Posters

Health economic investigation of the cost of informal care for people living with multiple sclerosis - A comprehensive systematic review.

Background: MS is a high-cost and high-burden disease that has substantial health and economic impacts. Economic studies in MS often exclude the costs of Informal Care (IC) which will likely underestimate the cost-effectiveness of interventions aimed to slow, prevent, or halt MS-related disability progression.  

Objectives: No studies have provided a comprehensive synthesis of global health economics evidence regarding IC, particularly in regard to regional differences and MS-related disability severity impacts. We aimed to summarise and synthesise health economics evidence regarding informal care costs for people living with MS. 

Methods: A registered study protocol adopting validated guidelines was followed (PROSPERO:CRD42023396457). Searches were conducted in eight biomedical/economic databases. Two authors independently screened and extracted healthcare utilisation and cost data for summary and synthesis. A quality appraisal of included studies was conducted. Proportions of IC costs were estimated using direct, indirect, and total costs. Costs were inflated using relevant central bank Consumer Price Indices and converted to 2022 United States dollars (USD). 

Results: N=6,305 articles were identified; 60 studies from 25 countries were included.  Most adopted a societal perspective (direct+indirect costs) gathered from the person with MS. Average monthly caregiving time was 60.1 hours. IC costs were 15% of total societal costs. Regionally (similar healthcare sectors), costs for Western Europe were USD9,313 and Eastern Europe USD1,488. Despite study heterogeneity, IC costs escalated with increased disability severity (mild disability severity USD1,109; severe USD16,023). 

Conclusions: Costs of IC contribute considerably to MS-related costs. MS cost-effectiveness studies that do not include IC costs are likely to be inaccurate. Importantly, when considering costs of IC, data should be extracted directly from the carer – our proposed MS carers cohort study will achieve this. 

Funding: This work is supported by Dr Julie Campbells MS Australia Research Fellowship number 19-0702 

Key words: multiple sclerosis, informal care costs, cost-effectiveness, country income  

Authors: Tadele Girum Adal (1), Ingrid van der Mei (1), Bruce V Taylor (1), Andrew J Palmer (1), Barbara de Graaff (1), Glen Henson (1), Julie A Campbell (1). 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Medical Sciences Precinct, 17 Liverpool Street, Hobart, Tasmania, Australia 7000 

Developing a Massive Open Online Course (MOOC) for the carers and supporters of people living with MS - Supporting MS Carers.

Background: There are physical, financial, and emotional impacts on the carers and supporters of people living with MS. There is disparate information available on the Internet for carers and supporters including podcasts, flyers, and targeted websites as resources for these caregivers and supporters.  

Objectives: No large scoping review has been undertaken to thematically synthetise this information. We aimed to identify evidence-based topics for the Supporting MS Carers MOOC by evaluating existing evidence from guidelines, podcasts, websites, and other grey literature.  

Methods: Following the PRISMA guidelines for scoping reviews literature was searched from grey literature databases, google scholar, MS targeted websites and specialized podcast sites using pre-determined search terms and inclusion criteria developed by considering person, concept, and context. The search results were exported to EndNote and Open code for assessment. Data was independently assessed and extracted by two authors and thematically analysed and presented in tables and diagrams. 

Results: From the initial 2,300 items, final analysis included 20 podcasts, 15 guidelines and 12 blogs/websites particularly from Australia, United Kingdom, and United States. From these articles, 90-codes, 31-categories, and 15-themes focusing on three domains were identified. They included, understanding MS disease course and carer role, provision of follow-up and safe care, and recognition and the need for self-care. Based on these items, a three module and 15-chapter MOOC was drafted. 

Conclusions: We established the key themes and gaps using available grey literature. The Supporting MS Carers MOOC will be released by May 2024. We will also conduct an evaluation of the MOOC at baseline and after delivery. 

Funding: This work was supported by Dr Julie Campbell’s Postdoctoral Research Fellowship number 19-0702 

Key words: MS carers, MS supporters, MOOC, scoping review, caregiver support. 

Authors: Tadele G Adal (1), Ingrid van der Mei (1), Bruce V Taylor (1), Julie A Campbell (1). 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Medical Sciences Precinct, 17 Liverpool Street, Hobart, Tasmania, Australia 7000 

Diffusion metrics changes of the cortico-thalamic-striatal tracts correlate with fatigue and disability in people with MS.

Background: Diffusion MRI (dMRI) is a highly sensitive imaging technique to microstructural changes in the white matter of people with multiple sclerosis (pwMS), which are linked to the development of progressive disability. Despite the clinical significance of fatigue in pwMS and extensive research using standard MRI techniques, the link between neurodegeneration and fatigue remains poorly understood. 

Objective: In a prospective study, we investigated how the microstructural neural integrity of cortico-thalamic-striatal (CTS) tracts correlates with fatigue and disability over time. 

Methods:  76 stable Relapsing-remitting MS(RRMS) were age and sex-matched to 43 healthy controls(HCs). Participants completed disability, cognitive, fatigue, and mental health assessments, and underwent structural and diffusion scans on a 3T-MRI at baseline(BL) and 2-years follow-up(2Y-FU). The primary outcome was the change in diffusion metrics over time; the secondary was the correlation of diffusion metrics with fatigue (MFIS) and disability (EDSS) scores. We estimated fractional anisotropy(FA), mean, radial and axial diffusivities(MD, RD, AD) of normal-appearing white matter(NAWM) and white matter lesions(WML) in nine tracts-of-interests(TOIs) segmented by TractSeg, using our MRtrix3 in-house pipeline. 

Results: Significant differences in diffusion metrics in TOIs were found in RRMS compared to HCs at BL and 2-YFU (p≤0.001). WML diffusivities decreased and FA increased significantly over time in most TOIs (p≤0.001), but no changes in diffusion metrics were observed in NAWM in pwMS. AD and MD positively correlated with fatigue scores (r≤0.33, p≤0.01) in NAWM-TOIs, while EDSS was negatively correlated with FA in most NAWM-TOIs (|r|≤0.31, p≤0.01) and EDSS correlated with all diffusivity parameters (r≤0.29, p≤0.05) in most WML-TOIs at both time-points. 

Conclusion: Significant changes in WML diffusion metrics may indicate integrity improvement in CTS tracts over time in stable treated RRMS, with moderate correlations to clinical outcomes. This suggests potential repair of damaged tracts and a possible outcome measure for future remyelination clinical trials. 

Funding: This study was supported by an independent grant provided by Novartis Pharmaceuticals Australia Pty Ltd. 

Keywords: RRMS; diffusion MRI; cortico-thalamic-striatal tracts; fatigue; TractSeg. 

Authors: Oun Al-Iedani (1, 2), Abdulaziz Alshehri (2, 3, 4), Nikitas Koussis (2, 5,) Ibrahim Khormi (2, 3, 6), Stasson Lea (2), Rodney Lea (2), Saadallah Ramadan (2, 3), Jeannette Lechner-Scott (2, 7, 8) 

Author affiliations: 
1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Australia, 2. Imaging Centre, Hunter Medical Research Institute, Australia,
3. School of Health Sciences, University of Newcastle, Australia,
4. Department of Radiology, Imam Abdulrahman Bin Faisal University, Saudi Arabia, 5. School of Psychological Sciences, University of Newcastle, Australia,
6. College of Applied Medical Sciences, University of Jeddah, Saudi Arabia,
7. Department of Neurology, John Hunter Hospital, Australia,
8. School of Medicine and Public Health, University of Newcastle, Australia. 

Training programs and educational tools for healthcare professionals related to health behaviour management of multiple sclerosis: A systematic scoping review. 
 

Background: Multiple Sclerosis (MS) can be managed by health behaviour modifications in parallel to first-line therapy. This requires multidisciplinary care to support people with MS to self-manage their disease with behavioural strategies. However, MS healthcare professionals report limited knowledge and resources to address this in practice. 

Objectives: To review existing training programs and educational tools for healthcare professionals related to health behaviour/ lifestyle management for MS, and to identify gaps and opportunities. The emerging insights will be valuable in developing new educational tools to enhance healthcare practices aiming to facilitate behaviour management. 

Methods: This systematic scoping review followed the Joanna Briggs Institute's guidelines and was reported in accordance with the PRISMA-ScR checklist. Five scientific databases, three search engines and grey literature were systematically searched to May 2023 to identify eligible sources. Duplicate independent reviewers followed a three-phased screening process. Data were extracted, and findings were descriptively and narratively synthesised based on the review’s aims. This review was registered in the Open Science Framework.  

Results: Forty-three sources were included, encompassing 22 training programs, 12 educational resources and seven toolkits. Of these, 55% were specifically designed for MS health behaviour management. A focus on physical activity (n=25) was most common, followed by stress, depression, anxiety (n=12), diet (n=12), smoking (n=6), comorbidities (n=4), vitamin D (n=4), alcohol (n=2) and body weight (n=2). About 73% of the tools were technology-based. Only seven tools were evaluated with the consumer. 

Conclusion: Globally, there is a lack of evaluated educational tools that address MS health behaviour management. This highlights the need to co-design new evidence-based tools that are informed by behavioural theories and consumer needs and preferences to support healthcare professionals in implementing changes to their practice. 

Funding Statement: Shoroog Allogmanny holds a PhD scholarship awarded from the Ministry of Education in Saudi Arabia. The funding body was not involved in writing the review and the decision to submit the abstract for publication in the Progress in MS Research Conference 2023.  

Keywords: health behaviour, healthcare professionals, education  

Authors: Shoroog Allogmanny  (1,2), Yasmine Probst  (1), Anita Stefoska-Needham (1) 

Author affiliations: 
1. School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong NSW 2522, Australia. 
2. Clinical Nutrition Department, College of Applied Medical Sciences, Taibah University, Madinah 42353, Kingdom of Saudi Arabia. 

Investigating the role of the Immunoproteome in Multiple Sclerosis: Novel Perspectives on disease pathogenesis.

Background: Multiple Sclerosis (MS) is a common non-traumatic disabling disease affecting young adults and characterized by chronic inflammation and demyelination. While MS is commonly classified as an autoimmune disease, the precise mechanisms responsible for the immune system's recognition of self-proteins as antigenic targets remain elusive. 

Objective: We aim to analyse the MS-associated immunological characteristics to identify the spectrum of autoantigens that potentially contribute to the onset and progression of the disease. Therefore, we could gain a better understanding of the disease's aetiology and a more precise diagnosis during its early stages

Methods: Using mass spectrometry-based proteomics (SYNAPT G2-Si nano ESI), we compared the proteome signature of plasma and brain samples from individuals with and without MS (UK MS Tissue Bank).  Differentially expressed proteins (≥ 1 unique peptide, max fold ≥ 1.2, P value ≤ 0.05) identified significant changes in functional pathways between control and MS samples (Metascape, Panther, KEGG, STRING). Both brain- and plasma-based proteomic analysis provided insight into immunological characteristics in the later stages of the disease.  

Results: Across all samples, a host of neurodegenerative, inflammatory, and immune-related proteins were specifically identified for their association with MS. Pathway and disease-based analysis revealed that most of these changes are shared by multiple brain disorders. In addition, analysis of MS-specific proteins indicated the involvement of autoimmune aspects of the disease.

Conclusion: MS exhibits various post-pathogenic changes commonly observed in various brain disorders.  However, in-depth studies examining the immune cross-reactivity involving host and foreign antigens are needed to distinguish MS-specific alterations and unravel crucial insights into the disease’s pathogenesis.

Keywords: Multiple Sclerosis, Neuroimmunology, Mass spectrometry, Proteomics, Biomarkers. 

Authors: Marie Amigo, Chandra Malladi, Meena Mikhael, Mourad Tayebi, David A. Mahns

Author affiliations:
School of Medicine, Western Sydney University, Campbelltown Campus NSW 2560. 

Activation of adaptive immune cells can be related to fatigue in Multiple Sclerosis.

Background: Fatigue affects more than 90% of people with multiple sclerosis (PwMS). It is often described as the most debilitating symptom and has major consequences for individuals living with MS. Though highly prevalent, the causes and treatment of fatigue in Multiple Sclerosis (MS) remain poorly understood.  

Objective: To date, innate and adaptive immune cells and their activation status have received relatively little attention in MS-related fatigue and in MS disease progression. The aim of this study was to use immune cell phenotyping to identify reliable biomarkers of fatigue in PwMS. 

Methods: 31 PwMS (mean age 52.8 years, 72.9% female) and 28 matched controls (47.5 years, 66.7% female) taking part in the ACT MS Cohort study were included. Fatigue was assessed with Fatigue Severity Score questionnaire. Immune cell marker expressions were assessed using flow cytometry. Principal component analysis of biomarkers was used for data reduction. Associations between immune principal components and fatigue were tested with multiple regression analysis controlling for confounding variables. 

Results: 62.2% of MS participants had relapsing remitting MS, 10.8% had primary progressive MS, and 8.11% had secondary progressive MS. Fatigue scores could range from 9-63. The overall mean score was 32.8, the scores for MS and controls being 40.8 and 23.3, respectively. Initial blood analysis of the 19 age-sex matched pairs suggested that several biomarkers differed significantly between PwMS and controls. Further analysis will be directed towards confirming these results across the whole cohort. 

Conclusion: These preliminary findings suggest that some biomarkers may be significantly associated with MS-related fatigue. By exploring this association further, we aim to facilitate the development of effective management strategies at an individual level, and hence improve the quality of life of PwMS. 

Keywords: Multiple Sclerosis- Fatigue- Inflammatory Biomarkers 

Authors: Abolfazl Amjadipour (1), Jo Lane (2), Nicolas Cherbuin (2), Christian Lueck (3), Jane Desborough (4), Geoffrey Herkes (5), Anne Bruestle (1) 

Author affiliations: 
1. John Curtin School of Medical Research, College of Health and Medicine, The Australian National University, Acton, Australia.  
2. National Centre for Epidemiology and Population Health, The Australian National University, Acton, Australia. 
3. School of Medicine and Psychology, College of Health and Medicine, The Australian National University, Acton, Australia. 
4. Department of Health Services Research and Policy, The Australian National University, Acton, Australia. 
5.  Division of Medicine, Adventist HealthCare, Sydney, Australia.

A Palaeolithic diet score is not associated with symptoms of anxiety, depression, and fatigue in Australian adults with multiple sclerosis. 

Background: A Palaeolithic diet, marketed to people with MS, encourages consumption of unprocessed meats, fish, vegetables, and fruit and avoidance of dairy, grain, and processed foods. There is, however, little evidence that a Palaeolithic diet benefits people with MS, including with respect to mental health. 

Objective: We tested associations between a Palaeolithic diet score and depression, anxiety, and fatigue over time in Australian adults with MS using data from the AusLong Study, a longitudinal cohort of people followed since clinically isolated syndrome. 

Methods: Dietary data (food frequency questionnaire) were collected at baseline, 5- and 10-year reviews. Symptoms of depression, anxiety (Hospital Anxiety and Depression Scale, HADS), and fatigue (Fatigue Severity Scale, FSS) were collected at 5- and 10-year reviews (10-year review: men=35, women=141). Palaeolithic diet (PD) score was calculated; we used bootstrapped mixed effects analysis to test associations over time between Palaeolithic diet scores (per 10-point increase) and HADS and FSS scores. 

Results: We found no statistically significant associations between Palaeolithic diet score and depression (males: coefficient=-0.60, 95% CI[-2.20, 0.90], p=0.414; females: coefficient=-0.10, 95% CI[-1.00, 0.70], p=0.771), anxiety (males: coefficient=-0.20, 95% CI[-1.70, 1.30], p=0.814; females: coefficient=-0.20, 95% CI[-1.20, 0.90], p=0.771), or fatigue (males: coefficient=-1.20, 95% CI[-8.50, 6.20], p=0.757; females: coefficient=-0.90, 95% CI[-3.80, 0.20], p=0.548). 

Conclusion: A Palaeolithic diet score was not statistically significantly associated with HADS or FSS scores in people with MS in our study. It is not clear whether a Palaeolithic diet is associated with other symptoms, health outcomes, or markers of disease progression in people with MS.  

Funding: Funding for the AusLong Study was provided by the National MS Society of the United States of America, the National Health and Medical Research Council of Australia and MS Australia. ED is supported by an MS Australia Postdoctoral Fellowship. AD is supported by MSWA. LJB is supported by MSWA and an MS Australia Postdoctoral Fellowship. 

Keywords: Multiple sclerosis, diet, mental health. 

Authors: Georgia Brice (a), Lucinda J Black (a,b), Alison Daly (a), Daniel Rudaizky (a), Ausimmune/AusLong Investigator Group, Eleanor Dunlop (a) 

Author affiliations:
A. Curtin School of Population Health, Curtin University 
B. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University 

Cumulative effect of COVID-19 vaccine boosters in people with MS depends on DMTs and viral variant.

* Presented by Professor Fabienne Brilot-Turville on behalf of Avani Yeola *

Background: COVID-19 vaccination induced Spike antibodies are attenuated in people living with MS (pwMS) on high efficacy disease modifying therapies (DMTs). It is currently unknown whether vaccine boosters elicit a greater protective antibody cross-reactivity against emerging SARS-CoV-2 variants including Omicron BA.1, BA.2, BA.5, XBB and XBB.1.5. 

Objective: We aimed to determine the longevity and breadth of Spike antibody immune-cross-reactivity in pwMS following COVID-19 vaccination. We also aimed to determine whether administration of additional vaccine boosters in pwMS treated by high efficacy DMTs improves the extent of protection against emerging SARS-CoV-2 variants. 

