healthcare system, participant out of pocket cost, community cost and total societal cost. Quality of life was evaluated using the EuroQoL. Participants cognitive performance was assessed with the Audio Recorded Cognitive Screen and the symbol digit modalities test. Spearman's rank correlation coefficient (r) was used to gauge the strength of the correlation between domain scores and cost metrics. Results: Memory, speed of writing and the symbol digit modalities test were all negatively correlated with all aspects of cost of care (r = 0.24¿0.59, P < 0.5). This was found to be independent of other factors, such as EDSS or mental health indices. Conclusion: Cognitive deficits are independently correlated with the economic burden of MS and should be monitored as part of routine care.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10¿5; rs12211604: HR 1.16, P = 3.2 × 10¿7; rs55858457: HR 0.93, P = 3.7 × 10¿7; rs10271373: HR 0.90, P = 1.1 × 10¿7; rs11256593: HR 1.13, P = 5.1 × 10¿57; rs12588969: HR = 1.10, P = 2.1 × 10¿10; rs1465697: HR 1.09, P = 1.7 × 10¿128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

Background: Multiple Sclerosis (MS) is a complex neurodegenerative condition that is influenced by a combination of genetic and environmental factors. Included in these factors is the venous system, however, the extent to which it influences the etiology of MS has yet to be fully characterised. The aim of this review is to critically summarize the literature available concerning the venous system in MS, primarily concerning specific data on the venous pressure and blood flow in this system. Methods: A systematic review was conducted with the application of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The advanced search functions of both the Scopus and PubMed databases were used to conduct the literature search, resulting in 136 unique articles initially identified. Applying relevant exclusion criteria, 22 of the studies were chosen for this review. Results: The selected studies were analysed for venous pressure and blood flow related findings, with 14 studies contributing data on the internal jugular vein (IJV) flow rate, 5 on blood flows of the intracranial venous sinuses, 2 on blood flow pulsatility and 6 supplying information relevant to the venous pressure (3 studies contributed to multiple areas). The general findings of the review included that the IJV flow was not significantly different between MS patients and controls, however, there were variances between stenotic (S) and non-stenotic (NS) MS patients. Due to the limited data in the other two areas defined in this review, further research is required to establish if any variances in MS are present. Conclusion: It remains unclear if there are significant differences in many flow variables between MS patients and controls considered in this review. It would be advantageous if future work in this area focused on understanding the hemodynamics of this system, primarily concerning how the flow rate, venous pressure and vascular resistance are related, and any impact that these factors have on the etiology of MS.

Background: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene¿environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker. Methods: We conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance. Results: Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity. Conclusion: RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.

Background: Many people with multiple sclerosis (MS) modify their dietary intake post diagnosis, but there is little evidence that dietary modifications influence MS outcomes. Methods: People with a first clinical diagnosis of central nervous system demyelination were followed annually for 10 years. Depression, anxiety, and fatigue were assessed at the 5-and 10-year reviews using the Hospital Anxiety and Depression Scale and Fatigue Severity Scale, respectively. Dietary intake in the preceding 12 months was assessed at baseline, and 5-and 10-year reviews using a food frequency questionnaire. We used the Australian Recommended Food Score (ARFS) and the Diet Quality Tracker (DQT) to assess diet quality. Results: A higher diet quality in the previous 12 months using the ARFS score, but not the DQT, was associated with lower levels of depression (e.g., highest vs lowest quartile: ß=-1.35,95%CI=-2.44,-0.26,p=0.01), but neither score was associated with anxiety or fatigue. After assessing diet quality prospectively with outcomes five years later, we found that higher ARFS score, but not DQT score, was associated with lower levels of subsequent anxiety and depression (highest vs lowest quartile; Anxiety: ß=-1.61,95%CI=-2.76,-0.46,p=0.01, Depression: ß=-1.25,95%CI=-2.44,-0.07,p=0.04), but not fatigue. No associations were observed between diet quality and subsequent change in depression and anxiety over five years, although an association was observed between diet quality and change in fatigue (e.g., highest vs lowest DQT quartile: ß=-1.06,95%CI=-1.92,-0.21,p=0.02). When examining the cumulative effect of diet quality across the study period with our 10-year outcomes, only the cumulative DQT score was associated with depression but not anxiety or fatigue. Conclusion: We found significant inverse associations between diet quality and depression and anxiety, but the effect sizes were modest and there was a lack of consistency between the two diet quality measures (ARFS and DQT). A diet measure that correlates with diet quality might underlie our observed associations.

Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease-modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard deviation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS.

