Publications by authors named "Vilija G Jokubaitis"

26 Publications

  • Page 1 of 1

High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients.

Ther Adv Neurol Disord 2021 16;14:1756286421998915. Epub 2021 Apr 16.

Department of Neuroscience, Monash University, 99 Commercial Rd, Melbourne, VC 3004, Australia.

Aims: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients.

Background: Natalizumab is highly effective for the treatment of relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment.

Methods: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia ( = 865) and 11 MS treatment centres in Brazil ( = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion.

Results: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17-3.71)  = 0.012].

Conclusion: In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.
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http://dx.doi.org/10.1177/1756286421998915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053827PMC
April 2021

The MSBase pregnancy, neonatal outcomes, and women's health registry.

Ther Adv Neurol Disord 2021 12;14:17562864211009104. Epub 2021 Apr 12.

Department of Neurology, South Eastern Health and Social Care Trust, Dundonald, UK.

Background: Family planning and pregnancy decisions are key considerations in the management of women with multiple sclerosis (MS), who are typically diagnosed between the ages of 20-40 years. Despite a strong evidence base that pregnancy is not harmful for women with MS, many knowledge gaps remain. These include: best management strategies through pregnancy in the era of highly effective disease-modifying therapies (DMT); foetal risks associated with DMT exposure or in relation to breastfeeding; knowledge base around the use of assisted reproductive technologies; the long-term impact of pregnancy on disease outcomes, as well as the impact of long-term DMT use on women's health and cancer risk.

Methods: Here, we describe the new MSBase pregnancy, neonatal outcomes and women's health registry. We provide the rationale for, and detailed description of, the variables collected within the registry, together with data acquisition details.

Conclusion: The present paper will act as a reference document for future studies.
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http://dx.doi.org/10.1177/17562864211009104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047930PMC
April 2021

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis.

Neurology 2021 Apr 20. Epub 2021 Apr 20.

Liverpool Hospital, Australia.

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 31 Dec 2010 from 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 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in 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 (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (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). 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 re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.
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http://dx.doi.org/10.1212/WNL.0000000000012084DOI Listing
April 2021

Association of Pregnancy With the Onset of Clinically Isolated Syndrome.

JAMA Neurol 2020 Dec;77(12):1496-1503

Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1001/jamaneurol.2020.3324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490748PMC
December 2020

MSCOVID19: Using social media to achieve rapid dissemination of health information.

Mult Scler Relat Disord 2020 Oct 24;45:102338. Epub 2020 Jun 24.

Alfred Health, Clinical Neurosciences, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne Australia.

Background And Objective: The global COVID-19 pandemic creates an obvious acute health care resourcing and response problem. The different timing of pandemic peak in geographically distinct locations creates a short window of response opportunity. Rapid dissemination of medical information from early affected areas to later ones is therefore crucial to optimise planning. Formulating the best system response for at-risk patient populations is especially complex. People with multiple sclerosis (pwMS) are exposed to long-term immunosuppressive disease modifying treatments (DMTs) and, in theory, could be at increased risk of contracting the virus and developing complications. Social media, such as Twitter, can provide a global platform to rapidly share information and individual experiences.

Methods And Results: This report summarizes the case experience of pwMS with COVID-19 infection in the first month of the pandemic as reported on Twitter using the #MSCOVID19 hashtag. 26 individual cases of COVID-19 in pwMS were reported from Europe and the United States of America. The cases involved a combination of relapsing and progressive MS phenotypes treated with a range of DMT (5 anti CD20 therapy, 4 cladribine, 4 fingolimod, 4 injectables, 3 alemtuzumab, 2 dimethyl fumarate, 2 untreated, 1 teriflunomide, 1 natalizumab). The cases shared present the earliest reported data on outcomes of COVID-19 infection in pwMS. Whilst limited, the cautiously reassuring nature of these early cases assisted in clinical management by allowing neurologists to continuously reassess their approach to DMT management.
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http://dx.doi.org/10.1016/j.msard.2020.102338DOI Listing
October 2020

Increased risk of cervical dysplasia in females with autoimmune conditions-Results from an Australia database linkage study.

PLoS One 2020 18;15(6):e0234813. Epub 2020 Jun 18.

Department of Neurology, MS and Neuroimmunology Service, Alfred Health, Melbourne, Australia.

Background: Autoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures.

Methods: Data linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed.

Results: Females with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group.

Conclusions: Females with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302686PMC
August 2020

Change in pregnancy-associated multiple sclerosis relapse rates over time: a meta-analysis.

Mult Scler Relat Disord 2020 Sep 30;44:102241. Epub 2020 May 30.

Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University London; Department of Neurology, Royal London Hospital, BartsHealth NHS Trust; Blizard Institute, QMUL.

Background: Women with MS are advised that relapse rates fall during pregnancy and rebound post-partum. This advice originates from 1998; smaller, more recent, studies have not been previously pooled.

Methods: All studies published since 1998 providing raw relapse data were considered for inclusion. Single arm meta-analysis was performed using a restricted maximum likelihood random effects model with inverse variance; secondary subgroup analysis and meta regression were then performed. Annualised relapse rates (ARR), or relapse numbers/rates suitable for conversion into ARR during pregnancy and the post-partum period were included. Secondary subgroup analysis examined year of data collection, DMT exposure, breastfeeding and data source.

Results: 7034 pregnancies from 6430 women were included. ARR fell from 0.57 (95%CI 0.45-0.70) pre-pregnancy to 0.36 (0.28-0.44), 0.29 (0.21-0.36) and 0.16 (0.11-0.21) during trimesters 1,2, and 3, with a post-partum rebound (ARR 0.85, 95%CI 0.70-1.00). ARR reduced pre-pregnancy and post-partum over time (p<0.001). Relapse rates were lower in claims databases than elsewhere.

Conclusions: Despite high heterogeneity, we confirm the historic assumption that ARR reduces during pregnancy, and demonstrate an overall reduction in ARR over time. Studies using data originating from claims databases demonstrated a lower relapse rate at all time points, which has not previously been demonstrated.
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http://dx.doi.org/10.1016/j.msard.2020.102241DOI Listing
September 2020

Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells.

Life Sci Alliance 2020 07 9;3(7). Epub 2020 Jun 9.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 in CD4 cells (q = 0.05) and rs12087340 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
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http://dx.doi.org/10.26508/lsa.202000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283543PMC
July 2020

Family planning is the second most relevant factor for treatment decisions after disease activity - Commentary.

Mult Scler 2020 05 21;26(6):644. Epub 2020 Feb 21.

Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1177/1352458520907902DOI Listing
May 2020

Pregnancy and multiple sclerosis: Clinical effects across the lifespan.

Autoimmun Rev 2019 Oct 8;18(10):102360. Epub 2019 Aug 8.

Department of Medicine, University of Melbourne, Parkville, Australia; Department of Neurology, Royal Melbourne Hospital, Parkville, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, MSNI Service, Alfred Health, Melbourne, Australia.

Multiple sclerosis (MS) is commonly diagnosed in women of childbearing age. Having a greater understanding of the effects of pregnancy on the course of MS will lead to improved family-planning counselling for women. We found well-established evidence for a protective effect of pregnancy on relapse occurrence in historical cohorts. More recent studies suggest that the protective effect of pregnancy against relapse may be lost in those women with more active disease treated with high efficacy therapies. Furthermore, a strong body of evidence suggests that gravidity after diagnosis of MS does not lead to worse long-term outcomes. More contentious however, is whether pregnancy can delay a first episode of demyelination or a confirmed diagnosis of MS. This review provides a detailed analysis of the literature relating to the clinical effects of pregnancy on MS outcomes across a woman's reproductive lifespan.
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http://dx.doi.org/10.1016/j.autrev.2019.102360DOI Listing
October 2019

Introducing the International Women in Multiple Sclerosis network.

Lancet Neurol 2019 06;18(6):521

Weill Institute for Neurosciences and Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1016/S1474-4422(19)30160-7DOI Listing
June 2019

Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis.

Mult Scler 2020 05 25;26(6):696-705. Epub 2019 Mar 25.

Department of Medicine and Radiology, University of Melbourne, Parkville, VIC, Australia/Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

Background: Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments.

Objectives: To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS.

Methods: Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0-10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified.

Results: Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor ( < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity.

Conclusion: Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.
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http://dx.doi.org/10.1177/1352458519837706DOI Listing
May 2020

Genotype and Phenotype in Multiple Sclerosis-Potential for Disease Course Prediction?

Curr Treat Options Neurol 2018 Apr 24;20(6):18. Epub 2018 Apr 24.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

Purpose Of Review: This review will examine the current evidence that genetic and/or epigenetic variation may influence the multiple sclerosis (MS) clinical course, phenotype, and measures of MS severity including disability progression and relapse rate.