Methods: Live cell-based flow-cytometry assay was used to assess Early Clade Spike antibodies in 643 patient sera (n=412 pwMS) at baseline (n=342), 1-month post-2nd dose (n=163), 1-month post-3rd dose (n=75), 1-month post-4th dose (n=63), and 489 controls. To investigate cross-reactive binding to emerging SARS-CoV-2 variants, Spike antibody responses to Omicron BA.1, BA.2, BA.5, XBB and XBB.1.5 were assessed in 109 patient sera at 1 month post 2nd, 3rd and 4th doses.  

Results: 138/163 sera at 1-month post 2nd dose, 62/75 at 1-month post 3rd dose and 60/63 post 4th dose were positive for Early clade Spike antibodies. Patients who did not seroconvert were on high efficacy DMTs. Compared to Early clade Spike, antibody titres decreased by 60-82% against different Omicron sub-variants tested. In pwMS treated by CD20-depleting DMTs, antibody titres against Early Clade Spike and Omicron sub-variants doubled only after fourth dose. 

Conclusion: DMTs like ocrelizumab, fingolimod and ofatumumab were shown to decrease antibody titres against all Omicron sub-variants as well as Early Clade Spike. Booster doses of COVID-19 vaccine exert cumulative effect on SARS-CoV-2 antibody titres, although this increase is dependent on DMTs and viral variant.  

Keywords: COVID-19, vaccine boosters, Spike antibody, DMT, cross-reactivity. 

Escalating prevalence of Multiple Sclerosis in Australia and the policy implications for healthcare decision makers of increased MS prevalence.

Background: Multiple sclerosis (MS) prevalence increased from 2.3 to 2.8 million people living with MS (PwMS) between 2013 and 2020. Our 2017 Australian MS prevalence estimate found prevalence increased by 4,324 PwMS over 8 years, from 21,283 in 2010 to 25,607 PwMS in 2016. 

Objective: We applied our previously utilised MS-medication-specific case-ascertainment method from 2010/2017 to prevalence of MS in Australia in 2021. We also used these estimates to update our cost-of-illness estimates from 2017 and establish if there was an escalating prevalence in Australia that aligns with global trends. 

Methods: Disease-modifying therapy (DMT) prescription data extracted from Australian Pharmaceutical Benefits Scheme data January - December 2021. Percentages of PwMS using DMTs (DMT penetrance) were calculated using data from the Australian MS Longitudinal Study. Prevalence was estimated by dividing the total number of monthly prescriptions by 12 or 2 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Australian and State and Territory prevalence estimates were also calculated. 

Results: There were 33,335 PwMS in Australia in 2021 – an increase of 30% in 4 years, and twice that seen between 2010-2017. Crude prevalence was 131.1/100,000 persons in 2021, compared to 103.7/100,000 in 2017 and 95.5/100,000 in 2010. All Australian States and Territories recorded similar trends with Victoria recording the largest increase, and Tasmania recording the highest crude prevalence of 212.7/100,000, in keeping with the positive latitudinal gradient. 

Conclusions: The prevalence of MS is increasing at an accelerating rate in Australia, in line with global estimates. The mechanisms underlying these change dynamics require further study. These estimates have been used to calculate the cost of illness for MS in Australia - $2.45 billion (2021). 

Funding: This work is supported by Dr Julie Campbells MS Australia Research Fellowship number 19-0702 

Key words: multiple sclerosis, MS prevalence, cost of illness, disease modifying therapies, DMT penetrance 

Authors: Julie A Campbell (*1) and Steve Simpson-Yap (*2), Ingrid van de Mei (1), Bruce V Taylor (1), Laura Laslett (1), Andrew J Palmer (1) 

*joint first author and equal contribution 

Author affiliations: 
1: Menzies Institute for Medical Research, University of Tasmania 
2: School of Population and Global Health, The University of Melbourne 
*denotes joint first authorship and equal contribution 

Preliminary findings from the ENLighTIND-MS trial - Feasibility and effects of morning light therapy for people with multiple sclerosis.

BACKGROUND: Fatigue and sleep issues are common in people with multiple sclerosis (PwMS) and negatively impact activities of daily living (ADL). The ENLighTIND trial aims to examine the feasibility and preliminary effects of light therapy on fatigue and sleep quality in (PwMS). 

OBJECTIVE: To evaluate the feasibility and preliminary effects of light therapy glasses plus sleep health guidelines versus sleep health guidelines alone on fatigue and sleep quality in PwMS.  

METHODS: Forty-six PwMS were randomised to receive four-weeks of light therapy plus sleep health guidelines (LT-SHG) or sleep health guidelines alone (SHG). Feasibility outcomes included: recruitment and retention rates, adherence to study interventions and adverse events. Fatigue and sleep quality were assessed at baseline, post-intervention and post-washout periods using the Fatigue Severity Scale and Pittsburgh Sleep Quality Index, respectively.   

RESULTS: Thirty-seven out of a possible seventy-four participants have been recruited for the trial (recruitment rate=50%) across a two-year period. Six participants (~16%) withdrew from the trial (retention rate=84%) due to deteriorating health. Pre vs post-intervention analyses revealed a small positive effect of LT-SHG (d=0.2) and medium negative effect of SHG (d=-0.64) on sleep quality. Small effects were observed for LT-SHG (d=0.07) and SHG (d=-0.01) on fatigue outcomes.  

CONCLUSIONS: LT-SHG is safe and appears to preserve sleep quality, when compared to SHG where deterioration was observed. While the safety profile was acceptable and positive effects were observed, the feasibility of this trial is questionable given the extended period of time for recruitment of PwMS.  

KEYWORDS: Fatigue, sleep quality, feasibility 

The association of comorbidities with sleep quality among Australians with multiple sclerosis: Insights from the Australian Multiple Sclerosis Longitudinal Study.

Introduction: Comorbidities and poor sleep are both common among people living with multiple sclerosis (MS). While longitudinal studies have shown that presence of comorbidities predict poorer health outcomes in MS, little is known about their impact on sleep quality.  

Objective: This study examined if the presence and number of individual comorbidities are associated with sleep quality and the relative contributions of groups of comorbidities to sleep quality in MS 

Methods: This cross-sectional study included 1,597 participants with MS, assessed by questionnaire regarding the presence of 30 medical comorbidities. Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI). We used linear regression to examine relationships between the number of comorbidities and the presence of individual comorbidities and sleep quality. General dominance analysis was applied to determine the relative contributions of 13 different groups of comorbidities to sleep quality.  

Results: In total, 16 of 28 comorbidities were associated with significantly worse sleep quality (p<0.05), with the strongest associations seen for “other autoimmune diseases” (β=1.98), depression (β=1.76), anxiety (β=1.72), and rheumatoid arthritis (β=1.62). Having more comorbidities was associated with poorer sleep quality (p for trend <0.001). 13 groups of comorbidities together explained 12.9% of the variance in PSQI; mental health disorders contributed half of this variance.  

Conclusions: Many individual comorbidities are associated with poorer sleep quality, with mental health disorders making the largest relative contribution. Optimal treatment and management of comorbidities that make the greatest contributions could improve sleep in people living with MS.  

Keywords: Comorbidities; PSQI; Dominance analysis; Multiple sclerosis; Sleep.    

Authors: Baye Dagnew (1,2), Laura L Laslett (1), Cynthia A Honan (3), Leigh Blizzard (1), Tania Winzenberg (1), Bruce Taylor (1), Ingrid van der Mei (1)

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 

2. College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia  

3. School of Psychological Sciences, University of Tasmania, Launceston, Australia. 

Impact of sleep quality on health-related quality of life domains and the mediating effects of symptoms in people with Multiple Sclerosis.

Introduction: Many people living with multiple sclerosis experience poor sleep, which is associated with diminished overall health-related quality of life (HRQoL). Little is known about the impact of poor sleep quality on super dimensions and individual domains of HRQoL in MS.  

Objectives: This study quantified the associations between sleep quality and HRQoL domains and examined the extent to which other MS symptoms could account for these associations. 

Methods: In this cross-sectional survey of 1,705 Australians with MS, we used Assessment of Quality-of-Life 8D (including two psychosocial and physical super dimensions as well as eight individual domains i.e., mental health, happiness, relationship, independent living, coping, self-worth, senses, and pain) and Pittsburgh Sleep Quality Index to assess HRQoL and sleep quality, respectively. Total, direct, and indirect effects of sleep quality on HRQoL domains were determined using mediation analysis.  

Results: Poor sleep quality was significantly associated with reduction in all HRQoL domains, with strongest associations seen for mental health (β=-0.08) and pain (β=-0.11). Indirect effects were mostly contributed by “feelings of anxiety and depression” for psychosocial, and “pain and sensory symptoms” for physical, super dimensions.    

Conclusions: Improving sleep could lead to substantial improvements in all HRQoL domains and the improvement in HRQoL could be partially achieved through the indirect improvements in sleep on MS symptoms.  

Keywords: Mental health, pain, poor sleep quality, multiple sclerosis  

Authors: Baye Dagnew (1,2), Laura L Laslett (1), Cynthia A Honan (3), Julie Campbell (1), Leigh Blizzard (1), Bruce Taylor (1), Ingrid van der Mei (1) 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 
2. College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia  
3. School of Psychological Sciences, University of Tasmania, Launceston, Australia. 

Higher protein intake is associated with lower likelihood of a first clinical diagnosis of central nervous system demyelination.

Background: A Mediterranean diet, an anti-inflammatory diet, higher consumption of fish and unprocessed red meat are associated with lower likelihood of a first clinical diagnosis of CNS demyelination (FCD). Whether specific nutrients, common to these dietary factors, are associated with likelihood of FCD, is unknown. 

Objective: To test associations between dietary components contributing to energy intake and the likelihood of FCD. 

Methods: We used data from the 2003–2006 Ausimmune Study, a multicentre, case control study (272 cases, 519 controls) of Australian adults (aged 18-59 years) with an FCD.  Covariate-adjusted logistic regression was used to test associations between FCD and dietary components contributing to energy intake (g/day) (protein, saturated fat, polyunsaturated and monounsaturated fats, carbohydrate, fibre, sugar, and alcohol). Final models were bootstrapped. 

Results: Higher protein intake was statistically significantly associated with lower likelihood of FCD (adjusted OR, per 100 g/day=0.31; 95% CI 0.10-0.97; p=0.045).  There were no statistically significant associations with the other dietary components and likelihood of FCD. 

Conclusion: The lower likelihood of FCD associated with higher protein intake lends support to our previously published findings, which focused on diets and foods. Whether protein intake is associated with disease progression in people with MS is unknown.  

Key words: Ausimmune Study; Australia; nutrition; protein; multiple sclerosis; diet 

Authors: Alison Daly (1), Michael Phillips (2), Eleanor Dunlop (1), Ausimmune Investigator Group, and Lucinda J Black (1,3) 

Author affiliations: 
1. Curtin School of Population Health, Curtin University, Perth, Australia  

2. Royal Perth Hospital, Medical Research Foundation, Perth, Australia 

3. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Melbourne, Australia 

Personality and Cognitive Factors Implicated in Depression and Anxiety in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Background: Depression and anxiety symptoms are highly prevalent in multiple sclerosis (MS) and are linked to a host of negative prognostic outcomes. Cognitive theories posit that personality traits and cognitive factors confer risk for the development of depression and anxiety.

Objectives: This meta-analytic review aimed to synthesise evidence on personality and cognitive factors related to depression and anxiety symptoms in MS, as well as estimate moderating effects of sociodemographic and clinical variables previously linked in MS.

Methods: Eligible publications were identified through systematic searches of five databases (Medline, Embase, PsycInfo, WebofScience, Proquest).

Results: A total of 91 studies met eligibility for inclusion in narrative synthesis (75 samples; 12259 plwMS; Mage= 42.41, SD= 6.93) and 72 studies contributed effects on 24 factors for meta-analyses. The most robust findings were identified for the relationships between depression and anxiety and higher neuroticism, lower extraversion, and illness perceptions relating to serious perceived MS consequences and a stronger MS identity (r’s=.28-.59). Relationships were found to vary as a function of age, gender, MS type and years since diagnosis – underlining the importance sociodemographic and clinical variables in formulating the impact of factors on depression and anxiety.

Conclusions: A set of personality traits and cognitive factors were identified as correlates with specificity for depression, including psychological flexibility (r= .65) and optimism (r= -.43). Depression and anxiety share a common core of personality and cognitive correlates, although depression may be partially discriminated by a specific set of traits and cognitive factors. 

Keywords: Multiple Sclerosis; Depression; Anxiety; Cognitive Factors; Personality Factors 

 

"I cannot control it (MS) entirely, but at least I have a feeling of control": A Qualitative Analysis of Personal Control, Coherence, and Self-Efficacy Perceptions Following an Educational Lifestyle Program for Multiple Sclerosis.

Background: Modification of lifestyle risk factors represents an opportunity to enhance individuals’ perceptions of MS and improve health outcomes. We developed two Multiple Sclerosis Online Courses (MSOCs) providing education on lifestyle risk factors for testing in a randomised controlled trial (RCT), adapted from an in-person evidence-based lifestyle modification program.

Objectives: We undertook a thematic analysis of qualitative interviews that formed part of the larger RCT methodology, with the aim of identifying perceived changes in individuals’ health behaviours and outcomes, illness perceptions and self-efficacy following completion of the MSOC.

Methods: RCT recruitment occurred via online advertisements worldwide and plwMS were randomised to complete the intervention course (ICC) or standard-care course (SCC), and a baseline survey examining health-related measures. Participants completing the MSOC, baseline and post-course evaluation surveys were invited for a semi-structured interview. Interviews were recorded, transcribed and analysed using reflexive thematic analysis.

Results: Most participants were female (86%), reported a RRMS type (82%), and were 48yrs-old (±12.25) and approximately 5yrs (±4.30) from diagnosis. Three themes were identified across the ICC arm: 1) “Self-efficacy in managing MS” (increased confidence and motivation to implement lifestyle changes); 2) “Personal control perceptions” (improved control over MS through engaging with lifestyle modification information); and 3) “Illness coherence perceptions” (more coherent understanding of MS).

Conclusion: Lifestyle-modification information may be beneficial for improving individuals’ sense of personal control over MS, disease coherence, and self-efficacy for disease management.  

Keywords: Personal control perceptions; Coherence perceptions; Self-efficacy; Lifestyle modification  

No association between plasma levels of omega-3 polyunsaturated fatty acids and likelihood of MS in a US case-control study.

Background: Higher intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been associated with lower likelihood of multiple sclerosis (MS); however, dietary intake data may not accurately reflect circulating levels of n-3 PUFAs. 

Objective: Circulating n-3 PUFAs represent intakes from food and supplements and endogenous production. We tested associations between individual and total plasma n-3 PUFAs and Omega-3 Index and MS or clinically isolated syndrome (CIS) using data from the MS Sunshine study, a US case-control study of adults. 

Methods: Case participants (n=589) and matched control participants (n=630) were recruited between 2011 and 2015. Plasma fatty acid profiling was conducted by gas-liquid chromatography. We estimated regression-adjusted average treatment effects with inverse probability weighting analysis. We tested associations between plasma levels of n-3 PUFAs and likelihood of MS/CIS, testing for interactions and adjusting for covariates.

Results: We found no statistically significant associations between total n-3 PUFAs (ATET=0.02, 95%CI [-0.20, 0.16] or Omega-3 Index (ATET=0.01, 95%CI [-0.17, 0.18] and likelihood of MS/CIS. Similarly, the individual n-3 PUFAs were not statistically significantly associated with likelihood of MS/CIS. 

Conclusion: Although we found negligible evidence for an association, blood levels of n-3 PUFAs were low across the population, which may mask any beneficial effect of higher blood levels of n-3 PUFAs that might be achieved through supplementation. 

Funding: This study was supported by an MS Australia Project Grant. ED is supported by an MS Australia Postdoctoral Fellowship. AD is supported by MSWA. LJB is supported by MSWA and an MS Australia Postdoctoral Fellowship. GP is supported by an NHMRC Investigator Grant. 

Keywords:  Multiple sclerosis, omega-3 fatty acids 

Authors: Eleanor Dunlop (1), Alison Daly (1), Trevor A Mori (2), Annette M Langer-Gould (3,4), Gavin Pereira (1), Lucinda J Black (1,5) 

Author Affiliations:  
1. Curtin School of Population Health, Curtin University 
2. Medical School, The University of Western Australia 
3. Department of Research and Evaluation, Kaiser Permanente 
4. Neurology Department, Los Angeles Medical Center, Southern California Permanente Medical Group, Kaiser Permanente 
5. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University 

The Multiple Sclerosis Self-Concept Change Scale: Development and validation of a new measure.

Background: Self-concept may impact psychological wellbeing and functioning in people with MS. However, the extent and nature of changes in self-concept that people with MS experience is poorly understood, likely owing to the lack of validated quantitative measures available to assess this construct.  

Objectives: The current study aimed to develop and validate a new measure by examining the factor structure, validity, and internal consistency of the newly developed Multiple Sclerosis Self-Concept Change Scale (MSSCCS).  

Methods: Items measuring self-concept change were created based on relevant literature and interviews with people living with MS. These items were reviewed by a panel of experts and pre-tested in a sample of 135 people with MS. A revised list of 51 items were then administered to 1307 Australian MS Longitudinal Study participants (80.3% female; Age M=59.21 years, SD=11.40), together with measures of disease impact and psychosocial functioning. 