Background: Perceived cognitive impairment in MS is associated with adverse changes in employment capacity, sexual function, and aspects of daily living. Studies have shown relationships between perceived cognitive impairment and objective neuropsychological functioning and mood. Subjective cognitive performance in people with MS has not previously been compared to their objective performance on a computerised cognitive battery. Methods: All participants completed at least 6-monthly serial testing on the MSReactor computerised cognitive testing platform consisting of 3 reaction time tasks. These measure psychomotor processing speed (simple reaction time), attention (choice reaction time) and working memory (One back task). In addition, we collected subjective cognitive performance and patient reported outcomes of depression, anxiety and quality of life. The strength and direction of the relationships between subjective and objective performance on the cognitive tasks were examined using Kendalls rank coefficient at year 1 and year 2. We calculated partial correlation estimates where subjective performance was also associated with patient reported outcomes. Results: Subjective overall performance correlated weakly with the working memory task (Tau -0.10; (95% confidence interval (CI) -0.19, -0.01). Subjective performance also correlated weakly with depression but not anxiety or quality of life. Subjective reaction speed correlated weakly with psychomotor processing speed (Tau -0.10; CI -0.19, -0.01); and subjective accuracy correlated weakly with the attention (Tau 0.12; CI 0.03, 0.21) and working memory (Tau 0.15; CI 0.05, 0.24) tasks, respectively. Conclusion: Participants¿ perceived performance on the MSReactor tests correlated only weakly with objective changes. Depression was associated with subjective cognitive performance reports. These results suggest that a person with MS¿ perception of their cognitive performance is only weakly associated with cognitive changes detected using MSReactor.

Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10-8 ) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.

Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/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). Results: 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, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2¿6 m compared to <1 m: HR = 9.57, 95% CI = 1.92¿47.64, p = 0.006). Conclusion: 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.

Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system (CNS). Early diagnosis of MS is highly desirable as treatments are more effective in preventing MS-related disability when given in the early stages of the disease. The main aim of this research is to predict the occurrence of a second MS-related clinical event, which indicates the conversion of clinically isolated syndrome (CIS) to clinically definite MS (CDMS). In this study, we apply a branch of artificial intelligence known as deep learning and develop a fully automated algorithm primed with convolutional neural network (CNN) that has the ability to learn from MRI scan features. The basic architecture of our algorithm is that of the VGG16 CNN model, but amended such that it can handle MRI DICOM images. A dataset comprised of scans acquired using two different scanners was used for the purposes of verification of the algorithm. A group of 49 patients had volumetric MRI scans taken at onset of the disease and then again one year later using one of the two scanners. In total, this yielded 7360 images which were then used for training, validation, and testing of the algorithm. Initially, these raw images were taken through 4 steps of preprocessing. In order to boost the efficiency of the process, we pretrained our algorithm using the publicly available ADNI dataset used to classify Alzheimer's disease. Finally, we used our preprocessed dataset to train and test the algorithm. Clinical evaluation conducted a year after the first time point revealed that 26 of the 49 patients had converted to CDMS, while the remaining 23 had not. Results of testing showed that our algorithm was able to predict the clinical results with an accuracy of 88.8% and with an area under the curve (AUC) of 91%. A highly accurate algorithm was developed using CNN approach to reliably predict conversion of patients with CIS to CDMS using MRI data from two different scanners.

The cross-sectional area of the superior sagittal sinus (SSS) is larger in multiple sclerosis than normal and correlates with disease severity and progression. The sinus could be enlarged due to a decrease in the pressure difference between the lumen and the subarachnoid space, an increase in wall thickness or increased wall stiffness. The cross-sectional area of the SSS and straight sinus (ST) were measured in 103 patients with multiple sclerosis and compared to 50 controls. The cross-sectional area of the SSS and ST were increased by 20% and 13% compared to the controls (p = 0.005 and 0.02 respectively). The deflection of the wall of the sinus was estimated. The change in pressure gradient, wall thickness or elastic modulus between groups was calculated by modelling the walls as simply supported beams. To account for these findings, the modelling suggests either a 70% reduction in transmural venous pressure or a 2.4 fold increase in SSS wall stiffness plus an 11% increase in wall thickness or a combination of changes. An increase in sinus pressure, although the most straight forward possibility to account for the change in sinus size may exist in only a minority of patients. An increase in sinus wall stiffness and thickness may need further investigation.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. Methods: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. Results: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 ¿ 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 ¿ 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 ¿ 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 ¿ 7.5]). Conclusions: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Background and Purpose: Fingolimod has been shown to be more effective in reducing relapse rate and disability than injectable therapies in clinical trials. An increase in N-acetylaspartate (NAA) as measured by MR spectroscopy is correlated with maintaining axonal metabolic functions. This study compared the neurometabolic and volumetric changes in relapsing-remitting multiple sclerosis (RRMS) patients on fingolimod or injectable therapies with healthy controls (HCs). Methods: Ninety-eight RRMS (52 on fingolimod, 46 on injectable therapies (27 on glatiramer acetate and 19 on interferon) were age and sex-matched to 51 HCs. RRMS patients underwent cognitive, fatigue, and mental health assessments, as well as an Expanded disability status scale (EDSS). MRI/S was acquired from the hippocampus, posterior cingulate gyrus (PCG), and prefrontal cortex (PFC). Volumetric and neurometabolic measures were compared across cohorts using a univariate general linear model and correlated with clinical severity and neuropsychological scores. Results: Clinical parameters, MR-volumetric, and neurometabolic profiles showed no differences between treatment groups (p¿>.05). Compared to HCs, both RRMS cohorts showed volume changes in white matter (-13%), gray matter (-16%), and cerebral spinal fluid (CSF) (+17-23%), as well as reduced NAA (-17%, p =.001, hippocampus), (-7%, p =.001, PCG), and (-9%, p =.001, PFC). MRI/S metrics in three regions were moderately correlated with cognition and fatigue functions. Conclusion: While both treatment arms showed overall similar volumetric and neurometabolic profiles, longitudinal studies are warranted to clarify neurometabolic changes and associations with treatment efficacy.