Recent Findings: There is little evidence that MS clinical phenotype is under significant genetic control. There is increasing evidence that there may be genetic determinants of the rate of disability progression. However, studies that can analyse disability progression and take into account all the confounding variables such as treatment, clinical characteristics, and environmental factors are by necessity longitudinal, relatively small, and generally of short duration, and thus do not lend themselves to the assessment of hundreds of thousands of genetic variables obtained from GWAS. Despite this, there is recent evidence to support the association of genetic loci with relapse rate. Recent progress suggests that genetic variations could be associated with disease severity, but not MS clinical phenotype, but these findings are not definitive and await replication. Pooling of study results, application of other genomic techniques including epigenomics, and analysis of biomarkers of progression could functionally validate putative severity markers.
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http://dx.doi.org/10.1007/s11940-018-0505-6DOI Listing
April 2018

Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS.

Neurology 2017 Sep 9;89(10):1050-1059. Epub 2017 Aug 9.

Objective: 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, = 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, = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, = 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.
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http://dx.doi.org/10.1212/WNL.0000000000004330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589791PMC
September 2017

A genetic basis for multiple sclerosis severity: Red herring or real?

Mol Cell Probes 2016 12 18;30(6):357-365. Epub 2016 Aug 18.

Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; Department of Neurology, Box Hill Hospital, Monash University, Box Hill, Australia.

Multiple Sclerosis (MS) is an autoimmune degenerative disease of the central nervous system, characterized by multifocal demyelination and neurodegeneration. The genetic architecture of MS is complex, where genetic risk has been attributed to over 100 polymorphic loci each with small odds ratios. MS is a highly heterogeneous disease with numerous clinical and paraclinical endophenotypes. To-date, no genetic variant has been associated with clinical outcome, however, evidence exists that MS outcomes, like risk, are to an extent also controlled by genetic variation. Here we summarise the current evidence for genetic determination of disease outcomes and make recommendations for future research directions.
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http://dx.doi.org/10.1016/j.mcp.2016.08.007DOI Listing
December 2016

Predictors of long-term disability accrual in relapse-onset multiple sclerosis.

Ann Neurol 2016 07 1;80(1):89-100. Epub 2016 Jun 1.

MS Center, Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University, Chieti, Italy.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).

Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
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http://dx.doi.org/10.1002/ana.24682DOI Listing
July 2016

Predictors of disability worsening in clinically isolated syndrome.

Ann Clin Transl Neurol 2015 May 27;2(5):479-91. Epub 2015 Mar 27.

Geelong Hospital Geelong, Australia.

Objective: To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS).

Methods: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression.

Results: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening.

Interpretation: This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.
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http://dx.doi.org/10.1002/acn3.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435703PMC
May 2015

Galanin is an autocrine myelin and oligodendrocyte trophic signal induced by leukemia inhibitory factor.

Glia 2015 Jun 29;63(6):1005-20. Epub 2015 Jan 29.

Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Australia; Department of Medicine, University of Melbourne, Australia.

In order to further investigate the molecular mechanisms that regulate oligodendrocyte (OC) survival, we utilized microarrays to characterize changes in OC gene expression after exposure to the cytokines neurotrophin3, insulin, or leukemia inhibitory factor (LIF) in vitro. We identified and validated the induction and secretion of the neuropeptide galanin in OCs, specifically in response to LIF. We next established that galanin is an OC survival factor and showed that autocrine or paracrine galanin secretion mediates LIF-induced OC survival in vitro. We also revealed that galanin is up-regulated in OCs in the cuprizone model of central demyelination, and that oligodendroglial galanin expression is significantly regulated by endogenous LIF in this context. We also showed that knock-out of galanin reduces OC survival and exacerbates callosal demyelination in the cuprizone model. These findings suggest a potential role for the use of galanin agonists in the treatment of human demyelinating diseases.
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http://dx.doi.org/10.1002/glia.22798DOI Listing
June 2015

Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution.

J Neurosci Res 2014 Jun 27;92(6):732-42. Epub 2014 Jan 27.

Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia; Melbourne Brain Center at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.

We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.
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http://dx.doi.org/10.1002/jnr.23349DOI Listing
June 2014

Fingolimod after natalizumab and the risk of short-term relapse.

Neurology 2014 Apr 7;82(14):1204-11. Epub 2014 Mar 7.