Results: Exploratory factor analysis using principal axis factor extraction in 643 randomly selected participants yielded 23-items measuring 5 latent factors: Connected Self, Humanitarian Self, Compassionate Self, Socially Engaged Self, and Industrious Self. Confirmatory factor analysis involving the remaining participants supported the 5-factor model, as well as a 2nd order model of “global change”. The MSSCSS demonstrated good internal consistency (α = .89) and good concurrent and construct validity. 

Conclusion: The MSSCCS is a reliable and valid assessment of self-concept change for people living with MS. This new scale may assist in enhancing understanding of how self-concept change is experienced by those living with MS. 

Funding statement: MS Australia funds the Australian MS Longitudinal Study. Professor van der Mei receives funding through a Senior Research Fellowship from MS Australia and an Accelerated Research Grant from the Australian Medical Research Future Fund funds the Menzies MS Flagship Program. Miss Emery was supported by an Australian Government Research Training Program Scholarship awarded by the College of Health and Medicine, University of Tasmania.  

Keywords: multiple sclerosis, self-concept, factor analysis, scale validation, psychosocial functioning. 

Authors: Holly Emery (1), Ingrid van der Mei (2), Christine Padgett (3), Tamara Ownsworth (4), Therese Burke (5), Lauren Giles (6), Cynthia Honan (1). 

Author affiliations:
1. School of Psychological Sciences, University Tasmania, Launceston, Australia 
2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 
3. School of Psychological Sciences, University of Tasmania, Hobart, Australia 
4. School of Applied Psychology & The Hopkins Centre, Griffith University, Mount Gravatt, Australia 
5. School of Nursing, University of Notre Dame, Darlinghurst, Australia 
6. Launceston General Hospital, Launceston, Australia 

Disability, Health-Related Quality of Life, and Self-Concept Change in People with Multiple Sclerosis: A Moderated Mediation.

Background: Disability informs self-concept (opinions of self) change following MS diagnosis. Health-related quality of life (HRQoL) and relationship satisfaction are also known to influence self-concept in people with MS. Whether these psychosocial factors account for the relationship between disability and self-concept change however is not known.  

Objectives: To investigate the potential mediation effect of HRQoL on the relationship between disability and self-concept change in people with MS, and whether relationship satisfaction is a moderator of the mediated relationship. 

Methods: 995 people with MS (79.5% female; Age M = 59.72 years, SD = 11.15) completed the Self-Reported Disease Steps Scales (assessing disability), the AQoL-8D (assessing HRQoL), and the MS Self-Concept Change Scale. Of these, 726 participants who indicated they were currently in a relationship also completed the Relationship Assessment Scale (assessing relationship satisfaction). Moderated mediation (conditional process) and parallel mediation analyses were used to analyse the data in SPSS. 

Results: The relationship between disability and self-concept change was partially mediated by HRQoL. Across the eight subdomains of HRQoL, only the ‘relationships’ and ‘coping’ subdomains mediated the relationship between disability and self-concept change. However, for those participants in a relationship, relationship satisfaction did not moderate any mediation effects.  

Conclusion: The findings highlight the role that perceptions of HRQoL in some domains may have in explaining the relationship between disability and self-concept change. Further research is needed to explicate the causal direction of these relationships in longitudinal studies. 

Funding statement: MS Australia funds the Australian MS Longitudinal Study. Professor van der Mei receives funding through a Senior Research Fellowship from MS Australia and an Accelerated Research Grant from the Australian Medical Research Future Fund funds the Menzies MS Flagship Program. Miss Emery was supported by an Australian Government Research Training Program Scholarship awarded by the College of Health and Medicine, University of Tasmania.  

Keywords: multiple sclerosis, self-concept change, health-related quality of life, relationship satisfaction 

Authors: Holly Emery (1), Ingrid van der Mei (2), Christine Padgett (3), Cynthia Honan (1). 

Author affiliations:
1. School of Psychological Sciences, University Tasmania, Launceston, Australia 
2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 
3. School of Psychological Sciences, University of Tasmania, Hobart, Australia 

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60.

Background: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with MS (pwMS). Given the lack of pwMS above age 50 in randomized controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS.  

Objective: We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon or glatiramer acetate in pwMS over the age of 60.

Methods: Using data from MSBase registry, this multicentre cohort study included pwMS above the age of 60 who switched to or started on ocrelizumab, interferon, or glatiramer acetate. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting (IPTW) method. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI). 

Results: 248 participants received ocrelizumab, whilst 427 received interferon/glatiramer acetate. The IPTW-adjusted ARR for ocrelizumab was 0.01 and 0.08 for interferon/glatiramer. The IPTW-weighted ARR ratio was 0.19 (95%CI 0.08-0.37, p<0.001) and hazard ratio for time to first relapse was 0.13 (95%CI 0.06–0.32, p<0.001) for ocrelizumab compared to interferon/glatiramer. The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months. There was no difference in CDP or CDI. 

Conclusion: In older pwMS, ocrelizumab effectively reduced relapses compared to interferon/glatiramer acetate, but did not reduce disability accumulation. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. 

Keywords: Ocrelizumab, multiple sclerosis, elderly, comparative efficacy, MSBase 

Case report of autologous stem cell transplant for refractory MOGAD.

Background: Autologous haematopoietic stem cell transplantation (aHSCT) represents an emerging therapy for autoimmune disorders. Myelin oligodendrocyte glycoprotein antibody- associated disease (MOGAD) is characterized by central nervous system demyelination and requires chronic immunotherapy. This paper describes a quaternary hospital’s experience with aHSCT for a patient with refractory MOGAD. 

Case Report:  A thirty-year-old woman was diagnosed with MOGAD after presenting with bilateral optic neuritis. She was treated with intravenous methylprednisolone followed by ongoing prednisolone but relapsed within months. Over six years despite multiple lines of immunotherapy she accumulated increasing disability from progressive vision loss in the setting of recurrent optic neuritis. She was continued on prednisolone throughout with associated steroid-related complications including cataracts and raised intra-ocular pressure. Optical coherence tomography demonstrated progressive retinal nerve fibre layer thinning. aHSCT was pursued after further relapses despite 12 months tocilizumab and plasma exchange, three years methotrexate, five months four-weekly IVIG and prednisolone (doses ≥15mg). Stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor. Prior to her aHSCT her methotrexate was weaned and ceased. Tocilizumab and IVIG were given just prior to standard conditioning with cyclophosphamide, rituximab and anti-thymocyte globulin (ATGAM) followed by stem cell infusion. Complications included ATGAM fever and pneumonia. Following aHSCT IVIG was commenced for hypogammaglobulinemia and prednisolone was weaned to 5mg. Tocilizumab remains ceased. In the 11 months post aHSCT she has experienced two pseudo-relapses only. Visual acuity remains poor with no radiologic evidence of optic neuritis recurrence.  

Conclusion: Our patient represents a case of refractory MOGAD with increasing disease and treatment-related morbidity undergoing aHSCT. At 11 months post-transplant her immunotherapy has been significantly reduced with no relapses. Further longitudinal data is required to assess the efficacy and optimal patient population for aHSCT in immune-mediated disorders. 

Key words: Novel Therapeutics, Neuroimmunology, MOGAD 

Authors: Hannah Ford (1), Tracie Tan (1, 2), Nabil Seery (1, 2), Louse Rath (1), Shu Wong (3), Katherine Buzzard (4), Cassie Nesbitt (1, 2), Anneke Van der Walt, (1, 2, 5), Mastura Monif (1,2, 5) 

Author affiliations:
1. Department of Neurology, Alfred Health, Melbourne, Victoria, Australia 
2. Department of Neuroscience, Central Clinical School, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria,
3. Australia Department of Haematology, Alfred Health, Melbourne, Victoria, Australia
4.Department of Neurology, Box Hill Hospital, Melbourne, Victoria, Australia  5.Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia 
 

Trajectories of multiple sclerosis disease progression are associated with differential risk of disability accumulation, relapse phenomenology, and MRI metric.

Background: The identification of disability trajectories after the diagnosis of multiple sclerosis (MS) and throughout the disease course could significantly enhance disease management strategies. Disability trajectories encapsulate longitudinal variations in MS outcomes. Studies on disability trajectories and their associations with MS outcomes are limited. 

Objective: To identify trajectories of disability progression post-diagnosis, and to examine whether they were associated with differential risk of disability accumulation, relapse symptoms, relapse complications, and MRI T2 lesion load. 

Methods: Outcomes data were obtained from the MSBase (10,716 cases, 59,725 person-years), and the TasMSPG and AusLong studies (566 cases, 4370 person-years). Utilising the MSBase cohort, disability trajectories were identified using latent class modelling of longitudinal disability scores. Multivariable Poisson models were used to estimate associations of disability trajectories with relapse symptoms, relapse complications, and T2 lesion load. Markov transition models were used to estimate the rates of changing disability levels. 

Results: Among 10,716 MSBase cases (360 primary progressive, 1038 secondary progressive, 9318 relapse-remitting; mean[SD] age, 40.2[10.5]years; 7611(71%) females), 4 disability trajectories were identified and validated in the TasMSPG-AusLong database: rapidly deteriorating (N=860[8.03%]); moderately deteriorating (N=676[6.31%]); slowly deteriorating (N=2511[23.43%]); and stable (N=6669 [62.23%]). Compared to the stable group, the other trajectories were associated with a higher burden of relapse symptoms and complications, higher T2 lesion load, and more rapid disability decline. 

Conclusion: These findings show a clinically meaningful gradient of increasing risk across the 4 disability trajectories. Future interventions should target individuals with higher predicted risk of progression as early as possible after diagnosis, to mitigate disability progression. 

Keywords: Multiple sclerosis, progression, disability, trajectories 

Funding: This work was supported by the National Health and Medical Research Council of Australia [APP1127819, 1947180, 544922], Kate-Scott Memorial Scholarship (to Valery Fuh-Ngwa); Multiple Sclerosis Research Australia (MSRA); National Health and Medical Research Council investigator Grant L1 [GNT1173155] (to Yuan Zhou); and the Macquarie Foundation MSRA Clinical Research Fellowship (to Bruce V. Taylor). 

Authors: Valery Fuh-Ngwa (1), Ingrid van der Mei (1), Yuan Zhou (1), Andrew J. Palmer (1), AusLong Investigators (2), MSBase investigators (3), and Bruce V. Taylor (1). 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania. 

2. The MSBase foundation

3. Multiple sclerosis research Australia

Establishing a robust data pipeline for the analysis of neutrophil phenotype in multiple sclerosis - a pilot study.

Background: Multiple sclerosis (MS) is an immune-mediated disease that causes episodic inflammation of the central nervous system (CNS). Neutrophils are theorised to contribute to early MS disease processes; however, since neutrophils rapidly degrade following activation, ex vivo analysis remains challenging.  

Objective: We aimed to investigate the phenotypes of neutrophils in patients recently diagnosed with Clinically Isolated Syndrome (CIS) or MS, compared with healthy controls. We hypothesised that neutrophils from individuals with CIS/MS would feature a higher expression of activation markers compared to controls. 

Methods: In this pilot study, whole blood was collected from patients with CIS/MS and healthy controls (29 subjects: 19 MS, 10 controls). Since neutrophils are short-lived and have poor viability following cryopreservation, all samples were processed within 4 hours of collection for flow cytometry acquisition. All whole blood samples were stained with a purpose-designed optimised multicolour flow cytometry panel. 

Results: We have developed an analysis pipeline for the highly detailed analysis of neutrophil phenotype. Since samples are collected on different days, we have included rigorous QC measures in the study design including Rainbow beads and compensation controls to counteract batch effects. Samples processed over 2 hours from collection were excluded from the final dataset. Analysis in this cohort is ongoing and is focused on activation marker expression across subclusters.  

Conclusion: The potential mechanisms by which neutrophils contribute to MS pathogenesis remains incompletely understood in the scientific literature. Findings from this cohort of patients with CIS or acute first MS episode provides a unique opportunity to better understand the underlying biological changes occurring in early MS.  

Funding sources: MS Australia Incubator Grant  

Keywords: Multiple sclerosis, clinically isolated syndrome, neutrophils, flow cytometry, dimensionality reduction 

Authors:  Alice White(1,2), Jonatan Leffler (1), Craig Schofield (3), Anne Bruestle (4), Marzena Pedrini (5,6),  Allan Kermode (5,7),  Prue Hart (1), Luke Garratt (#2,3) and Stephanie Trend (#1,5) 

Author Affiliations:  
1. Inflammation, Pregnancy and Early Life Immunology, Telethon Kids Institute 
2. Medical School, The University of Western Australia 
3.Airway Epithelial Research, Respiratory Health Program, Telethon Kids Institute 
4.Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University 
5. Perron Institute for Neurological and Translational Science 
6.Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University 
7. Institute for Immunology and Infectious Disease, Murdoch University 
# Joint senior author 

A qualitative assessment of healthcare professionals bone health knowledge and management of people with multiple sclerosis.

Background: People with multiple sclerosis (MS) have a higher prevalence of osteoporosis (27% vs 12.6%) and earlier onset age (41.5yrs±7.9) compared to the general population (>50 years). Under-recognised and under-managed osteoporosis in people with MS may reduce independence and impair quality of life. 

Objective: This study aimed to assess the healthcare professionals who are part of the multidisciplinary care team for people with MS about their knowledge, current practices, barriers and enablers to bone health management in MS.   

Methods: Participants were 30 healthcare professionals, including: neurologists (4), endocrinologists (8), MS nurses (9), general practitioners (5), and physiotherapists (4), recruited through network contacts. Participants were interviewed using a semi-structured script (mean: 26min, range: 17.8 – 33.1min). Interviews were undertaken and recorded using Zoom.  Transcription was performed using Otter.ai and reviewed for accuracy by the interviewing researcher (LAJ). Transcripts were coded in NVivo Plus (v12) using framework analysis.  

Results: Most participants with experience in managing MS healthcare acknowledged the higher risk of osteoporosis in MS. Apart from endocrinologists and nurses, many participants reported limited bone health knowledge in MS, which hindered bone health management. MS-related priorities overshadowed bone health concerns. Many endocrinologists and half of the general practitioners found bone health management practices in MS insufficient. Improved clinician and patient educational materials were recommended.  

Conclusion: There is a clear need for greater proactive management of bone health in people with MS. This would be supported by guidelines for managing bone health in MS and development of educational resources for people with MS and healthcare professionals.  

Keywords: Multiple sclerosis; bone health; healthcare; clinicians; multidisciplinary

Authors: Luis A Jayanata (1), Peter R Ebeling (1), Ayse Zengin (1) Lisa Grech (1) Linh Le-Kavanagh (1)

Author affiliations:
1. School of Clinical Sciences at Monash Health, Monash University, Clayton Victoria.  

The effects of green-blue light therapy on quality-of-life outcomes in multiple sclerosis.

Background: It’s well established that people living with multiple sclerosis (PwMS) experience reduced quality of life (QOL), compared to general population. Light therapy can prevent declines in QOL within cancer populations; however, its impact in PwMS is yet to be thoroughly investigated. 

Objective: This study investigates the impacts of four weeks of green-blue light therapy on QOL in PwMS. Specifically, on QOL aspects including anxiety, depression, fatigue, sleep and positive affect and well-being.  

Methods: This study is part of an ongoing intervention trial, which is investigating feasibility, sleep and fatigue measures. Anxiety, depression, fatigue, sleep and positive affect and well-being measures were collected via the Neuro-QOL (short forms) at baseline and post intervention timepoints. The intervention period spanned four weeks, with Neuro-QOL assessments completed remotely. The Neuro-QOL has been validated in PwMS as a tool to assess different patient reported outcomes. 

Results: Preliminary results reveal green-blue light therapy led to small (d >0.2) improvements in anxiety, fatigue, sleep and positive affect and well-being QOL measures. Green-blue light therapy also had a positive effect on depression QOL, albeit very small (d >0.01). In comparison sleep health guidelines alone only showed very small improvements in QOL measures. 

Conclusion: The results from this analysis show that green-blue light therapy improves QOL. While further studies are still required, these results indicate that green-blue light therapy may be beneficial for improving QOL in PwMS.  

Keywords: Fatigue, quality-of-life  

Effect of Cladribine and Ocrelizumab on Activated Regulatory T Cells in Multiple Sclerosis Patients.

Background: CD4+CD25+CD127lowFoxp3+T cells are Treg which contain subpopulations identified by variable expression of Foxp3 and CD45RA. Population I is CD45RA+, Population II is CD45RA-CD25hiFoxp3hi, and Population III is CD45RA-CD25+Foxp3+. MS patients have low Population I, high Population II; along with changes in CD19+ B cells. 

Objective: We monitored Treg, NK cells, T, and B cell subpopulations in MS patients receiving cladribine (a purine antimetabolite) and ocrelizumab (an anti-CD20 monoclonal antibody). Changes in cell populations in peripheral blood pre-treatment and at 1, 3, 6, 12, and 24 months were compared. 

Methods: Peripheral blood mononuclear cells were isolated using Ficoll-Hypaque density gradient centrifugation and stained with fluorochrome-labelled antibody panels for T/B/NK cells, Treg, T, and B cells. Data was acquired on the BD FACSCanto-II® flow cytometer and analysed using FlowJo software. 

Results: There was no significant change in the proportion of CD4+ cells, Population I, II, and III with both ocrelizumab and cladribine. Cladribine demonstrated no change in total CD19+ count; while transitional B cells increased, memory B cells decreased, and plasmablast counts increased. Ocrelizumab caused a marked depletion of B cells for at least 24 months, but analysis of subpopulations was unreliable due to the lack of B cells. 