Background: 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. Methods: 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. Results: 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 Maori 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. Conclusion: The prevalence of NMOSD in the Maori 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.

Background: Computer-aided diagnosis can facilitate the early detection and diagnosis of multiple sclerosis (MS) thus enabling earlier interventions and a reduction in long-term MS-related disability. Recent advancements in the field of artificial intelligence (AI) have led to the improvements in the classification, quantification and identification of diagnostic patterns in medical images for a range of diseases, in particular, for MS. Importantly, data generated using AI techniques are analyzed automatically, which compares favourably with labour-intensive and time-consuming manual methods. Objective: The aim of this review is to assist MS researchers to understand current and future developments in the AI-based diagnosis and prognosis of MS. Methods: We will investigate a variety of AI approaches and various classifiers and compare the current state-of-the-art techniques in relation to lesion segmentation/detection and prognosis of disease. After briefly describing the magnetic resonance imaging (MRI) techniques commonly used, we will describe AI techniques used for the detection of lesions and MS prognosis. Results: We then evaluate the clinical maturity of these AI techniques in relation to MS. Conclusion: Finally, future research challenges are identified in a bid to encourage further improvements of the methods.

Background: In a previous study, multiple sclerosis (MS) was found to be associated with an increase in intracranial arterial pulsation volume and a reduction in venous sinus compliance, affecting pulsation dampening. There was a suggestion that the reduction in compliance of the sagittal sinus in MS was caused by an increase in venous pressure, secondary to transverse sinus stenosis. Some differences were noted depending on the gender of the patients, however, the original study was relatively underpowered for further sub-classification. The purpose of the current study is to enroll a larger number of patients to allow sub-classification on gender and disease type to further evaluate the markers of possible venous pressure alteration. Methods: 103 patients with MS were prospectively recruited from an MS clinic and compared to 50 matched non-MS patients. Using 3DT1 post contrast images, the sagittal sinus cross-sectional area was measured. The narrowest portion of the transverse sinuses was located and the cross sectional areas and wetted circumferences were measured to calculate the minimum hydraulic and effective diameters. The jugular bulb heights were measured. Voxel wise brain morphometry was performed to evaluate atrophy. Statistical analysis was performed using non-parametric methods and was assessed using a=0.05. Results: Compared to controls, the MS patients¿ sagittal sinuses were 23% larger in cross-section (p<0.0001), the transverse sinuses had an average effective stenosis of 39% by area (p<0.0001) and there was a 62% increase in jugular bulb height (p=0.0001). The MS patients showed a reduction in normalized grey matter volume of 2.8% (p= 0.0001). Males with MS showed worse outcomes compared to females, with an increased EDSS and grey matter loss and had a 23% larger sagittal sinus area (p=0.02), 22% higher jugular bulb height (p=0.03) but a lower transverse sinus stenosis percentage (19% vs 48%, p<0.0001). Progressive forms of MS also had worse outcomes and had a 19% larger sagittal sinus area (p=0.04) compared to relapsing remitting MS. Conclusion: In this larger cohort, worse outcomes in both males and progressive forms of MS were associated with larger sagittal sinuses. The possible cause of the altered sinus pressure in females was narrower transverse sinuses. In males, higher jugular bulbs may be associated with increased venous sinus pressure.

Background and Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS.

Purpose: Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as ¿-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients. Methods: 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS). Results: RRMS patients had higher fatigue scores relative to HC (p = 0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p = 0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p = 0.008) and Glx (r = 0.511, p = 0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p = 0.04) and positively with PFC Glx (r = 0.480, p = 0.028). Conclusion: The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.