From the Department of Medicine (V.G.J., T.K., H.B.), Melbourne Brain Centre (RMH), The University of Melbourne; Department of Neurology (V.G.J., V.L., T.K., H.B.), Royal Melbourne Hospital, Australia; Hospital Universitario Virgen Macarena (G.I.), Seville, Spain; Liverpool Hospital (S.H.), New South Wales, Australia; Amiri Hospital (R.A.), Kuwait City, Kuwait; John Hunter Hospital (J.L.-S.), Newcastle, Australia; MS Center (A.L.), Department of Neuroscience and Imaging, University "G. d'Annunzio," Chieti, Italy; Hôpital Notre Dame (P.D., M.G.), Montreal, Canada; Brain and Mind Research Institute (M.B.), Sydney, Australia; Neuro Rive-Sud (F.G.), Hôpital Charles LeMoyne, Quebec, Canada; Department of Basic Medical Sciences (M.T.), Neuroscience and Sense Organs, University of Bari, Italy; Flinders University and Medical Centre (M.S.), Adelaide, Australia; Ospedale di Macerata (G.G.), Italy; Geelong Hospital (C.S.), Australia; Karadeniz Technical University (C.B.), Trabzon, Turkey; AORN San Giuseppe Moscati (D.L.A.S.), Avellino, Italy; Groene Hart Ziekenhuis (F.V.), Gouda, the Netherlands; Department of Neurology (J.H., H.B.), Eastern Health Victoria; Monash University (J.H., H.B.), Melbourne; and Melbourne EpiCentre (D.L.), The University of Melbourne and Melbourne Health, Australia.

Objective: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod.

Methods: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod.

Results: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001-0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2-4 months compared to no gap (HR 2.10; p = 0.041).

Conclusions: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse.

Classification Of Evidence: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies.
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http://dx.doi.org/10.1212/WNL.0000000000000283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001200PMC
April 2014

Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis.

Acta Neuropathol Commun 2013 Jul 9;1:32. Epub 2013 Jul 9.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.

Background: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system.

Results: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury.

Conclusions: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
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http://dx.doi.org/10.1186/2051-5960-1-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893401PMC
July 2013

The Australian Multiple Sclerosis (MS) immunotherapy study: a prospective, multicentre study of drug utilisation using the MSBase platform.

PLoS One 2013 19;8(3):e59694. Epub 2013 Mar 19.

Melbourne Brain Centre, RMH, Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.

Objective: To prospectively characterise treatment persistence and predictors of treatment discontinuation in an Australian relapsing-remitting multiple sclerosis (RRMS) population.

Methods: Tertiary MS treatment centres participating in the MSBase registry prospectively assessed treatment utilisation, persistence, predictors of treatment discontinuation and switch rates. Multivariable survival analyses were used to compare treatment persistence between drugs and to identify predictors of treatment discontinuation.

Results: 1113 RRMS patients were studied. Patients persisted on their first disease-modifying therapy (DMT) for a median of 2.5 years. Treatment persistence on GA was shorter than on all IFNβ products (p<0.03). Younger age at treatment initiation and higher EDSS were predictive of DMT discontinuation. Patients persisted on subsequent DMTs, for 2.3 years. Patients receiving natalizumab (NAT) as a subsequent DMT persisted longer on treatment than those on IFNβ or GA (p<0.000). The primary reason for treatment discontinuation for any drug class was poor tolerability. Annualised switch or cessation rates were 9.5-12.5% for individual IFNβ products, 11.6% for GA and 4.4% for NAT.

Conclusion: This multicentre MS cohort study is the first to directly compare treatment persistence on IFNβ and GA to NAT. We report that treatment persistence in our Australian RRMS population is short, although patients receiving IFNβ as a first DMT persisted longer on treatment than those on GA. Additionally, patients receiving NAT as a subsequent DMT were more likely to persist on treatment than those switched to IFNβ or GA. EDSS and age at DMT initiation were predictive of DMT discontinuation. Treatment intolerance was the principal reason for treatment cessation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602083PMC
September 2013

Country, sex, EDSS change and therapy choice independently predict treatment discontinuation in multiple sclerosis and clinically isolated syndrome.

PLoS One 2012 29;7(6):e38661. Epub 2012 Jun 29.

Department of Neurology, Royal Melbourne Hospital, Victoria, Australia.

Objectives: We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS).

Methods: The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation.

Results: A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation.

Conclusion: In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387159PMC
November 2012

Increasing age at disability milestones among MS patients in the MSBase Registry.

J Neurol Sci 2012 Jul 14;318(1-2):94-9. Epub 2012 Apr 14.

NYU-Multiple Sclerosis Care Center, Department of Neurology, NYU School of Medicine, New York, NY 10003, USA.

Objective: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period.

Methods: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria.

Results: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets.

Conclusions: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed.
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http://dx.doi.org/10.1016/j.jns.2012.03.017DOI Listing
July 2012

Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination.

J Neurosci 2008 May;28(20):5195-206

Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl, Mer, and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 +/- 3.1 vs 11.8 +/- 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor alpha mRNA expression was reduced approximately 48%). In Gas6-/- mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-pi (glutathione S-transferase-pi)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6-/- mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6-/- mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.
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http://dx.doi.org/10.1523/JNEUROSCI.1180-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844801PMC
May 2008