Conclusion: Treg populations are spared on both therapies. The effect of ocrelizumab is more pronounced than cladribine in complete depletion of B cells, whilst changes in B cell subpopulations were observed with cladribine. The relevance of this to clinical MS progression is yet to be established. 

Keywords: Multiple sclerosis, T regulatory cells, Ocrelizumab, Cladribine 

Authors: Helen Han (1,2), Nirupama D Verma (1,2), Nicole Carter (1), Giang Tran (1,2), Ranje Al-atiyah (1,2), Bruce M Hall (1,2,3) and Suzanne J Hodgkinson (1,2,4) 

Author affiliations:
1. Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, Liverpool;
2. Southwest Sydney School of Clinical Medicine, University of New South Wales;
3. Renal Medicine, Liverpool Hospital and 4Department of Neurology, Liverpool Hospital 

The Subjective Wellbeing of People Living with Multiple Sclerosis in Australia: Insights from the Personal Wellbeing Index. 

Background: Few studies have investigated subjective wellbeing for people living with MS. Measurement of subjective wellbeing assists researchers in understanding the effects of disabilities and interventions beyond their impacts on levels of functioning. However, few studies have investigated subjective wellbeing for people living with MS. 

Objectives: This study’s primary aim was to determine which domains of subjective wellbeing were most important to people living with MS. It also investigated whether this importance differed between people living with MS and the general population, and how MS-related disability affects subjective wellbeing. 

Methods: Cross-sectional data was obtained from the How Is Your Life Australian general population study and the AMSLS from August-October 2020. Subjective wellbeing was measured as life satisfaction using the Personal Wellbeing Index. This instrument measures global life satisfaction and life satisfaction in the domains of standard of living, personal health, achieving in life, personal relationships, personal safety, community connectedness, and future security. Descriptive and multivariable regression analyses were conducted. 

Results: 1021 general population and 1683 MS participants entered the study (mean age 52.4 and 58.6; female 79.9% and 52.4%, respectively). For people living with MS the most important domains of life satisfaction were standard of living and achieving in life (similar to the general population). The domains of life satisfaction most affected by MS-related disability were personal health, achieving in life, and community connectedness (p<0.01 for all domains).  

Conclusion: Cumulatively, study results indicated that personal health and achieving in life were paramount components of life satisfaction for people living with MS. To improve their subjective wellbeing, this study recommends interventions to support healthy perceptions of illness, self-efficacy, and employment continuation. 

Keywords: Health Economics, Subjective Wellbeing, Personal Wellbeing Index, Life Satisfaction 

Authors: Glen J Henson (1), Bruce V Taylor (1), Ingrid van der Mei (1), Andrew J Palmer (1), Julie A Campbell (*1) and Gang Chen (*2) 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania 
2. Centre for Health Economics, Monash University 
*Joint Senior Authors 

Step exergame training to reduce falls in people with multiple sclerosis: The i-FIMS multi-centre randomised controlled trial.

Background: Cognitive-motor step training is safe and can improve stepping, balance and mobility in people with multiple sclerosis (MS), but efficacy of the cognitive-motor step training in preventing falls has not been demonstrated.  

Objective: This multi-site randomised controlled trial aimed to determine whether a six-month home-based step exercise training program could reduce falls and improve associated fall risk factors compared with usual care in people with MS. 

Methods: 461 people with MS aged 22-81 years (n=366 women, Expanded Disability Status Scale score 1.5-6.0) were randomly allocated to usual care (control) or a six-month home-based step exergames training program (120 minutes/week). The primary outcome was rate of falls over six months. Secondary outcomes included physical, cognitive, and psychosocial function at six months and number of falls over twelve months. 

Results: Mean (SD) exergames play duration was 70 (51) min/week over six months. Fall rates did not differ between groups (incidence rate ratio 0.96, 95% confidence interval 0.69 - 1.34, p = 0.816). Participants in the intervention group performed faster in tests of choice-stepping reaction time at six months, compared with control participants. No serious training-related adverse events occurred.  

Conclusion: The step exergame training program did not reduce falls among people with MS. However, it significantly improved voluntary stepping in cognitively challenging tests. 

Keywords: Accidental falls, fall prevention, cognitive training, balance training, stepping, Multiple Sclerosis. 

Funding sources: MSRA (Postdoctoral Fellowship 13-003_PH); MS Plus (Grant-in-aid) 

Authors: Phu D. Hoang1,2, Daina L. Sturnieks1,3, Carly Chaplin1, Cameron Hicks1, Sophie Robinson, Natassia Smith1, Stephen R. Lord1, Jasmine C Menant1,3. 

Author affiliations: 
1. Neuroscience Research Australia, Randwick NSW 

2. MS Plus 

3. University of New South Wales 

Development of the Menzies Multiple Sclerosis Insomnia Scale (MMSIS): A Rasch analysis.

Background: Poor sleep is common in multiple sclerosis (MS) and recent research suggests poor sleep may even be a symptom of MS. However, there are no specific instruments to quantify the extent of insomnia-related sleep difficulties that may occur due to MS symptomology.

Objectives: To examine the psychometric properties of a newly developed self-report scale (the MMSIS) that assesses the frequency of insomnia-related sleep difficulties in people with MS that are attributable to MS symptoms.

Methods: The MMSIS comprises 15 items, measuring the frequency of sleep interference in the past month from restless legs, pain, sensitivity to temperature, needing to go to the toilet, and anxiety/stress or low mood, in three stages of insomnia (falling asleep, staying asleep, waking too early). It was completed in 1,672 participants (Mage 57.4 years, 79.7% female) from the Australian MS Longitudinal Study. Rasch analysis probabilistic modelling assessed the scale’s unidimensionality and psychometric properties.

Results: Unidimensionality with items grouped according to MS symptom type was indicated (Mean-square outfit .95-.98, item reliability >.99, person reliability .64-.80). Unidimensionality with items grouped according to stage of sleep was also indicated, although person reliability for these alternative structured subscales was weaker (Mean-square outfit .99-1.03, item reliability >.99, person reliability .55-.61). Cronbach’s alpha was excellent for MS symptom (.83-.92) and acceptable for sleep stage (.71-.76), subscales.

Conclusion: We newly developed MMSIS demonstrated good construct validity and internal reliability. This scale enables more accurate estimates of the frequency and extent of insomnia symptoms due to MS-related symptoms.

Funding statement: MS Australia funds the Australian MS Longitudinal Study. Professor Taylor receives funding through a Fellowship-Investigator Grant from the Australian National Health and Medical Research Council (2009389). Professor van der Mei receives funding through a Senior Research Fellowship from MS Australia. An Accelerated Research Grant from the Australian Medical Research Future Fund funds the Menzies MS Flagship Program.

Keywords: sleep difficulties, insomnia, questionnaire development, Rasch analysis

Authors: Cynthia A Honan (1), Barnabas Bessing (2), Laura L Laslett (2), Jason Turner (1), Bruce Taylor (2), Ingrid van der Mei (2)

Author affiliations:
1. School of Psychological Sciences, University Tasmania, Launceston, Australia
2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia

Disease-modifying therapies do not affect sleep quality or daytime sleepiness in a large Australian MS cohort.

Background: Poor sleep is common in multiple sclerosis (MS) and may impact daily functioning. The extent to which disease-modifying therapies (DMTs) contribute to sleep outcomes is under-examined.  

Objectives: To compare the effects of DMTs on sleep outcomes in an Australian cohort of people with MS and investigate associations between DMT use and beliefs about sleep problems and daily functioning (social functioning and activity engagement). 

Methods: 1,715 participants from the Australian MS longitudinal study completed sleep outcomes measures including the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. DMT use and functioning were self-reported. 

Results: 64% of the participants used a DMT. No differences in sleep outcomes were detected between participants who did and did not use DMTs, the type of DMT used (lower vs higher efficacy, interferon-β vs other DMTs), the timing of administration, or adherence to standard administration recommendations. Beliefs that DMT use worsened sleep were associated with poorer sleep quality and perceptions that sleep problems interfered with daily functioning.  

Conclusion: DMT use does not appear to affect self-reported sleep outcomes in people with MS. However, beliefs that DMT use makes sleep worse were associated with poorer sleep quality and poorer daily functioning, suggesting a need for education to diminish negative perceptions of DMT use. 

Funding statement: MS Australia funds the Australian MS Longitudinal Study. Professor Taylor receives funding through a Fellowship-Investigator Grant from the Australian National Health and Medical Research Council (2009389). Professor van der Mei receives funding through a Senior Research Fellowship from MS Australia. An Accelerated Research Grant from the Australian Medical Research Future Fund funds the Menzies MS Flagship Program.  

Keywords: disease modifying therapies, sleep quality, daytime sleepiness, activities of daily living, social functioning 

Authors: Jason A Turner  (1), Laura L Laslett  (2), Christine Padgett ( 1), Chai K Lim  (3), Bruce Taylor  (2), Ingrid van der Mei  (2), Cynthia A Honan (1) 

Author affiliations:
1. School of Psychological Sciences, University Tasmania, Launceston, Australia 
2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 
3. Macquarie Medical School, Macquarie University, Sydney, Australia 

Maximizing Work Productivity and Employment Retention - Preliminary Findings from the MS WorkSmart Feasibility Study for working Australians with Multiple Sclerosis.

Background: In Australia, almost one-third of the societal cost associated with MS stems from income loss due to illness and early retirement. Scalable online interventions to improve work productivity in people with MS are urgently needed, especially in rural areas where employment support is lacking. 

Objective: The MS WorkSmart Feasibility Study assesses the feasibility of delivering a 10-week online intervention with individualised coaching support (n=22), compared to usual care (n=22). It aims to investigate key uncertainties (recruitment, retention, adherence, engagement, primary outcome selection) for a subsequent definitive trial.  

Methods: This unblinded parallel-arm randomized controlled study includes 44 employed Australians with MS who report work instability (MS Work Instability Score>10). Participants complete a baseline survey, a 1-month post-intervention survey and a feedback survey. Study outcomes include recruitment rates, retention rates, intervention engagement and acceptability, and primary outcome selection. Data analyses are primarily descriptive and focus on feasibility and acceptability of the MS WorkSmart intervention and study procedures. 

Results: Recruitment data indicated significant interest in MS WorkSmart, with a 71% response rate from 300 invitees. Among those who declined, 63% were ineligible, and 20% were interested but cited time constraints. Out of the 104 who agreed to participate, 42.7% were eligible following Work Instability screening, highlighting the need and interest for such an intervention. Data on the other outcomes will be reported at the conference.  

Conclusion: If proven effective and cost-efficient, MS WorkSmart will enhance the health and well-being of employed individuals with MS, while reducing the societal and economic burden associated with this illness. This extends to rural areas of Australia where employment support is lacking for people with MS.  

Keywords: Employment, Digital Health, Symptoms Management, Multiple Sclerosis 

Authors: Alisée Huglo (1), Sarah Thomas (2), Sue Shapland (3), Laura Laslett (1), Bruce Taylor (1), Cynthia Honan (4), MS WorkSmart Investigator Group (*), Ingrid van der Mei (1). 

Author Affiliations:
1. Menzies Institute for Medical Research, University of Tasmania, Australia 
2. Bournemouth University Clinical Research Unit, Faculty of Health and Social Sciences, Bournemouth University, United Kingdom 
3. Multiple Sclerosis Western Australia, Australia 
4. School of Psychological Sciences, College of Health and Medicine, University of Tasmania, Australia 

* MS WorkSmart Investigator Group includes Isabelle Bauer, Desmond Graham, Rebecca Graham, Jodi Haartsen, Cynthia Honan, Alisée Huglo, Laura Laslett, Leigh McCaffrey, Bree Mitchelson, Andrew Potter, Karin Ridgeway, Sue Shapland, Kerri Tomlin, Sarah Thomas, Bruce Taylor, Ingrid van der Mei 

Neuroimaging biomarkers of depression in individuals with MS: a systematic review and meta-analysis.

Introduction/Background: There is a lack of systematic and meta-analytic reviews examining neuroimaging biomarkers associated with depression in MS and whether there are changes in these biomarkers after psychological intervention for depression. 

Objective: This study aims to examine the following questions:  

1) Is there a difference in structural and functional neuroimaging biomarkers associated with depression in individuals with MS? 

2) Are structural and functional neuroimaging changes associated with severity of depression in individuals with MS? 

3) Are structural and functional neuroimaging changes associated with the severity of depression in individuals with MS after psychological intervention? 

Methods: Comprehensive searches using MEDLINE, PsycINFO, PubMed, EMBASE, CINAHL, Cochrane Library and Global Health will be conducted. Grey literature will be sourced using ProQuest Dissertations & Theses Global and OSF Preprints. The Covidence platform will be used to undertake and document all stages of this process. Data on methodology, demographics, and main outcome measures will be extracted and analysed. Main outcomes will include: 1) comparisons between MS patients with and without a diagnosis of MDD/MDE/self-reported symptoms of depression, 2) brain lesion location and volume, functional brain measures, structural brain measures, as well as electrical and metabolic activities of the brain (measured by MRI, fMRI, PET, DTI, EEG, or SPECT) and 3) moderators of the relationship between depression and functional and structural brain measures (i.e., age, gender, MS type, length of MS and depression diagnosis, level of ambulation, intervention type if applicable). 

Results: With the use of Comprehensive Meta-Analysis software, we will examine the severity of depressive symptoms, number and type of biomarkers of depression and the degree of reduction or change in biomarkers of depression in those with MS and depression. Meta-regression will examine moderators such as demographics, disease, and functional measurements. Methodological quality will be assessed using Cochrane Risk of Bias tool. Subsets of data based on imaging modality will also be assessed.  

Keywords: depression, neuroimaging, biomarkers, systematic review, meta-analysis 

Authors: Kiropoulos L (1), Schmaal L (2), Ma Y (1), Dang, L (1)

Author affiliations:

1. Head, Mood and Anxiety Disorders Lab, Melbourne School of Psychological Sciences, The University of Melbourne 
2. Head, Mood and Anxiety Disorders Research, Centre for Youth Mental Health and Orygen, The National Centre of Excellence in Youth Mental Health, University of Melbourne 

Eating disorders in multiple sclerosis: examining longitudinal relationships between personality, body image and self-esteem.

Introduction/Background: There is a lack of research into eating disorders (ED) and the factors contributing to EDs in individuals with MS with some evidence to suggest that the risk of ED among individuals with MS may be elevated compared to the general population. Evidence in non-MS samples suggests relationships between neuroticism, body image dissatisfaction, self-esteem and disordered eating. The current study will be the first to examine longitudinal relationships between these variables in individuals with MS.  

Objective: This study aims to examine longitudinal relationships between neuroticism, self-esteem, body image dissatisfaction and disordered eating in individuals with MS. Specifically, it will investigate whether body image dissatisfaction and self-esteem mediate the relationship between neuroticism and disordered eating. 

Methods: Individuals with MS completed an online questionnaire at two timepoints: baseline and at 6-months follow up. A longitudinal serial mediation will be used to examine whether self-esteem and body image dissatisfaction mediate the relationship between neuroticism and disordered eating in a sample of individuals with MS. Data collection is ongoing. 

Results: Preliminary results showed that both self-esteem and body dissatisfaction mediated the relationship between neuroticism and disordered eating in individuals with MS at both baseline and 6-months follow up timepoints.  

Conclusion: Understanding how self-esteem and body image dissatisfaction influence disordered eating in individuals with MS will have implications for the development of tailored psychological assessment and treatments targeting eating disorders in MS. 

Keywords: eating disorders, body image, self-esteem, depression, personality 

Authors: Kiropoulos L (1), Krug, I. (2), Dang, L (1)

Author affiliations:
1. Mood and Anxiety Disorders Lab, Melbourne School of Psychological Sciences, The University of Melbourne 

2. Head of the Eating Disorder Lab, Melbourne School of Psychological Sciences, The University of Melbourne

Cognitive, neurological, and psychological presentation in patients planned for CAR-T therapy: a real-world approach.

Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common consequence of chimeric antigen receptor T-cell (CAR-T) therapy, with a wide range of cognitive and neurological presentations. Patients are rarely examined prior to CAR-T, adding a layer of complexity to distinguishing new symptoms from pre-existing dysfunction.  

Objective: The study aimed to characterise a real-word baseline cognitive, neurological, and psychological status of haematology patients planned for CAR-T. The utility of two cognitive screening approaches was examined for identifying patients with suspected cognitive impairment to be prioritized for further evaluation.  

Method:  Sixty patients underwent a specialist cognitive assessment, and 39 were examined by a neurologist prior to receiving CAR-T at Peter MacCallum Cancer Centre. Data were obtained from clinical examinations, objective psychometric measures, and a self-report questionnaire of psychopathology and subjective cognitive function. Where available, paraclinical data was collected, including MRI, CSF and electrophysiology results. A subset of patients completed a screening measure of cognition. 

Results:  Sixteen (27.0%) patients were cognitively impaired, with six unique patterns of dysfunction. The findings did not support utility of a screening approach for identifying cognitive impairment. Twenty-six (66%) patients reported preexisting neurological diagnoses, with 11 (28%) individuals exhibiting objective abnormality on examination. Peripheral neuropathy and tremor were the most common. Of patients who underwent an MRI, 9 (48%) had abnormal findings. Nine (15.8%) individuals were elevated on a measure of psychopathology. 