Background: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). Objectives: To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. Methods: This study included baseline food frequency questionnaire dietary intake (entry to the Ausimmune Study) and 5-year follow-up; iterated principal factor analysis was applied. MS conversion and relapse risks were assessed by Cox proportional hazards models, adjusted for age, sex, study site, education, body mass index (BMI), smoking and omega-3 supplement use. Results: In cases with a first clinical diagnosis of central nervous system (CNS) demyelination, we identified three major dietary patterns, ¿Prudent¿, ¿High-Vegetable¿ and ¿Mixed¿, explaining 43%, 37% and 24% of diet variance in dietary intake, respectively. Fruits, vegetables, fish, wholegrains and nuts loaded highly on the Prudent pattern, starchy vegetables and legumes on the High-Vegetable pattern, and meats and alcohol on the Mixed pattern. Diet factor scores were not associated with MS conversion risk. Those with baseline Prudent scores above the median had significantly lower relapse risk (adjusted hazard ratio = 0.54, 95% confidence interval (CI) 0.37, 0.81) with some evidence of a plateau effect. Conclusion: Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ¿ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2¿34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3¿36.8), females with EDSS < 6 and ARR ¿ 1 44.8 weeks (95% CI = 24.5¿65.1), and females with EDSS ¿ 6 and ARR < 1 54.3 weeks (95% CI = 47.2¿61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. Methods: 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. Results: 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 (ß = 0.16, p < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p = 0.01) and EDSS (ß = -0.06, p < 0.001). Neither presentation was associated with changes in relapse risk. Conclusion: 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.

Background/objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Objective To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Methods Using data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. Results We included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27-0.32), fell to 0.19 (0.14-0.24) in the third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60-0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04-0.32], p < 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. Conclusion Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Our inability to reliably predict disease outcomes in multiple sclerosis remains an issue for clinicians and clinical trialists. This study aims to create, from available clinical, genetic and environmental factors; a clinical-environmental-genotypic prognostic index to predict the probability of new relapses and disability worsening. The analyses cohort included prospectively assessed multiple sclerosis cases (N=253) with 2858 repeated observations measured over 10 years. N=219 had been diagnosed as relapsingonset, while N=34 remained as clinically isolated syndrome by the 10th-year review. Genotype data were available for 199 genetic variants associated with multiple sclerosis risk. Penalized Cox regression models were used to select potential genetic variants and predict risk for relapses and/or worsening of disability. Multivariable Cox regression models with backward elimination were then used to construct clinical-environmental, genetic and clinical-environmental-genotypic prognostic index, respectively. Robust timecourse predictions were obtained by Landmarking. To validate our models, Weibull calibration models were used, and the Chisquare statistics, Harrell's C-index and pseudo-R2 were used to compare models. The predictive performance at diagnosis was evaluated using the Kullback-Leibler and Brier (dynamic) prediction error (reduction) curves. The combined index (clinical-environmental- genotypic) predicted a quadratic time-dynamic disease course in terms of worsening (HR=2.74, CI: 2.00-3.76; pseudo- R2=0.64; C-index=0.76), relapses (HR=2.16, CI: 1.74-2.68; pseudo-R2=0.91; C-index=0.85), or both (HR=3.32, CI: 1.88- 5.86; pseudo-R2 = 0.72; C-index=0.77). The Kullback-Leibler and Brier curves suggested that for short-term prognosis (_5 years from diagnosis), the clinical-environmental components of disease were more relevant, whereas the genetic components reduced the prediction errors only in the long-term (_5 years from diagnosis). The combined components performed slightly better than the individual ones, although their prognostic sensitivities were largely modulated by the clinical-environmental components. We have created a clinical-environmental-genotypic prognostic index using relevant clinical, environmental, and genetic predictors, and obtained robust dynamic predictions for the probability of developing new relapses and worsening of symptoms in multiple sclerosis. Our prognostic index provides reliable information that is relevant for long-term prognostication and may be used as a selection criterion and risk stratification tool for clinical trials. Further work to investigate component interactions is required and to validate the index in independent data sets.