Conclusion:  A substantial proportion of haematology patients referred for CAR-T presented with neurological abnormalities and a broad spectrum of cognitive dysfunction prior to infusion. The findings emphasise the importance of baseline specialist neuro-cognitive evaluation in detection and management of neurotoxicity symptoms that might arise after CAR-T.  

Funding: Valeriya Kuznetsova received a graduate scholarship from the University of Melbourne. There were no other sources of funding obtained for this research. 

Keywords: Neurotoxicity, CAR-T, neurology, cognition, psychopathology 
 

Authors: Valeriya Kuznetsova (*1,2,3), Harsh Oza (2), Hannah Rosenfeld (1,2), Carmela Sales (2), Samantha van der Linde (1), Izanne Roos (2,3), Stefanie Roberts (2,3), Fiore D’Aprano (4), Samantha M Loi (5,6), Mark Dowling (1,7), Michael Dickinson (1,7), Tomas Kalincik (2,3), Simon J Harrison (1,7), Mary Ann Anderson (#1,7,8), Charles B Malpas (#2,3,4) 
 

Author affiliations:
1. Centre of Excellence for Cellular Immunotherapy and Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital 
2. Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital 
3. Clinical Outcomes Research (CORe) Unit, Department of Medicine (RMH), The University of Melbourne 
4. Melbourne School of Psychological Sciences, The University of Melbourne 
5. Neuropsychiatry, The Royal Melbourne Hospital 
6. Department of Psychiatry, The University of Melbourne 
7. Sir Peter MacCallum Department of Oncology, The University of Melbourne 
8. Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute 
*Corresponding author 
#Equally credited authors  

Reduced Likelihood of High-efficacy Disease Modifying Therapy Prescription during the COVID-19 Pandemic.

Background: The COVID-19 pandemic significantly impacted the treatment of people with multiple sclerosis (pwMS). Clinicians made treatment choices with concerns that immunotherapy could worsen COVID-19 infections.  Subsequent studies demonstrated an association between certain high-efficacy disease modifying therapies (DMT) and greater COVID-19 severity.  

Objective: This study aimed to examine the impact of the COVID-19 pandemic on DMT prescribing patterns in pwMS. Primary outcome was high-efficacy DMT use pre- and during-pandemic (onset defined as 11 March 2020). Secondary outcomes were the prescribing patterns of specific DMTs pre- and during-pandemic.  

Methods: A multi-centre longitudinal study was conducted using data from the MSBase COVID-19 sub-study. Trends in DMT prescribing rates between 2018-2022 were analysed using multivariable mixed-effects logistic regression. DMT initiation referred to the first prescription of any DMT in that timeframe, DMT switches denoted a change in DMT regimen within 6 months of last DMT use.  

Results: During the pandemic, there was a significant decrease in odds of initiating high-efficacy DMTs (OR 0.42,p<0.001). Odds of initiating or switching to anti-CD20 monoclonal antibodies (Ocrelizumab, Rituximab) were significantly lower (OR 0.32,p<0.001;OR 0.66,p=0.03). Odds of DMT initiation with injectable immunomodulators (glatiramer acetate, interferons) and immunosuppressive agents were lower during-pandemic (OR 0.42,p=0.001;OR 0.13,p<0.001). Odds for DMT switches to natalizumab, immunosuppressive agents and injectable immunomodulators were higher during-pandemic (OR 1.92,p=0.05;OR 2.30,p=0.02;OR 5.52,p=0.006). 

Conclusion: During the COVID-19 pandemic, there was a reduction in overall initiation of high-efficacy DMTs. Clinicians were less likely to initiate or switch patients to anti-CD20 monoclonal antibody therapies, potentially impacting disease activity in pwMS. Swift, evidence-based guidance is crucial during such global health events. 

Keywords: COVID-19, Disease-modifying therapy, prescribing patterns, anti-CD20 monoclonal antibodies, natalizumab 

A phospholipid-based intervention to support remyelination and attenuate the progression of multiple sclerosis: Protocol for a randomised phase II trial (MYRESTOR).

Background: Currently available disease modifying therapies (DMTs) prevent further myelin injury in multiple sclerosis (MS), but there is critical need for therapeutics to enhance remyelination. Our proprietary formulation of purified alkylglycerols, provided as oral supplements, preserves myelin integrity and locomotor function in murine models of acute and chronic demyelination. Alkylglycerols, abundant in mammalian milk, are phospholipid-plasmalogen precursors that play a key role in myelin membrane's insulatory function and nerve-signal transduction. Modulating myelin-lipid plasmalogen homeostasis can potentially promote remyelination pathways, restore oligodendrocyte bioenergetics, and protect against degeneration. 

Objective: We aim to test the efficacy of formulated alkylglycerol therapy in halting demyelination and promoting remyelination in early-stage demyelinating disease (i.e., newly diagnosed clinically isolated syndrome or first presentation of MS defined by a first demyelinating event or high brain lesion load).  

Methods: 60 therapy-naïve patients will be randomly assigned (2:1) to placebo or alkylglycerols, alongside standard care for 18-months. Primary measures include brain disease activity and myelin homeostasis using MRI, and clinical disability progression through Expanded Disability Scales and MS Severity Score at baseline, 9-month, and 18-months. Exploratory measures comprise psychosocial considerations (quality of life, fatigue, cognition), phospholipid lipidome, and blood biomarkers to assess disease activity and neuroaxonal damage for treatment response. 

Conclusion: The anticipated outcome is to accelerate the translation of new therapies into practice. We have demonstrated that therapeutic levels of purified alkylglycerols are safe and well tolerated, providing potentially, a new DMT opportunity that can be fast-tracked into clinical practice for treatment of early MS. 

Funding sources:
Government of Western Australia, Department of Health 
(Western Australian Future Health Research & Innovation Fund) 
Raine Medical Research Foundation 
MSWA 

Simplifying MS symptom severity using symptom classes.

Background: MS symptom severity is highly correlated within each person, making analysing symptom data complex. Therefore, approaching symptoms as an interrelated entity may be more appropriate than analysing each symptom separately, and may help identify areas for intervention and allow treatment tailoring.  

Objective: To differentiate people with MS into different symptom ‘classes’ based on MS symptom scores over 14 MS symptoms in a cross-sectional analysis of data of 1411 people with MS (PwMS) from the Australian MS Longitudinal Study. 

Methods: 13 MS symptoms were assessed using MS Symptom Scores (range 0-10, higher=worse severity), and sleep symptoms using the Pittsburgh Sleep Quality Index (PSQI), rescaled to a 0-10 score. Data were analysed using latent profile analysis and the classes were validated vs AQoL-8D health-related quality of life utility scores (range 0-1) using linear regression. 

Results: Participants were adults with MS (average age 59 years, 80% female, 62% relapse onset). We found four latent “classes” of MS symptom load: ‘low’ (12%), ‘moderate’ (20%), ‘mixed’ (16%) and ‘high’ (53%). Classes had different demographic and clinical characteristics, indicating underlying heterogeneity. Mixed, moderate, and high (vs low) were associated with lower\ health-related quality of life in a dose response manner.  

Conclusion: We identified four distinct symptom classes (low, moderate, mixed, and high symptom load). Classes have distinct demographic and clinical profiles, suggesting drivers of symptom classes are complex. Findings can be used to support PwMS by developing tailored symptom management interventions. 

The Australian MS Longitudinal Study is funded by MS Research Australia. 

Key words: Symptoms; sleep; cohort study, epidemiology 

Authors: Laura Laslett (1), Leigh Blizzard (1), Valery Fuh Ngwa (1), Jessica Roydhouse (1), Cynthia Honan (2), Bruce Taylor (1), Ingrid van der Mei (1) 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania. 
2. School of Psychology, University of Tasmania. 

DNA methylation discriminates between responder and non-responder status in a long-term study of cladribine tablet use in Multiple Sclerosis.

Background: DNA methylation at CpG sites is an epigenetic mechanism that can influence gene expression. Epigenome-wide association studies (EWASs) of immune cells have implicated differential methylation in Multiple Sclerosis (MS) and are associated with treatment use. However, whether EWASs can predict response to treatment is unknown. 

Objective: The objective of this study was to assess if there are changes in global DNA methylation between three- and 30-months post first dose of cladribine tablets that can predict response to cladribine tablets in people with MS (pwMS). 

Methods: Whole blood DNA was collected from the prospectively followed cohort of the CLOBAS study, which is a phase IV, multicentre, open label, six-year study of cladribine tablets for pwMS. Non-responders were participants who had a clinical relapse or new MRI activity. Global DNA methylation was analysed using the ChAMP R package. GLMNet was used to select meaningful features of baseline DNA methylation that could discriminate between responders and non-responders. 

Results: Fifteen of 102 participants were non-responders after 30 months of cladribine tablet use. The most significant feature was cg15041948, which maps to the transcription start site of the GPBP1 gene (Vasculin protein).  This CpG has a good ability to discriminate between responders and non-responders (Area Under the Curve (AUC) = 0.78). Using the top 28 features identified by GLMNet, the ability to discriminate between responders and non-responders was perfect (AUC=1.0) 

Conclusion: We are able to use global DNA methylation profiles to discriminate between responders and non-responders to cladribine treatment. Low numbers mean results should be interpreted with caution, however, the CLOBAS study is a six-year prospective cohort, therefore, longer term follow studies will follow. 

Funding Source: This study was funded by a Investigator Initiated grant from Merck Healthcare Pty. Ltd. 

Key words: Epigenetics, Cladribine, DNA methylation  

Authors: Vicki E. Maltby (1,2,3), Alexandre Xavier (3,5), Mastura Monif (5,6,7), Myintzu Min (1), Marzena J. Fabis-Pedrini (8), Katherine Buzzard (6,9), Tomas Kalincik (6,10), Allan G. Kermode (8,11), Bruce Taylor (12), Suzanne Hodgkinson (13,14,15), Pamela McCombe (16), Meaghan Osborne (17), Helmut Butzkueven (5,9,18), Michael Barnett (19,20), Rodney A. Lea (2,3,21), Jeannette Lechner-Scott (1,2,3). 

Author Affiliations: 
1. Department of Neurology, John Hunter Hospital, New Lambton Heights, NSW 

2. School of Medicine and Public Health, University of Newcastle, Newcastle NSW 

3. Immune Health Program, Hunter Medical Research Institute, Newcastle NSW 

4. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle Australia 

5. Department of Neuroscience, Monash University, Melbourne ,VIC 

6. MS Centre, Department of Neurology, Melbourne Health, Melbourne, VIC 

7. Department of Neurology, Alfred Health, Melbourne, VIC 

8. Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, University of Western Australia, Perth, WA. 

9. Department of Neuroscience, Eastern Health Clinical School, Eastern Health, Melbourne, VIC 

10. CORe, Department of Medicine, University of Melbourne, VIC 

11. Institute for Immunology and Infectious Disease, Murdoch University, Western Australia, Perth, WA. 

12. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 

13. University of New South Wales, Sydney, NSW 

14. Department of Neurology, Liverpool Hospital, Sydney, NSW 

15. Immune Tolerance Laboratory (ITG), Ingham Institute, Sydney, NSW 

16. Centre for Clinical Research, University of Queensland, Brisbane, QLD. 

17. Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia 

18. Managing Director, MSBase Foundation 

19. Brain and Mind Centre, University of Sydney, Sydney, NSW 

20. Sydney Neuroimaging Analysis Centre, Sydney, NSW 

21. Institute of Health and Biomedical Innovations, Genomics Research Centre, Queensland University of Technology, Kelvin Grove, QLD 

Insights into environmental risk factors for relapse-onset and progressive-onset multiple sclerosis.

Background: Progressive-onset multiple sclerosis (POMS) features a distinct clinical course than relapse-onset multiple sclerosis (ROMS), but the underlying mechanism and whether it has distinct risk factors or shares the same risk factors with ROMS remains uncertain. Assessing POMS alone in a meaningful number was previously not possible. 

Objective: Examining whether the association between pre-established risk factors for multiple sclerosis (MS), such as smoking, low sun exposure, infectious mononucleosis, and possible protective factors like young sibling exposure and pregnancy, also exist in POMS, and whether these factors have different effects compared to ROMS. 

Methods: The study included 155 POMS, 204 ROMS and 555 healthy controls. Data on smoking, infectious mononucleosis (IM) history, sun exposure from age 6 to disease onset, sibship structure, parity, and gravidity were collected by questionnaires. Odds ratios (OR) with 95% confidence intervals were calculated using unconditional logistic regression to assess association, adjusting for age, sex and latitude band. Conditional logistic regression was employed as sensitivity analysis. 

Results: Smoking and IM had positive while greater sun exposure and reproductive history showed inverse associations with case status for both phenotypes. Having younger siblings was only associated with POMS. Comparing magnitudes, greater sun exposure (OR 0.62 vs. 0.85) showed stronger while higher parity (0.56 vs. 0.31) showed weaker associations for POMS; smoking (1.66 vs. 1.55) and IM (1.81 vs.1.88) were similarly associated in both. Results were consistent in sensitivity analysis. 

Conclusion: POMS and ROMS shared common environmental and lifestyle risk factors, albeit with some variations in magnitudes. This suggests shared etiology between different clinical phenotypes, with potential variations in their magnitude. There may be novel and distinct factors but were not captured in this analysis. 

Keywords: Multiple Sclerosis, epidemiology, risk factors 

Cuprizone causes region-specific copper depletion in mouse brain.

BACKGROUND: Cuprizone is a common pre-clinical model of demyelination, however its mode(s) of action are not known. One chemical property of cuprizone is to chelate copper, so many postulate demyelination is caused by brain Cu deficiency. Proof of cuprizone-induced brain Cu deficiency, however, has remained elusive. 

OBJECTIVE: The aim of our study was to directly map Cu distribution at micron spatial resolution with nM detection limit in mouse brain tissue sections, to determine if Cu deficiency does or does not exist in the cuprizone model. 

METHODS: Brain tissue was obtained from 14-week-old male C57BL/6 mice fed 0.2 % W/W cuprizone for 6 weeks, and age-matched controls (n = 7). To prevent sample preparation-induced distortion of Cu content or distribution, tissue was rapidly frozen in liquid nitrogen-cooled isopentane without perfusion or fixation. Cryosections (10-µm-thick tissue sections) were cut and air-dried onto X-Ray transparent substrate for elemental mapping with X-Ray fluorescence microscopy (XFM) at ANSTO-Australian Synchrotron. 

RESULTS: XFM revealed brain Cu content (and Cl, K, Ca, Fe, Mn, Zn) at 4 µm spatial resolution with 0.1 ngcm-2 detection limit. Luxol fast blue assessment of myelin showed pronounced demyelination of lateral corpus callosum and striatal white matter, with minimal demyelination at medial locations (coronal sections, bregma 1 mm). Two-Way ANOVA revealed significant localised reduction in Cu in lateral, but not medial corpus callosum and striatum white matter. 

CONCLUSION: This is the first study to definitively visualise cuprizone-induced brain Cu deficiency. This observation provides key evidence that Cu deficiency is a driver of demyelination in the cuprizone model, making it relevant to recently observed alterations in Cu homeostasis during clinical multiple sclerosis. 

KEY WORDS: X-Ray Fluorescence, Synchrotron, Demyelination, Glia, Metals 

The Impact of An Education Program for Allied Health Professionals On Delivering Telehealth Exercise And Behavioural Change to People With Multiple Sclerosis.

Background: Exercise is effective for managing multiple sclerosis (MS). People with MS want exercise promotion from allied healthcare providers (AHP), and AHP indicate interest in promoting exercise for MS. We created a clinician-co-created educational program for AHP to deliver MS exercise guidelines via telehealth, embedding behaviour change principles. 

Objective: We sought to assess the impact of the online multi-modal educational training program on professional quality of life, self-confidence, attitude toward prescribing evidence-based exercise prescription in MS, and knowledge on exercise delivery in MS.

Methods: We completed a single-arm educational intervention study in neurological AHP. Participants first completed a survey to determine demographical (age, sex, location) and professional information (profession, MS caseload). Before and after training, we gathered survey data via the professional quality of life scale (ProQOL) and the practitioner confidence and attitude scale (PCA). Following training, we determined their knowledge to implement the program via the theoretical domains framework (TDF) for healthcare professionals. 

Results: Five AHP have completed the training (3 exercise physiologists; 2 physiotherapists). AHP agreed that following training, they had the knowledge (100%), skills (80%), and confidence (80%) for remotely delivering exercise for MS, and that they plan to do so in the next six months (100%). Training improved knowledge (Pre: 20% to Post:100%), confidence (20% to 100%), and preparation (40% to 100%) to prescribe and deliver telehealth exercise for MS care. 

Conclusion: Our educational program successfully improved AHP knowledge, preparation, and confidence to prescribe and deliver telehealth exercise for MS care. The study is currently delivering training to 10 AHP for completion in September 2023. 

Keywords: exercise; telehealth; behavioural change; physical activity. 

Authors: Georgios Mavropalias, Yvonne Learmonth.

Exploration of Melanopsin (OPN4) as a risk factor for sleep disturbances in multiple sclerosis.

BACKGROUND: Melanopsin (OPN4) is a blue-light sensitive opsin-type G-protein coupled receptor. Expression levels are high in photosensitive retinal ganglion cells which mediate responses to light, ultimately affecting the regulation of circadian rhythm and sleep. 

OBJECTIVE: The objective of this study was to identify genetic variants in the OPN4 gene associated with a variety of sleep traits, including total sleep time and wake after sleep onset, in a sample of individuals with multiple sclerosis. 

METHODS: Genetic association analyses were performed to identify genetic variants associated with sleep traits in participants enrolled in the Effects of Novel Light Therapy in Individuals with Neurological Disorders (ENLighTIND MS) feasibility study. The ‘SNPassoc’ R package was used to fit linear models with the sleep traits being the terms of interest, controlling for age and sex. 

RESULTS: Suggestive associations were found between sleep traits and OPN4 variants. Due to the nature of feasibility trials, we are currently seeking to increase sample size to confirm findings in ENLighTIND MS. 

CONCLUSION: Our results support a role for genetics contributing to heterogeneity in sleep traits in multiple sclerosis. The variants uncovered may be useful for stratification of individuals at risk for poor sleep quality and sleep disturbances, which has potential applications for interventional trial participant selection and both future and retrospective efficacy analyses. 

KEYWORDS: Genes, Melanopsin, Sleep, Risk 

CLADIN: CLADribine and INnate Immune responses in Multiple Sclerosis.

Introduction: Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS). P2X7R is a purinergic receptor implicated in neuroinflammatory processes.

Objective: To investigate the mechanism of action of Cladribine on peripheral monocytes.

Methods: This is a Phase IV study where 40 RRMS patients commencing Cladribine were prospectively recruited into this study. Bloods was sampled at baseline, week 1, week 8, week 26 and week 52 after Cladribine commencement.  Peripheral monocytes were isolated from whole blood using negative selection and underwent immunophenotyping. P2X7R Pore activity was assessed using YOPRO dye uptake experiments and confocal microscopy. ELISA was used to quantify the following cytokines: G-CSF, GM-CSF, IFN-γ, IL-1a, IL-1β, IL-10, IL-17, IL-2, IL-4, IL-5, IL-6, CCL17, TNF-a, CCL2 at each time point. Results: Forty percent of the population had a relapse in the 12 months prior to cladribine commencement, and 22% (9 out of 40 patients) had a relapse during the 12-month study period. EDSS remained stable during the study period. There was evidence of reduction in monocyte count at week 1 post-cladribine commencement compared to baseline (0.55 ±0.04 vs 0.08 ± 0.0187; p=10^-6). Interestingly, CD14lo CD16+ ‘non-classical’ monocyte population were significantly reduced at week 1 post commencement of Cladribine (p= 0.0001) compared to other time points. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1 (p<0.0001) and then the levels stabilized to that of pre cladribine levels. In vitro, Cladrabine induced a reduction in P2X7R pore activity (p<0.001).

Conclusion: This study demonstrates a novel mechanism of action for Cladribine, highlighting that it exerts its effects acutely on peripheral monocytes, and possibly via P2X7R.  It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.  

Key words: Cladribine, innate immunity, monocytes, cytokines, disease activity  

Authors: Richard Sequeira (1), Andrea Muscat (1), Sian Stukey (1), Viet Minh (3,11), Naomi Loftus (3), Veronica Voo (1), Katherine Fazzolari (2), Melinda Moss (3), Vicki E. Maltby (4,5), Paul Sanfilippo (1), Ai-Lan Nguyen (2,6), Robb Wesselingh (1,3), Nabil Seery (1,3), Cassie Nesbitt (3,10), Josephine Baker (3), Chris Dwyer (2), Lisa Taylor (2), Louise Rath (3), Anneke Van der Walt (1,3), Mark Marriott (2,6), Tomas Kalincik (2,6), Jeannette Lechner-Scott (4,5), Terence J. O’Brien (1,3), Helmut Butzkueven (1,3) Mastura Monif (1,2,3,9) 

Author Affiliations: 
1. Department of Neuroscience, Monash University, Melbourne VIC 
2. Department of Neurology, Melbourne Health, Melbourne VIC 
3. Department of Neurology, Alfred Health, Melbourne, VIC 
4. John Hunter Hospital, Department of Neurology, New Lambton Heights, NSW 
5. School of Medicine and Public Health, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW 
6. Department of Medicine, University of Melbourne, Melbourne VIC 
7. Australian Centre for blood diseases, Monash University, Melbourne, Australia  
8. Department of Neurology, Eastern Health, Melbourne Vic, Australia  
9. Department of Physiology, The University of Melbourne, Melbourne, Vic 
10. Department of Neurology, Barwon Health, Melbourne, Vic  
11.School of Nursing, Midwifery and Paramedicine, Australian Catholic University, Fitzroy, Australia 

Environmental risk factors, HLA-DR15, epigenetic alterations and MS onset risk.

Background: Environmental and genetic risk factors of MS may act through epigenetic programming. Of particular interest are Epstein-Barr virus (EBV) exposure, low sun exposure, and low vitamin D levels. Among other aspects, the role of specific immune cell-types in these pathways is not well understood.  

Objective: We aimed to evaluate i) the association between machine learning-derived clusters of MS-associated CpGs measured at FCD onset (later confirmed MS by 10 years follow-up) and common environmental risk factors of MS, and ii) the cell-specific enrichment of gene sets underlying these clusters.  

Methods: The Ausimmune multicentre case-control study includes 206 people followed from MS onset, and 348 matched controls with whole-blood DNA methylation measures. Unsupervised machine learning with Weighted Gene Correlation Network Analysis produced four clusters from 2432 FCD-associated CpGs (all pBenjamini-Hochberg adjusted<5x10-6). Linear regression assessed association between environmental/genetic MS risk factors and Principal Component 1 of each cluster. WebCSEA was applied to examine immune cell-specific enrichment of the cluster gene sets. 

Results: Several environmental and genetic risk factors were associated with both the Blue (hub: cg05099186) and Turquoise (hub: cg24641254) CpG clusters, including low deseasonalised vitamin D and HLA-DRB15 genotype. The Blue cluster was also associated with anti-EBNA Ig titre, history of glandular fever, and several low sun exposure measures (all p<0.05). Both clusters’ gene sets were enriched for monocytes, while the Blue cluster was also enriched for neutrophils (all p<0.05).  

Conclusion: Two clusters of MS-associated CpGs are associated with several environmental risk factors and HLA-DR15 genotype at MS onset. Both cluster gene sets are enriched in monocytes, implicating this immune cell population in MS onset. 

Funding sources: Funding sources for this work include the National Health and Medical Research Council of Australia, MS Research Australia, and the National Multiple Sclerosis Society of the United States of America.  

Keywords: multiple sclerosis, environment, epigenetics, cell-specific enrichment 
 

Authors: Ellen Morwitch (1) & Steve Simpson-Yap (2,3,4), Sam Tanner (1), Sarah Thomson (1), Rod A Lea (5,6,7), Trevor Kilpatrick (1), Jeanette Lechner-Scott (6,7,8), Rodney J Scott (7,9), Alexandre Xavier (7,9), Vicki E Maltby (6,7,8), Bruce Taylor (4), Brett Lidbury (10), Simon Broadley (11), Ingrid van der Mei (4), Maja Jagodic (12), Lars Alfredsson (12,13), Ausimmune/AusLong Investigators Group, Anne-Louise Ponsonby (1,10,14) 

Author affiliations:
1. Florey Institute of Neuroscience and Mental Health, The University of Melbourne 

2. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne 

3. CORe, Royal Melbourne Hospital, The University of Melbourne 

4. MS Flagship, Menzies Institute for Medical Research, University of Tasmania 

5. Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology 

6. School of Medicine and Public Health, Newcastle University 

7. Hunter Medical Research Institute, Newcastle University 

8. Department of Neurology, John Hunter Hospital, New Lambton Heights 

9. School of Biomedical Sciences and Pharmacy, Newcastle University 

10. National Centre for Epidemiology and Population Health, College of Health and Medicine, Australia National University 

11. School of Medicine and Dentistry, Gold Coast Campus, Griffith University 

12. Department of Clinical Neuroscience, Karolinska Institutet 

13. Institute of Environmental Medicine, Karolinska Institutet  

14. Murdoch Children’s Research Institute, The University of Melbourne 

Engaging with healthy lifestyle behaviours reduces fatigue, depression, and disability, in people with multiple sclerosis.

Background: Fatigue, depression, and disability are commonly experienced by people with MS (pwMS). Engaging with healthy lifestyle behaviours have been associated with better health outcomes. We assessed whether certain lifestyle behaviours are more impactful, and whether there are additive benefits in engaging with multiple healthy behaviours. 

Objective: To assess the independent and additive associations of five healthy lifestyle behaviours with fatigue, depression, and disability, using longitudinal observational data from a large international population of pwMS.  

Methods: Lifestyle behaviours assessed were consumption of a no meat/dairy plus omega-3 supplementation diet, ≥once/week meditation practice, ≥30min/day ≥thrice weekly physical activity, non-smoking, and vitamin D intake (≥5000IU/day supplementation or intentional sun exposure). Linear mixed-effects models assessed associations between individual (0=no; 1=yes) and additive (0=0-1; 1=2; 2=3; 3=4-5) behaviours and fatigue (Fatigue Severity Scale), depression (Patient Health Questionnaire), and disability (Patient Determined MS Severity Score), adjusting for demographic and clinical covariates. 

Results: Engagement with individual lifestyle behaviours at baseline was inversely associated with at least one outcome at follow-up. However, only physical activity was consistently associated with all three outcomes. Engagement with ≥2 behaviours was associated with reduced fatigue at 2.5-year follow-up and with reduced depression at 5-year. Engagement with ≥3 behaviours was associated with reduced disability across time-points. Engagement with 4-5 behaviours had strongest associations with all outcomes across all time-points. 

Conclusions: Regular physical activity was prospectively associated with less fatigue, depression, and disability, over 5 years’ follow-up, and engaging in multiple lifestyle behaviours showed additive benefits on health outcomes. Multimodal lifestyle modification programs including these lifestyle behaviours may be beneficial for MS management.  

Keywords: prospective cohort study, multimodal lifestyle behaviours, fatigue, depression, disability 
 

Authors: Nupur Nag (1*), Maggie Yu (1), Steve Simpson-Yap (1,2, 3), George Jelinek (1), Sandra Neate (1), Alexander Fidao (1,4)  

Author affiliations:
1. Neuroepidemiology Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. 
2. COre, School of Medicine, The University of Melbourne, Melbourne, Australia. 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 
4. Victorian Department of Health, Melbourne, Australia. 

Modifiable lifestyle behaviours predict 5-year mastery trajectories in people with multiple sclerosis.

Background: Mastery is a sense of control of one’s situation.  High mastery, and engaging in healthy lifestyle behaviours, are associated with better quality of life in people with multiple sclerosis (pwMS). Understanding mastery trajectories and lifestyle predictors may provide insight into potential interventions to improve wellbeing. 

Objective: To identify long-term trajectories of mastery in a large population of pwMS and assess associations of modifiable lifestyle behaviours (diet, vitamin D and omega-3 supplement use, meditation, physical activity, and non-smoking) as predictors of these trajectories. 

Methods: Data from 602 pwMS, across 3 timepoints over 5-years were analysed. Lifestyle behaviours were: diet (high-quality, meat  and dairy non-consumption); supplements (5000IU/day vitamin D and omega-3); ≥once/week meditation; ≥30min/day ≥3 times/week physical activity; and non-smoker. Mastery was queried via the Pearlin Mastery Scale. Group-based trajectory modelling identified mastery trajectories, and multinominal logistic regression assessed associations between lifestyle behaviours and mastery trajectories, with appropriate adjustments applied. 

Results: Four distinct mastery trajectories were identified, with proportions of pwMS as follows: low = 10%; mild = 43%; moderate = 34%; and high = 13%. Meditation, physical activity, and both omega-3 and vitamin-D supplementation, were independently associated with increased probability of assignment to either moderate or high mastery trajectories, while meat and dairy non-consumption were associated with reduced probability. Smoking was not associated with moderate to higher mastery trajectories. 

Conclusions: Specific modifiable lifestyle behaviours are predictors of long-term mastery. These behaviours may represent points of interventions to increase mastery, and thereby increase quality of life, in pwMS. Future studies may consider assessing mastery as a moderator of associations between lifestyle and QoL.  

Keywords: mastery, lifestyle behaviours, prospective study. 
 

Authors: Nupur Nag (1*), Xirun Yang (1), Amin Zarghami (2), George Jelinek (1), Sandra Neate (1), Xin Lin (1,2) 

Author affiliations:
1. Neuroepidemiology Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. 
2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 

Characteristics and associations between physical activity and quality of life differ by MS phenotype.

Background: Multiple sclerosis (MS) is a progressive neuroinflammatory condition, classified as non-progressive and progressive phenotypes, depending on patterns of cognitive and physical impairment progression.  Few studies have reported on characteristics or associations separately between MS phenotypes.  

Objective: To quantitatively assess differences in characteristics, and associations between healthy lifestyle behaviours and health outcomes (disability and quality of life (QoL)), between people with non-progressive and progressive MS phenotypes.  

Methods: Sociodemographic characteristics queried included employment and marital status, socioeconomic status, countries of birth and residence, relative with MS, support persons. Clinical characteristics included medication use, MS durations from onset and from diagnosis, and health outcomes. Lifestyle behaviours assessed included diet, supplement use, physical activity, and wellness activities. Linear and log-binomial regression was utilised to assess differences in characteristics, and associations between lifestyle and health outcomes, based on MS phenotype.   

Results: Of 4,000 people with MS, those with progressive MS were older, and more likely to be male, not working due to disability or retirement, and had moderate/severe disability, longer MS duration, and lower QoL. People with progressive MS were less likely to use immunomodulatory medications or engage in wellness activities or regular physical activity. Differences in physical activity and QoL associations were seen by phenotype, being stronger in non-progressive MS.  

Conclusions: Differences in characteristics, and in associations between physical activity and QoL, were observed between MS phenotypes. MS phenotype is an important consideration for treatment and management recommendations.  

Keywords: epidemiology, MS phenotype, lifestyle behaviours, health outcomes  

Authors: Nupur Nag (1*), Maggie Yu (1), Steve Simpson-Yap (1,2,3), George Jelinek (1), Sandra Neate (1), Hollie Schmidt (4) 

Author Affiliations:
1. Neuroepidemiology Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. 
2. COre, School of Medicine, The University of Melbourne, Melbourne, Australia. 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 
4. Accelerated Cure for Multiple Sclerosis, Waltham, MA 02451, USA. 

Transplantation of haematopoietic stem cells overexpressing NgR-Fc enhance neurorepair by modifying macrophages and microglia phenotype in an MS animal model.

BACKGROUND: Activated macrophages and microglia lead to persistent central nervous system damage with no current treatment available to initiate repair during progressive MS. Chief among the inhibitory factors is Nogo-A and its cognate receptor. Delivery of a modified receptor has shown improvements in similar demyelinating pathologies. 

OBJECTIVES: Targeted cellular delivery of a soluble form of the Nogo receptor, NgR-Fc, to neuroinflammatory lesions is required to promote neurorepair. This was achieved using hemopoietic stem cells as a novel cellular delivery method of the modified receptor. 

METHODS: The hematopoietic stem cells were genetically modified using a lentiviral vector to overexpress the NgR-Fc therapeutic protein. Recipient mice underwent autologous HSC transplantation prior to their experimental autoimmune encephalomyelitis induction, to produce MS-like disease. Clinical scoring and locomotor performance of mice were monitored for 30 days. Histopathology analyses were conducted to assess the polarisation of the macrophages and microglial cells. 

RESULTS: A shift from classically activated macrophages and microglia towards their neuroprotective alternatively activated phenotypes were observed in lesioned areas following the transplantation of HSCs expressing NgR-Fc. Furthermore, expedited clearance of myelin debris, an inhibitor to remyelination and axon regeneration, was observed, with neurorepair being demonstrated in neurologically recovering mice.  

CONCLUSION: These results suggest that the delivery of the cellular delivery of NgR-Fc directly to neuroinflammatory lesions can modify macrophages and microglia by shifting the proinflammatory environment towards neurorepair in an animal model of MS.  

FUNDING SOURCE:  J.Y.L. was supported by the Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation Postgraduate Scholarship; S.P. was supported by the National Multiple Sclerosis Society Project Grant (RG4398A1/1); International Progressive Multiple Sclerosis Alliance Challenge Award (PA0065); Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation (15-022); Bethlehem Griffiths Research Foundation (BGRF1706); and MS Australia Project Grant (212-0000000058).D.N. is supported by the MS Australia Postgraduate scholarship (22-3-058).  

KEYWORDS: macrophage, microglia, myelin debris, classically-active macrophages, alternatively-activated macrophage 

AUTHORS: Danica Nheu (1), Sining Ye (1*), Paschalis Theotokis (2*), Jae Young Lee (3*), Min Joung Kim (1*), Olivia Ellen (1), Thomas Bedford (1), Padmanabhan Ramanujam (1),  David K. Wright (1) Stuart J. McDonald (1) Amani Alrehaili (1,4), Maha Bakhuraysah (1,4), Jung Hee Kang (1), Christopher Siatskas (5), Cedric S. Tremblay (6), David J. Curtis (6,7), Nikolaos Grigoriadis (2*), Mastura Monif (1), Stephen M. Strittmatter (8) and Steven Petratos (1) 

AUTHOR AFFILIATIONS:
1. Department of Neuroscience, Central Clinical School, Monash University, Australia  
2. Department of Neurology, Laboratory of Experimental Neurology and Neuroimmunology, AHEPA University Hospital, Greece  
3. ToolGen Inc., Korea  
4. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Saudi Arabia  
5. STEMCELL Technologies Inc. , Canada  
6. Australian Centre for Blood Diseases, Central Clinical School, Monash University, Australia 
7. Clinical Haematology, Alfred Hospital, Australia  
8. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, USA 

Preclinical trial of a small molecule to promote neuroprotection and repair in an animal model of neuroinflammatory demyelination.