Importance: Multiple sclerosis (MS) is usually diagnosed in women during their childbearing years. Currently, no consensus exists on whether pregnancy can delay the first episode of demyelination or clinically isolated syndrome (CIS). Objective: To investigate the association of pregnancy with time to CIS onset. Design, Setting, and Participants: This multicenter cohort study collected reproductive history (duration of each pregnancy, date of delivery, length of breastfeeding) on all participants between September 1, 2016, and June 25, 2019. Adult women being treated at the MS outpatient clinics of 4 tertiary hospitals in 2 countries (Charles University and General University Hospital in Prague, Czech Republic; Royal Melbourne Hospital in Melbourne, Australia; Alfred Hospital in Melbourne, Australia; and John Hunter Hospital in Newcastle, Australia) were recruited to participate in the study. Preexisting data (date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale result) were collected from MSBase, an international registry of long-term prospectively collected data on patients with MS. Data analyses were performed from June 1, 2019, to February 3, 2020. Exposures: Gravida (defined as any pregnancy, including pregnancy that ended in miscarriage and induced abortion) and parity (defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth) before CIS onset. Main Outcomes and Measures: Time to CIS onset. The following were assessed: (1) whether women with previous pregnancies and childbirths had a delayed onset of CIS compared with those who had never been pregnant and those who had never given birth, and (2) whether a dose response existed, whereby a higher number of gravidity and parity was associated with a later onset of CIS. Results: Of the 2557 women included in the study, the mean (SD) age at CIS onset was 31.5 (9.7) years. Of these women, before CIS onset, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. The mean (SD) age at first pregnancy was 23.3 (4.5) years and at first childbirth was 23.8 (4.5) years. Women with previous pregnancies and childbirths had a later onset of CIS compared with those who had never been pregnant (HR, 0.68; 95% CI, 0.62-0.75; P <.001), with a median delay of 3.3 (95% CI, 2.5-4.1) years. Women who had given birth also had a later CIS onset compared with women who had never given birth (HR 0.68; 95% CI, 0.61-0.75; P <.001), with a similar median delay of 3.4 (95% CI, 1.6-5.2) years. A higher gravidity and parity number was not associated with delay in CIS onset. Conclusions and Relevance: This study suggests an association between previous pregnancies and childbirths and timing of CIS onset, but having more pregnancies or childbirths did not appear to be associated with a later CIS onset. Further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of multiple sclerosis 2020 American Medical Association. All rights reserved.

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-ß (IFNß) treatment in MS patients. Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNß therapy in MS patients and to better investigate its functional role. Methods: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNß and TTFR. Results: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10-4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10-6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNß treatment and related to TTFR. Conclusions: Rs7298096 could influence MS disease activity during IFNß treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

AIMS: To systematically review the diagnostic value of the central vein sign (CVS) in multiple sclerosis (MS) and to meta-analyse the proportion of positive lesions for CVS needed to distinguish MS from non-MS mimics. MATERIALS AND METHODS: A literature review was performed and a proportion meta-analysis was performed to examine the proportion of the CVS in MS lesions. Studies reporting a threshold of the CVS containing lesions with 100% diagnostic accuracy were included in the meta-analysis. This was compared to MS mimics in order to establish the discriminative value of the CVS. RESULTS: The CVS was found to be viable at lower field strengths (3 T and 1.5 T) and automated analysis is currently less accurate than manual counting. Five studies were included for the proportional meta-analysis. From the analysis, a proportion of 45% of lesions having the CVS was suggested given that the findings that the weighted proportion was 46.4% (95% confidence interval [CI]: of 40.3%¿52.6%) with low heterogeneity (I2 = 0.0%; p=0.5). CONCLUSION: Although the CVS is a clinically relevant and viable sign, further work is needed to integrate this into the existing diagnostic criteria. As manual determination is a time-consuming process, the development of automated methods will be beneficial. With improvements in computational imaging techniques, the CVS will have an important role in the diagnosis and differentiation of MS.

Background: Monitoring and screening of cognitive function in the ambulatory setting requires simple, brief cognitive tests that are reproducible. MSReactor (MSR) is a web-based platform that screens psychomotor (processing) speed, attention and working memory using a game-like interface. The Processing Speed Test (PST) is a validated computerized version of the Symbol Digit Modalities test (SDMT) and component of the Multiple Sclerosis Performance Test (MSPT). Objective: To determine the baseline and 6-month predictive correlations between the MSReactor computerised cognitive battery and the PST. Methods: Prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients completed the MSR and the PST during 6-monthly clinic visits. Pearson's product-moment coefficients with partial correlation adjustment were calculated between the PST and MSR reaction times for Simple reaction test (SRT), Choice reaction test (CRT) and One- back test (OBK). Results: 379 RRMS patients from six tertiary MS centres in Australia were enrolled. The mean age was 40.4 years (SD 10.3) and median Expanded Disability Status Scale (EDSS) score was 1.5 (IQR 1.0 ¿ 2.0). Most (66%) were on high efficacy disease-modifying treatment. Baseline PST scores correlated with the MSR reaction times: SRT (R=-0.40), CRT (R= -0.44) and OBK (R= -0.47), p <0.05. There was a moderate correlation between the first visit MSR and 6-month PST test for SRT (R= -0.37, p<0.001), CRT (R=-0.44, p < 0.001) and OBK (R= -0.43, p < 0.001) speed. Conclusions: MSR-measured psychomotor speed, attention and working memory at baseline moderately correlates with baseline and 6-month PST; suggesting overlapping cognitive processes are being tested. Six-month test-retest reliability was acceptable for both tests.