Background: Myelin producing human oligodendrocyte cells express the main thyroid hormone plasma membrane transporter known as monocarboxylate transporter 8 (MCT8). Our group has demonstrated that MCT8 is dysfunctional in conditions of developmental or acquired myelin diseases such as progressive MS. 

Objective: To trial novel small molecules that may improve re-myelination and provide neuroprotection in the central nervous system (CNS) following immune-mediated damage in rodent disease models that mimic MS-like disease. 

Methods: 

• Proteomic studies on Human tissue and Animal disease models: Western blots, immunoprecipitation, metabolomic analysis. 
• Mouse model of neuroinflammation: Experimental Autoimmune Encephalomyelitis (EAE) 
• Transmission Electron Microscopy: analysis of myelin thickness (G-ratio), size, distribution and integrity in EAE mice treated with experimental drugs. 
• Transgenic mouse model of de/re-myelination: Cuprizone neurotoxicant model of demyelination in PDGFRα Cre-Lox mice. 

Results:

• Dysregulated thyroid hormone-dependent signaling during acute inflammatory spinal cord demyelination and axonal damage during the peak-stage of EAE. 
• Human post-mortem tissue proteomics demonstrated dysregulated thyroid hormone-dependent signaling in chronic degenerative demyelinating lesions together with deficits in mitochondrial function in metabolomic analyses. 
• Downregulated MCT8 expression in mature oligodendrocytes during the peak stage of EAE leads to profound cell death and demyelination around inflammatory lesions. 
• DITPA acted independent of MCT8 through integrin-dependent non-genomic signaling. 
• Enhanced re-myelination in the optic nerves of DITPA treated mice during EAE. 

Conclusion: Our consolidated data stresses the reliance of MCT8 in oligodendrocyte survival, maturation, and differentiation in the CNS. We conclude that DITPA is a capable alternative to MCT8 for transporting thyroid hormone into the CNS and may result in a novel therapeutic target in treating MS. 

Keywords: Diiodothyropropionic acid (DITPA), re-myelination, experimental autoimmune encephalomyelitis, monocarboxylate transporter 8, oligodendrocytes. 

Neutropoenia in Ocrelizumab and Rituximab treated patients.

Background: Ocrelizumab and rituximab are both anti-CD20 monoclonal antibodies commonly used in Australia and overseas for treatment of multiple sclerosis and other autoimmune disorders. Neutropaenia is a rare but potentially life-threatening complication of both ocrelizumab and rituximab treatment. 

Objective: This case series reports 12 patients experiencing neutropaenia following ocrelizumab or rituximab treatment and aims to characterise the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of infections experienced and types of treatment necessary before patients reached count recovery. 

Methods: This study consists of retrospective collation of data, describing 12 patients from three health services who developed neutropaenia after treatment with ocrelizumab or rituximab. Patients at Alfred Health, Melbourne Health and St Vincent’s Hospital Sydney with multiple sclerosis, neuromyelitis optica spectrum disorder or autoimmune encephalitis treated with ocrelizumab or rituximab who developed marked neutropaenia were included in this study. 

Result: We present 12 cases of individuals with MS/neuroinflammatory disorders treated with ocrelizumab/rituximab who subsequently developed neutropaenia. In most cases, neutropaenia was complicated by fever and a potential source of infection requiring close monitoring and treatment with G-CSF and/or anti-infective agents. The timing of neutropaenia to the last dose of therapy differed with the earliest case occurring 4 days after treatment, and the latest case being 6 months after treatment. Overall, these cases highlight a rare and unexpected complication of B-cell depleting therapies and indicate the need for close monitoring for these patients. 

Conclusion: This case series illustrates that timing, severity and predisposing factors for neutropaenia after ocrelizumab and rituximab administration can result in potentially devastating infections, which highlights the need for careful patient monitoring through routine surveillance bloods for early detection and treatment of neutropaenia.  

Keywords: multiple sclerosis; ocrelizumab; rituximab; neutropoenia 

Authors: Venus Pang, Nabil Seery, Robb Wesselingh, Wei Yeh, Michael Zhong, Tracie Tan, Chris Dwyer, Cassie Nesbitt, Louise Rath, Mastura Monif 

Randomized Clinical Trial of Intermittent Calorie Restriction in People with Multiple Sclerosis: Effects on Immunometabolic and Cognitive Measures.
 

BACKGROUND: Intermittent calorie restriction (iCR) reduces inflammation in preclinical models and in people with Multiple Sclerosis (pwMS). Mechanisms could be related to changes in levels of adipose tissue-derived adipokines with reduced systemic inflammation and in gut microbiota composition. 

AIMS: To evaluate the effects of iCR on adipokines levels, metabolic and immune/inflammatory biomarkers, clinical and brain MRI measures compared to a control unrestricted diet (Ctr) in people with relapsing remitting MS (pwMS). 

METHODS: Participants with relapsing remitting MS were randomly assigned to the iCR or Ctr groups for 12 weeks. Blood and stool samples were collected at baseline, 6 and 12 weeks; dual-energy X-ray absorptiometry (DEXA) was performed at baseline and 12 weeks. Primary outcome of the study was effects of iCR on leptin and adiponectin levels in blood compared to the Ctr diet. Secondary outcomes included: peripheral blood metabolic and immunologic profiling, anthropometric (weight and body mass index) and total body fat measures (waist circumference and fat mass), lipidomic analyses, clinical and cognitive measures. Differences between iCR and unrestricted diet were examined using a linear, repeated measures mixed model and adjusted for baseline levels, age, sex and disease modifying treatment.  

RESULTS: Forty-two pwMS were randomized (22 iCR and 20 Ctr), 34 finished the study (17 iCR and 17 Ctr). We observed a significant reduction of anthropometric and body adiposity measures over the 12-weeks in participants randomized to iCR. Leptin levels decreased over 6 and 12 weeks in the iCR group and were significantly lower in the iCR compared to the Ctr group at 6 and 12 weeks. An increase in adiponectin in the iCR group over 6 and 12 weeks of diet was observed. Immune profiling showed a significant decrease in Th1 and an increase in CD45RO+ regulatory T cell numbers after 6 weeks of iCR. Lipids in the species of lysophosphatidylcholine, lysophophatidylethanolamine and phosphatidylinositol were significantly increased after 12 weeks of iCR compared to baseline, they were higher at 12 weeks compared to Control and significantly correlated with immune cell subsets. Cognitive testing demonstrated an amelioration in the symbol digit modality test (SDMT) score in the iCR group over the 12 weeks of intervention, with a significant improvement compared to the Ctr group at 12 weeks. No major adverse effects were associated with the dietary intervention. 

CONCLUSIONS: Short term iCR is safe and feasible in pwMS and can ameliorate metabolic, immunologic and cognitive profiles in pwMS.  

Authors: L. Ghezzi (1), V. Tosti (1), C. Cantoni (2), A. Salter (3), S. Lancia (3), L. Shi (4), A. Don (4), Y. Zhou (5), K. Obert (1), R. Mikesell (1), A. Ge (4), M K. Sen (4),  A. H. Cross (1), R. T. Naismith (1), L. Piccio (1,4) 

Author affiliations:
1. Department of Neurology Washington University in St. Louis – School of Medicine, St. Louis, MO, US 
2. Barrow Neurological Institute, Phoenix, AZ, US 
3. UT Southwestern Medical Center, Dallas TX, US 
4. Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia  
5. University of Connecticut, Farmington, CT, US 

Mapping the Australian Dietary Guidelines to dietary assessment tools used in studies of people living with multiple sclerosis.

Background: Dietary changes may reduce symptom severity and disease progression in multiple sclerosis (MS); however, the specific role and/or dietary patterns is not sufficiently understood. Greater adherence to Dutch dietary guidelines was associated with improved MS outcomes, but this has not been determined in Australian studies. 

Objective: To apply the Australian Dietary Guidelines (ADG) food composition database to the Dietary Questionnaire for Epidemiological Studies Version 2 (DQES v2) to enable determination of adherence in dietary intakes. 

Methods: The ADG food composition database was applied to the DQES to convert habitual intake data into a score of ADG adherence. Mapping involved matching DQES items to ADG database foods, then converting the weight (g) consumed reported by the DQES into the equivalent number of serves per day from ADG food groups. For each food group, intake was considered ‘adherent’ if equal to/greater than the recommended serves. 

Results: Food items of the DQES were successfully mapped to the ADG database with consideration given to discretionary food types. An ADG adherence tool was developed to provide an overall score per habitual intake collected with the DQES v2 giving outcomes related to vegetables and legumes, fruit, grain foods, meat and alternatives, and dairy and alternatives food groups as well as unsaturated fats/oils and discretionary foods. 

Conclusion: Applying our ADG adherence score to studies of people living with MS will enable researchers to determine how closely habitual intakes align with Australian dietary guidelines and allow exploration of associations with MS outcomes, including changes over time. 

Keywords: Multiple sclerosis, dietary intake, food frequency questionnaire, dietary guidelines, food groups 

Psychological Correlates and Psychological Treatments of Death Anxiety in Multiple Sclerosis: A Systematic Review.

Background: Death Anxiety (DA) is a transdiagnostic variable linked with anxiety and depression in those with an illness. Although MS is associated with high levels of anxiety and depression, there appears limited literature exploring the role of DA for those with MS.

Objective: To review and appraise the latest literature examining psychological correlates and psychological treatments of DA in individuals with MS. To provide direction for future research. The full systematic review included those with cancer and eating disorders. Only the MS related results will be presented here. 

Methods: Searches were conducted in four databases; PsycInfo, Medline, Embase and CINAHL. Grey literature from ProQuest Dissertations & Theses Global and Trove. No date restrictions were applied. Inclusion criteria included: Quantitative studies in English. Any adult formally diagnosed with MS by a neurologist. A measure of DA (e.g., Templer’s Death Anxiety Scale), a correlate of this measure (e.g., self-esteem) or any psychological intervention targeting DA.

Results: A total of 4,564 articles and n = 223 full-texts were identified for screening in this review. Five studies focussing on DA for those with MS were included. Three of these examined psychological correlates of DA, such as stress, anxiety, depression, and acceptance. Two studies examined psychological treatments, including Acceptance and Commitment Therapy. A narrative synthesis and quality appraisal of the experimental studies and psychological interventions will be provided.​​​​​​​

Conclusion: Specific recommendations regarding future research of psychological correlates and psychological treatments will be provided, based on the narrative synthesis and quality appraisal. 

Funding Statement: There are no funding sources to acknowledge. 

Keywords: anxiety, death anxiety, psychology, transdiagnostic, systematic review 

Authors: Pourliakas A (1), Dang PL (1), Baes N (1), Krug I (1), Kiropoulos LA (1).
1. Melbourne School of Psychological Sciences, The University of Melbourne.  

A qualitative study of online health information seeking in people with multiple sclerosis following Multiple Sclerosis Online Course (MSOC) participation.

Background: People with multiple sclerosis (pwMS) increasingly seek information on a range of topics related to self-management of MS, particularly lifestyle-related behaviour modification. Online health information seeking behaviour by pwMS in this area remains under-investigated and deeper exploration is required to design better online educational resources.  

Objective: To determine the relevance and accessibility of online health-related information by pwMS. Through qualitative interviews with pwMS who completed a novel lifestyle educational intervention, the MS online course (MSOC), we describe the behaviours and perceptions of participants seeking MS-related health information online throughout their disease.  

Methods: We conducted a randomised controlled trial (RCT) to test the effectiveness of the MSOC at improving health outcomes in pwMS compared with a standard-care course. The intervention course provided comprehensive multimodal lifestyle modification information, with the standard-care course providing general lifestyle modification information based on MS websites. Semi-structured interviews of participants were conducted one month after course completion. Reflexive thematic analysis was used to explore participants’ views and experiences.  

Results: Analysis of qualitative data from 38 pwMS (22 intervention and 16 standard-care participants) identified two main themes: Motivations for learning and MS information in the online world. Participants approaches to accessing online spaces were varied, with the time of diagnosis identified as the most critical and challenging time for seeking online information. Recognisable institutions and select websites and social media sites were preferred information sources due to their perceived trustworthiness. 

Conclusions: This study enables increased understanding of the online information seeking behaviours and experiences of pwMS. These findings could be incorporated by researchers and educational content designers to develop online MS-related resources customised to improve participant engagement in online learning throughout different stages of their disease.   

Key words: Qualitative analysis, randomised controlled trial, digital health education, lifestyle behaviour

Trial registration: This trial was registered prospectively with the Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, identifier ACTRN12621001605886 

Date of registration: 25 November 2021. 

Source of Funding: We gratefully acknowledge the financial support of Mr Wal Pisciotta and other anonymous philanthropic donors to the Neuroepidemiology Unit. Funders played no role in the design, review or approval of the study. 

Authors: Jeanette Reece (1), Rebekah A. Davenport (2), Sandra Neate (1), Maggie Yu (1), Pia Jelinek (1), Steve Simpson-Yap (1,3,4), George Jelinek (1), Nupur Nag (1), William Bevens (1) 
 

Authors affiliations:
1. Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia 
2. Melbourne School of Psychological Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, VIC, Australia 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia 
4. CORe, School of Medicine, The University of Melbourne, Melbourne, VIC, Australia 

Feasibility testing of an online nutrition education program for people with multiple sclerosis.

Background: High-quality diets that align with dietary guidelines improve symptoms and comorbidities in people with multiple sclerosis (MS). However, people with MS receive conflicting information, including targeted marketing of non-evidence-based diets. People with MS want evidence-based MS-specific dietary advice; however, suitable nutrition education programs are lacking. 

Objective: To test phase 1 of an online nutrition education program for people with MS, including the demand in recruiting/participation, participant retention, acceptability and usability of the program, as well as limited efficacy testing for food literacy, nutrition literacy and diet quality. 

Methods: A seven-module asynchronous online program was developed with people with MS and stakeholders using co-design principles. The program was grounded in behaviour change theory and used behaviour change techniques and multimodal delivery. The intervention was assessed using a pre-post single-arm evaluation design, used validated food and nutrition literacy questionnaires and dietary habits questionnaire. Other factors known to impact on healthy eating were also assessed, such as depression, anxiety, and fatigue.  

Results: Of the 67 participants enrolled, 75% completed some of the program and 57% completed the entire program in the 9-week timeframe. The median value/usefulness rating of the program was 5.9 out of 7 (‘very true’). Compared to pre-program, participants who completed any of the program had statistically significant improved food literacy (P<0.0001), nutrition literacy (P<0.0001), and diet quality scores (P<0.0001). Higher fatigue and depression were associated with lower diet quality.  

Conclusions: This is the first online evidence-based nutrition program for people with MS, demonstrating demand, practicability, acceptability, and efficacy. Phase 2 will explore further tailoring of content from phase 1 learnings, to support people with MS to make healthier dietary choices and achieve evidence-based dietary advice.

Funding sources: This research was supported by MSWA, the Future Health Research and Innovation (FHRI) Fund, and an MS Australia Incubator Grant (#21-1-072).  

LJB is supported by MSWA and an MS Australia Postdoctoral Fellowship.  

AD is supported by MSWA. 

ED and LG are supported by MS Australia Postdoctoral Fellowships. 

Keywords: Nutrition, codesign, food literacy, lifestyle factors 

Authors: Rebecca RUSSELL (1), Andrea BEGLEY (1), Alison DALY (1), Eleanor DUNLOP (1), Ngoc Mihn PHAM (1), Lisa GRECH (2) and Lucinda BLACK (3) 

Author affiliations:
1. Curtin School of Population Health, Curtin University 
2. Department of Medicine at Monash Health, Monash University 
3. Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University 

Identifying Metabolic Markers and Pathogenic Mechanisms Implicated in Multiple Sclerosis Onset and Progression.

Background: Metabolites are small molecules that drive a wide range of essential biological functions. Genetic and metabolic profiling has promising applications for disease risk stratification and can inform treatment strategies of high-risk individuals. However, metabolic biomarkers with high specificity are not available for multiple sclerosis (MS).  

Objective: To systematically evaluate metabolites as biomarkers of MS onset and progression and gain novel insight into the molecular pathogenesis of MS.   

Methods: We integrated independent metabolomic and lipidomic data using Mendelian randomisation (MR) to assess causal relationships of circulating metabolites/lipids with MS onset and severity. Next, we will validate our findings using cross-sectional and longitudinal data from the AusLong cohort study (over 15 years’ follow-up) which have multi-omics measurements (including ~1,300 metabolites and 570 lipids). We will then integrate multi-omics data for the same participants to elucidate the molecular underpinnings.  
 

Results: Preliminary MR analysis found elevated low-density lipoprotein were associated with reduced MS onset risk (odds ratio=0.88, p=9.8x10-5), though this association attenuated in a multivariable MR model adjusting for BMI. Additionally, we identified candidate biomarkers for MS severity, including serine (odds ratio=1.09, p=5.2x10-3) and several phosphatidylcholine species. We are working to incorporate multi-omics measurements in the AusLong cohort and develop metabolite/lipid-based risk scores for MS onset and progression. 
 

Conclusion: This will be the largest systematic evaluation of metabolic markers in MS onset and progression to-date, including a world-first longitudinal multi-omics study for MS (work in progress). Our findings will generate opportunities for novel biomarker-based risk scoring and facilitate further mechanistic studies and therapeutic development.  