Background: Fatigue is a common and debilitating symptom in multiple sclerosis (MS). Over the past decade, a growing body of research has focussed on the pathophysiological mechanisms underlying central (cognitive and physical) fatigue in MS. The precise mechanisms causing fatigue in MS patients are complex and poorly understood, and may differ between patients. Advanced quantitative magnetic resonance imaging (MRI) techniques allow for objective assessment of disease pathology and have been used to characterise the pathophysiology of central fatigue in MS. Objective: To systematically review the existing literature of MRI-based studies assessing the pathophysiological mechanisms of MS-related central fatigue. Methods: A systematic literature search of four major databases (PubMed, Medline, Embase, Scopus and Google Scholar) was conducted to identify MRI-based studies of MS-related fatigue published in the past 20 years. Studies using the following MRI-based methods were included: structural (lesion load/atrophy), T1 relaxation time/magnetisation transfer ratio (MTR), diffusion tensor imaging (DTI), functional MRI (fMRI) and magnetic resonance spectroscopy (MRS). Results: A total of 92 studies were identified as meeting the search criteria and included for review. Structurally, regional gray/white matter atrophy, cortical thinning, decreased T1 relaxation times and reduced fractional anisotropy were associated with central fatigue in MS. Functionally, hyperactivity and reduced functional connectivity in several regional areas of frontal, parietal, occipital, temporal and cerebellum were suggested as causes of central fatigue. Biochemically, a reduction in N-acetyl aspartate/creatine and increased (glutamine+glutamate)/creatine ratios were correlated with fatigue severity in MS. Conclusion: Several advanced quantitative MRI methods have been employed in the study of central fatigue in MS. Central fatigue in MS is associated with macro/microstructural and functional changes within specific brain regions (frontal, parietal, temporal and deep gray matter) and specific pathways/networks (cortico-cortical and cortico-subcortical). Alternations in the cortico-striatal-thalamocortical (CSTC) loop are correlated with the development of fatigue in MS patients.

Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing. Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS. Methods: 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. Results: 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. Conclusions: 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.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure: Conversion to objectively defined secondary progressive MS. Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P <.001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P <.001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P =.005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P =.009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P =.046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P =.03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P <.001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Background: Transition probabilities are the engine within many health economics decision models. However, the probabilities of progression of disability due to multiple sclerosis (MS) have not previously been estimated in Australia. Objectives: To estimate annual probabilities of changing disability levels in Australians with relapsing-remitting MS (RRMS). Methods: Combining data from Ausimmune/Ausimmune Longitudinal (2003¿2011) and Tasmanian MS Longitudinal (2002¿2005) studies (n = 330), annual transition probabilities were obtained between no/mild (Expanded Disability Status Scale (EDSS) levels 0¿3.5), moderate (EDSS 4¿6.0) and severe (EDSS 6.5¿9.5) disability. Results: From no/mild disability, 6.4% (95% confidence interval (CI): 4.7¿8.4) and 0.1% (0.0¿0.2) progressed to moderate and severe disability annually, respectively. From moderate disability, 6.9% (1.0¿11.4) improved (to no/mild state) and 2.6% (1.1¿4.5) worsened. From severe disability, 0.0% improved to moderate and no/mild disability. Male sex, age at onset, longer disease duration, not using immunotherapies greater than 3 months and a history of relapse were related to higher probabilities of worsening. Conclusion: We have estimated probabilities of changing disability levels in Australians with RRMS. Probabilities differed between various subgroups, but due to small sample sizes, results should be interpreted with caution. Our findings will be helpful in predicting long-term disease outcomes and in health economic evaluations of MS.

Objective Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. Methods 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). Results 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). Conclusion 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.

Background: Despite evidence of perceived stress as a risk factor for multiple sclerosis activity, the evidence for managing stress is limited. Objective To evaluate a stress management programme on perceived stress and quality of life, over 6 months. Methods: One hundred people with multiple sclerosis were randomly assigned to either a stress management programme of mindfulness, meditation and progressive muscle relaxation, or wait list. Perceived stress and quality of life were assessed at three intervals across 6 months. Salivary cortisol levels were assessed at two intervals: baseline and first follow-up. Results: The stress management programme did not significantly reduce perceived stress, when comparing mean scores. Secondary analysis using median scores found a significant improvement for quality of life, favouring the intervention group. Conclusion: Stress management had no significant effect on the primary outcome of perceived stress but did improve quality of life in a secondary analysis of median scores.

Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of ¿post-DMT¿ relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age = 18 at index DMT start; =12 months on index DMT prior to discontinuation; =24 months of follow-up post-discontinuation; did not restart DMT for =6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for =1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNß preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) ¿ fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.

Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including =3 visits with disability recorded, =3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures: Cumulative hazard of disability progression. Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P =.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P =.01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P =.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P =.16). Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00¿2.96 vs OR: 1.26 (95% CI: 1.22¿1.29). DMT change with new MRI lesions occurred most frequently with ¿injectable¿ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28¿1.59 vs before, OR: 0.98, 95% CI: 0.520¿1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.

Objective: This propensity score¿matched analysis from MSBase compared the effectiveness of cladribine with interferon ß, fingolimod or natalizumab. Methods: 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. Results: 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. Conclusion: 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 ß and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.

Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a significant amount of conflicting evidence. Some of the evidence for EBV involvement in MS includes: almost 100% of MS patients showing past EBV infection, an association with Infectious Mononucleosis (acute EBV infection), higher titres of EBV antibodies associated with an increased risk of MS development, and an overall altered immune response to EBV found in peripheral blood and the CNS of MS patients. However, evidence for EBV presence in the CSF and T cell responses to EBV in MS have been particularly conflicting. Several hypotheses have been proposed for direct and indirect EBV involvement in MS such as 1) Molecular Mimicry 2) Mistaken Self 3) Bystander Damage and 4) Autoreactive B cells infected with EBV. More recently, an association between EBV and human endogenous retrovirus in MS has been shown, which may provide an alternative pathogenetic target for MS treatment. However, if EBV is not the major contributor to MS and is instead one of several viral or infectious agents able to elicit a similar altered immune response, MS development may be the result of a failure of viral clearance in general. This review aims to evaluate the evidence for the currently discussed theories of EBV involvement in MS pathogenesis.

Objectives: 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. Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Neurological and psychological symptoms in multiple sclerosis can affect cognitive function. The objective of this study was to explore the relationship between psychological measures and cognitive performance in a patient cohort. In 322 multiple sclerosis patients, psychological symptoms were measured using the Depression Anxiety and Stress Scale, and cognitive function was evaluated using Audio Recorded Cognitive Screen. Multifactor linear regression analysis, accounting for all clinical covariates, found that anxiety was the only psychological measure to remain a significant predictor of cognitive performance (p<0.001), particularly memory function (p<0.001). Further prospective studies are required to determine whether treatment of anxiety improves cognitive impairment.

Objective: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy. Methods 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. Results: 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. Conclusions: 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.

Background: Since 1959, multiple sclerosis (MS) prevalence has been estimated for the east coast Australian city of Newcastle. Previous surveys, conducted in 1988 and 2003, have described an increase in the prevalence and incidence of MS. Objectives: In this study, we evaluated whether these trends continue and provide 50 years of MS epidemiological follow-up for this southern hemisphere city. Methods: Expressed per 100,000 people, prevalence of MS in Newcastle was calculated for those with a confirmed diagnosis of MS on 9 August 2011 and incidence based on the number of cases with MS diagnosis made during the preceding decade. Data were age-standardised to the total Australian population. Statistical comparisons were undertaken using Poisson regression analysis. Results: In 2011, the estimate of MS prevalence was 124.2, with female-to-male ratio reaching 3.1, a 53% increase in female predominance since 1996. MS incidence increased to 6.7, with a significantly higher proportion of new female cases since the previous survey. Conclusion: Prevalence of MS in Newcastle has risen linearly and is contributed to by a substantial increase in new cases over the preceding decade. Female predominance of MS cases continues to increase with a new diagnosis three times more likely in women.

Background: The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity. Objective: To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity. Methods: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to ¿No Evidence of Disease Activity¿ (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression. Results: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment (p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects (p < 0.05). Conclusion: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

Background Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. Methods In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Findings Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14¿0·23] vs 0·53 [0·46¿0·61], p<0·0001) and fingolimod (0·15 [0·10¿0·20] vs 0·34 [0·26¿0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14¿0·26] vs 0·19 [0·15¿0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36¿1·22], p=0·37), fingolimod (1·27 [0·60¿2·70], p=0·67), and natalizumab (0·81 [0·47¿1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65¿1·49], p=0·93) and fingolimod (0·50 [0·25¿1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20¿0·59], p=0·0006). Interpretation Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. Funding National Health and Medical Research Council, and the University of Melbourne.

To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS). Methods: 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. Results: 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, ß =-0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results. Conclusions: 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. Classification of evidence: This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) 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-ß 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-ß-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 × 106) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10 5) and near ZNF697 (combined P-value 8.15 × 10 5).

Introduction: Patients presenting with clinically isolated syndrome (CIS) may proceed to clinically definite multiple sclerosis (CDMS). Midsagittal corpus callosum area (CCA) is a surrogate marker for callosal atrophy, and can be obtained from a standard MRI study. This study explores the relationship between CCA measured at CIS presentation (baseline) and at 5¿years post presentation, with conversion from CIS to CDMS. The association between CCA and markers of disability progression is explored. Methods: Corpus callosum area was measured on MRI scans at presentation and 5-year review following diagnosis of a first demyelinating event, or evidence of progressive MS, in 143 participants in the Ausimmune/AusLong Study. Relationships between CCA (at baseline and follow-up) and clinical outcomes were assessed. Results: Mean CCA at baseline study was 6.63¿cm2 (SD 1.01). Patients who converted to MS by 5-year review (n¿=¿100) had a significantly smaller mean CCA at follow-up (6.22 vs. 6.74, P¿=¿0.007). Greater CCA reduction was associated with higher annualized relapse rate over follow-up. Conclusion: Baseline CCA obtained from standard MRI protocols may be compared with subsequent MRI examinations as a surrogate for neurodegeneration and cerebral atrophy in patients with MS. This study demonstrates an association between CCA and disability in individuals presenting with CIS who convert to MS.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.

Objective: 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). Methods: 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. Results: 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<0.001) 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<0.001). 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. Conclusion: 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.

Background Discontinuation of injectable diseasemodifying 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. Objectives (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. Methods 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 propensityscore 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. Results 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. Conclusions 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.

Background The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies. Methods Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-Associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (I "EDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS). Results We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted I "EDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: Those having =5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with =2. The CGRS for I "EDSS was also significant: Those carrying =6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with =2, and the CGRS model explained 32% of the variance in disability in this study cohort. Conclusions These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic.

Background: We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-ß (IFN-ß)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries. Methods: The study population initiated IFN-ß/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had =3 months of on-treatment follow-up, and had active RRMS, defined as =1 gadolinium-enhancing lesion on cerebral MRI at baseline or =1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n 366/group) and subgroups with higher baseline disease activity. Results: First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-ß/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p 0.01), compared with first-line IFN-ß/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. Conclusions: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-ß/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. Classification of evidence: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-ß/GA.

Background: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). Methods: Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). Results: Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. Conclusion: These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.

Background: 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. Methods: 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. Results: 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=3.83×10-23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10-17). We found that the AAO of female patients was ~5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ~9 years later than relapsing-onset patients (p=1.40×10-265). Conclusions: 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.

Background and Purpose: Early relapse outcomes in long-term stable patients switching from interferon ß/glatiramer acetate (IFNß/GA) to oral therapy are unknown. Objective: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNß/GA, relative to a propensity-matched comparator of patients remaining on IFNß/GA. Methods: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNß/GA ('stayers') using a Cox marginal model. Results: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). Conclusion: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

Background: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients' lives. Objective: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment. Methods: ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score. Results: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment. Conclusion: PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.

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.

Background and purpose: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. Methods: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. Results: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS= third quartile vs. = first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. Conclusions: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.

Background: Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females. Methods: Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS. Results: In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change. Conclusion: Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and-negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10-16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10-7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10-37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10-22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10-6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

Objective: In patients suffering multiple sclerosis activity despite treatment with interferon ß 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. Methods: 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. Results: 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 (20.12 vs 0.04 per year, respectively, p<0.001). Interpretation: 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.

Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing-remitting multiple sclerosis.

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.

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.

Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10^-3). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology. © The Author(s) 2013.

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 ß-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. Crown Copyright © 2014.

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 individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual 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. Crown Copyright © 2014.

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 individual 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. Crown Copyright © 2014.

Objective: 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.

Objectives: 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. Methods: 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. Results: 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. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes in MS patients. Based on our gene expression results, we wanted to identify whether polymorphisms in the genes associated with the plasminogen pathway could predict MS risk. We genotyped 1153 trio families, 727 MS cases and 604 healthy controls for 17 polymorphisms in MMP9, plasminogen activator urokinase (PLAU), PLAU receptor (PLAUR) and serpin peptidase inhibitor/clade 2/member B2 (SERPINB2) genes. No associations were found between the 17 polymorphisms and MS. Also, gene expression levels were analysed according to genotype: no associations were observed. In conclusion despite the consistent evidence for the role of MMP9 and the plasminogen activation cascade in MS, we found no associations between genotype nor gene expression. This suggested there are other potentially modifiable factors influencing gene expression in MS. © The Author(s) 2013.

Background: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system which responds to therapies targeting circulating immune cells. Objective: 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. Methods: We used RNA-seq to interrogate the whole blood transcriptomes of 72 individuals (40 healthy controls, 32 untreated MS). A cohort of 862 control individuals 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. Results: 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<0.0004), and lower in winter than summer (p<4.6E-06). The seasonal pattern correlated with monthly UV light index (R=0.82, p<0.002), and was also identified in the BSGS cohort (p<0.0016). Variation in expression of RPS6 was not strongly heritable. RPS6 expression was reduced by IFNB therapy. Conclusions: 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.© The Author(s) 2013.

Background: 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. Objective: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. Methods: 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. Results: 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. Conclusion: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Preconception 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.© The Author(s) 2013.

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 Author (2013).

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P=4×10-6). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P=0:001) and were highly significant in the combined dataset (P=6 × 10-8). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 × 10-9, replication set P = 7 × 10-4, combined P=2 × 10-10). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association. © 2010 Field et al.