Funding: This work was supported by funding from the Medical Research Future Fund (B.T., EPCD000008) and the Australian National Health and Medical Research Council (B.T., 2009389 & Y.Z., 1173155). 

Keywords: Multi-omics, metabolomics, biomarkers, longitudinal, risk scoring

Authors: Eleanor Sabey (1) and Xin Lin (1), Yuanhao Yang (2,3), Steve Simpson-Yap (1,4,5), Bruce Taylor (1†), Yuan Zhou (1,†). 

Author Affiliations:
1. Menzies Institute for Medical Research, University of Tasmania, TAS, Australia. 
2. Mater Research Institute, Translational Research Institute, QLD, Australia. 
3. Insitute for Molecular Bioscience, The University of Queensland, QLD, Australia. 
4. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, VIC, Australia. 
5. CORe, School of Medicine, The University of Melbourne, VIC, Australia. 
†These authors jointly supervise this work. 

Identification of pain distribution subgroups that differ in pain, demographic and clinical characteristics in Multiple Sclerosis.

Background: Despite its high prevalence, pain in Multiple Sclerosis (MS) is often underdiagnosed and undertreated. This is due, in part, to the difficulty in assessing and measuring pain. A better understanding of pain in MS is necessary to improve the diagnosis and management of this symptom. 

Objective: To examine patterns of pain distribution and their clinical relevance in a nationally representative sample of people with MS. 

Methods:  A cohort of individuals with MS (n=2576) have been followed since 2001. Hierarchical clustering analysis was applied to examine pain distribution subgroups.  Regression analyses were performed to determine subgroup differences in pain prevalence, severity (Brief pain inventory), interference (Pain interference scale), confidence (Pain self-efficacy scale), coping (Pain catastrophising scale), number of relapses, levels of disability (Disability-patient-determined disease steps), fatigue (Fatigue severity scale), depression, and anxiety (Hospital depression and anxiety scale).  

Results: Subgroups, each displaying unique patterns of body region selection, were identified. Among those with a subgroup membership that exhibited the highest frequency of body region selection compared to others with lower frequencies, a significant association was observed with higher pain intensity, pain self-efficacy, pain catastrophising, number of relapses (past 12 months), levels of disability, fatigue, depression, and anxiety. These associations remained after adjusting for MS duration, age, education, and sex. 

Conclusion: This study provides evidence of pain distribution subgroups in MS with unique body region selection patterns. Pain and clinical characteristics varied significantly across these subgroups. If causal, subgroup assignment may aid understanding of pain distribution in clinical settings. 

Authors: Alice Saul (1), Bruce Taylor (1), Kristen LFever (2), Julie Campbell (1), Laura Laslett (1), Ingrid van der Mei (1). 

Author Affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Australia 
2. School of Medicine, University of Queensland, Brisbane, Australia. 

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Background: Significant variability exists in prevalence and severity of multiple sclerosis worldwide, partly explained by latitude of country of residence. However, geographical variation in the risk of secondary progressive multiple sclerosis (SPMS) is unknown. 

Objective: To evaluate differences in the risk of SPMS in relation to latitude and country of residence, modified by high-to-moderate-efficacy immunotherapy. 

Methods: Relapsing-remitting multiple sclerosis (RRMS) patients from the MSBase registry with at least one recorded assessment of disability were included. A proportional hazards model was used to estimate the risk of SPMS by latitude, adjusted for clinical and demographic characteristics at inclusion, national MS prevalence, government health expenditure, and treatment with high-to-moderate-efficacy disease-modifying therapy. Geographical variation in time from RRMS to SPMS was modelled through a proportional hazards model with spatially correlated frailties.  

Results: 51126 patients (72% female) from 27 countries were included. The median survival time from definite RRMS to SPMS was 39 (95% CI: 37-43) years. Higher latitude (median HR= 1.21, 95% CI [1.16, 1.26]), higher national MS prevalence (1.07 [1.03, 1.11]), male sex (1.30 [1.22, 1.39]), older age at onset (1.35 [1.30, 1.39]), higher disability (2.40 [2.34, 2.47]) and frequent relapses (1.18 [1.15, 1.21]) at inclusion were associated with increased hazard of SPMS. Higher proportion of time on high-to-moderate-efficacy therapy substantially reduced the hazard of SPMS (0.76 [0.73, 0.79]) and reduced the effect of latitude (interaction: 0.95 [0.92, 0.99]). At the country-level, Oman, Kuwait, and Canada had higher risk of SPMS relative to the other studied regions. 

Conclusion: Higher latitude of residence is associated with a higher probability of developing SPMS. High-to-moderate-efficacy immunotherapy can mitigate some of this geographically co-determined risk. 

Funding: This study was funded by the NHMRC [grant 1129189 and fellowship 1140766]. The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Roche, Bayer Schering, Sanofi Genzyme, and Teva Pharmaceutical Industries. The study was conducted separately and apart from the guidance of the sponsors. 

Keywords: secondary progressive multiple sclerosis; disease-modifying therapy; latitude; geography; health expenditure 

Authors:  Sifat Sharmin; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Izanne Roos; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Steve Simpson-Yap; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Neuroepidemiology Unit, Melbourne School of Population & Global Health, University of Melbourne, Melbourne, Australia; Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia 

Charles Malpas; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Jeannette Lechner-Scott; School of Medicine and Public Health, University Newcastle, Newcastle, Australia 

Katherine Buzzard; Department of Neurology, Box Hill Hospital, Melbourne, Australia 

Olga Skibina; Department of Neurology, Box Hill Hospital, Melbourne, Australia 

Anneke van der Walt; Department of Neurology, The Alfred Hospital, Melbourne, Australia 

Helmut Butzkueven; Department of Neurology, The Alfred Hospital, Melbourne, Australia 

Allan Kermode; Perron Institute, University of Western Australia, Nedlands, Australia 

Ernest Butler; Monash Medical Centre, Melbourne, Australia 

Michael Barnett; Brain and Mind Centre, Sydney, Australia  

Suzanne Hodgkinson; Liverpool Hospital, Sydney, Australia 

Pamela McCombe; University of Queensland, Brisbane, Australia 

Bruce Taylor; Royal Hobart Hospital, Hobart, Australia 

Mark Slee; Flinders University, Adelaide, Australia 

Richard Macdonell; Austin Health, Melbourne, Australia 

Justin Garber; Westmead Hospital, Sydney, Australia 

Pamela McCombe; Royal Brisbane and Women's Hospital, Brisbane, Australia 

Cameron Shaw; Geelong Hospital, Geelong, Australia 

Neil Shuey; St Vincents Hospital, Fitzroy, Melbourne, Australia 

Jennifer Massey; St Vincent's Hospital Sydney, Sydney, Australia 

Todd Hardy; Concord Repatriation General Hospital, Sydney, Australia 

John Parratt; Royal North Shore Hospital, Sydney, Australia 

Tomas Kalincik; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia on behalf of the MSBase investigators. 

Environmental and genetic mixture effect on MS risk mediated by differential DNA methylation in the Ausimmune case-control study.

Background: A number of environmental factors have been implicated in MS risk, including sun/vitamin D and Epstein-Barr virus (EBV), as well as HLA-DRB1*1501 risk genotype. How and whether these factors may act in combination to affect first clinical demyelination (FCD) risk is unclear.  

Objective: To apply weighted quantile sum (WQS) regression to assess the association between a mixture of environmental and genetic factors and FCD risk; to evaluate the population attributable fraction; and to assess if and to what extent this association is mediated by differential DNA methylation 

Methods: 206 FCD cases subsequently converting to MS by 10-year follow-up with whole-blood DNA-methylation data compared with 348 controls. Six CpG clusters derived from 2,432 EWAS-defined FCD-associated CpGs using weight-gene correlation network analysis. WQS assessed mixture effect on FCD of glandular fever history, anti-EBV-EBNA-Ig, deseasonalised-25(OH)D, pre-FCD summer/winter sun exposures, smoking, and HLA-DRB1*1501 (each scored 0/1). PAF estimated using PAF_calc_continuous R package. Mediation by the CpG clusters assessed using medflex R package. 

Results: The environmental-genetic mixture significantly predicted FCD risk (10-90% OR=11.02,95%CI=2.48-48.91, p<0.001), PAF=87.2%, persisting if the genetic component, HLA-DRB1*1501 was excluded from the mixture (OR=6.75,95%CI=1.73-26.31, p<0.001), PAF=77.2%. Blue and Turquoise CpG clusters each independently mediated 19% and 12% of associations with FCD risk (22% and 12% if HLA-DRB1*1501 excluded), and jointly mediated 28% of association with FCD risk (34% if HLA-DRB1*1501 were excluded). No other CpG clusters showed comparable mediation.  

Conclusion: We have shown that key environmental and genetic risk factors act in combination to predict FCD risk, and that a substantial amount of this association acts via differential DNA methylation at MS onset, indicating multiple potentially modifiable epigenetic mechanisms to reduce MS risk.  

Funding sources: Funding sources for this work include the National Health and Medical Research Council of Australia, MS Research Australia, and the National Multiple Sclerosis Society of the United States of America.  

Keywords: multiple sclerosis, environment, HLA-DRB1*1501, epigenetic, mediation 

Authors: Steve Simpson-Yap (1,2,3,4) & Ellen Morwitch (1), Sarah Thomson (1), Sam Tanner (1), Rod A Lea (5,6,7), Trevor Kilpatrick (1), Jeannette Lechner-Scott (6,7,8), Rodney Scott (7,9), Alexandre Xavier (7,9), Vicki E Maltby (6,7,8), Bruce Taylor (4), Brett Lidbury (10), Simon Broadley (11), Ingrid van der Mei (3), Maja Jagodic (12,13), Lars Alfredsson (12,13), Ausimmune Investigators Group, Anne-Louise Ponsonby (4,10,14) 
 

Author affiliations: 
1. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia; 
2. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia; 
3. CORe, Department of Medicine, The University of Melbourne, Parkville, Australia; 
4. MS Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 
5. Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Kelvin Grove, Australia; 
6. School of Medicine and Public Health, Newcastle University, Callaghan, Australia; 
7. Hunter Medical Research Institute, Newcastle University, Callaghan, Australia; 
8. Department of Neurology, John Hunter Hospital, New Lambton Heights, Australia; 
9. School of Biomedical Sciences and Pharmacy, Newcastle University, Callaghan, Australia; 
10. National Centre for Epidemiology and Population Health, ANU College of Health and Medicine, Australia National University, Acton, Australia; 
11. School of Medicine and Dentistry, Gold Coast Campus, Griffith University, Southport, Australia; 
12. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 
13. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;                                                                                                                     
14. Murdoch Children’s Research Institute, The University of Melbourne, Parkville, Australia. 

Changing epidemiology of multiple sclerosis over 60 years in Newcastle, Australia: 1961 to 2021.
 

Introduction: Newcastle, Australia has been serially studied for MS epidemiology since 1961, showing a consistently increasing prevalence and incidence rate to its most recent assessment in 2011.  

Objectives: To assess the 2011-2021 epidemiology of MS in Newcastle local government area (LGA) and to compare with previous measures.  

Methods: Demographic/clinical data extracted from medical records of MS cases residing in Newcastle LGA identified by public and private clinicians. Prevalence and incidence rate estimated for 2021 and age-standardised to the 2021 Australian population. Historical estimates derived from previously published studies at this site, age standardised to the 2021 Australian population.   

Results: The 2021 prevalence was 173.1/100,000 (age-standardised=178.7/100,000, F/M sex ratio=3.3), a 42.2% increase from 2011 (F/M sex ratio=3.1) and 175.0% from 1996 (F/M sex ratio=2.6). The 2011-21 age-standardised onset incidence rate was 3.6/100,000 person-years (F/M sex ratio=3.1), 72.6% increase from 1971-81 (F/M sex ratio=2.3) and 47.8% from 1986-96 (F/M sex ratio=1.1). The age-standardised diagnosis incidence rate was 6.2/100,000 (F/M sex ratio=2.4), statistically unchanged from that in 2001-2011 (6.8/100,000, F/M sex ratio=3.2).  

Conclusion: The Newcastle region continues to be a high frequency zone for MS. The incidence rate from onset is significantly increased from previous estimates, but incidence rate from diagnosis is stable. Prevalence and incidence from onset sex ratios have stabilised at roughly 3.0, similar to other Australian sites. 

Keywords: multiple sclerosis; epidemiology, prevalence, incidence  

Authors: Stacey Hall (1), Steve Simpson-Yap (2,3,4), Rodney Lea (5,6), Vicki Maltby (7), Mike Boggild (8), Tomas Kalincik (2,9), Cameron Shaw (10), Bruce Taylor (4), Anneke van der Walt (11), Jeannette Lechner-Scott (1,5,7). 

Author affiliations: 
1. Department of Neurology, John Hunter Hospital, New Lambton, Australia; 
2. CORe, Department of Medicine, The University of Melbourne, Parkville, Australia; 
3. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia; 
4. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 
5. Hunter Medical Research Institute, New Lambton, Australia; 
6. Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Kelvin Grove, Australia; 
7. School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, Australia; 
8. Department of Neurology, Townsville University Hospital, Douglas, Australia; 
9. Neuroimmunology Centre, The Royal Melbourne Hospital, Melbourne, Australia; 
10. Geelong Clinical School, School of Medicine, Deakin University, Geelong, Australia; 
11. Department of Neuroscience, Monash University, Melbourne, Australia. 

Higher DII score associated with increased clinical severity in people with MS: a cross-sectional study within the UK MS Register.

Background: A pro-inflammatory diet may be associated with MS progression, potentially via inflammatory pathways. Studies examining associations between pro-inflammatory diets and MS progression are limited, however. 

Objectives: To assess the relationships between Dietary Inflammatory Index (DII) and clinical severity, as a measure of MS progression in a population of people with MS (pwMS). 

Methods: Data extracted from the UK MS Register in 2016 and 2022. Diet assessed via EPIC-Norfolk Food Frequency Questionnaire and scored using the DII algorithm. Clinical outcomes included ambulatory disability (MS Walking Scale (MSWS), MS Impact Scale-Physical (MSIS)), fatigue (Fatigue Severity Scale) and depression and anxiety (Hospital & Anxiety Depression Scale). Analyses by quantile or log-binomial/multinomial regression, adjusted for total energy intake, age, sex, and MS phenotype, as appropriate.  

Results: Of 2,278 and 2,887 participants in 2016 and 2022, mean DII was 0.18 (SD=1.66) and 0.30 (SD=1.61), and mean energy-adjusted DII was -1.31 (SD=1.86) and -1.35 (SD=1.83), respectively. Higher DII was associated with worse disability [MSWS (aβ=1.73 & aβ=1.33) and MSIS-Physical (aβ=1.01 & aβ=1.48)] and higher frequencies of fatigue (aPR=1.04 & aPR=1.05), depression (aPR=1.12 & aPR=1.21), and severe (aPR=1.05 & aPR=1.08), respectively. Similar associations were seen with energy-adjusted DII.  

Discussion: Subject to replication in prospective studies, these results suggest a role for inflammatory dietary characteristics and clinical outcomes in MS.  

Funding: This project is supported by Multiple Sclerosis Australia (22-2-089) and the UK MS Society catalyst award (B001-22.2). The UKMSR is funded by the UK MS Society. 

Keywords: multiple sclerosis; diet; dietary inflammatory index; progression 

Authors: Steve Simpson-Yap (1,2,3), Shelly Coe (4), Sandra Neate (1), Athanasios Tektonidis (4), Sherry Price (5,6), James R. Hébert (5,6), Lucinda Black (7), Nupur Nag (1), Yasmine Probst (8,9), Rod Middleton (10), Richard Nicholas (11), Jeanette Reece (1),

Author affiliations: 
1. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Australia; 
2. CORe, School of Medicine, The University of Melbourne, Australia; 
3. Menzies Institute for Medical Research, University of Tasmania, Australia;  
4. Department of Sport, Health Sciences and Social Work, Oxford Brookes University, United Kingdom; 
5. Department of Epidemiology and Biostatistics and Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA 
6. Department of Nutrition, Connecting Health Innovations LLC (CHI), Columbia, SC, USA 
7. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Australia; 
8. School of Medical, Indigenous and Health Sciences, University of Wollongong, Australia; 
9. Illawarra Health and Medical Research Institute, Australia; 
10. Population Data Science, FHMLS, Swansea University, United Kingdom; 
11. Imperial College London, United Kingdom. 

Healthier dietary intake associated with less clinical severity in people with MS: a cross-sectional study within the UK MS Register.

Background: MS is a progressive autoimmune condition with diverse symptoms, commonly including fatigue, disability, and depression. Diet has been implicated in MS progression, but the relationship is not well-defined.  

Objectives: To assess relationships between quality of dietary intake and clinical severity of disease in a population of people with MS. 

Methods: Data extracted from the UK MS Register in 2016 and 2022. Dietary intake assessed using EPIC-Norfolk Food Frequency Questionnaire, and principal components analysis applied. Outcomes included ambulatory disability (MS Walking Scale (MSWS), MS Impact Scale-Physical (MSIS)), fatigue (Fatigue Severity Scale), and depression and anxiety (Hospital and Anxiety Depression Scale). Analyses by quantile and log-binomial/multinomial regression, adjusted for total energy intake, age, sex, and MS phenotype.  

Results: In 2,278 and 2,887 participants from 2016 and 2022, two diet components were derived: Prudent and Western. In 2016 and 2022, Prudent score was associated with lower MSWS (aβ=-1.41; aβ=-1.02), lower MSIS-Physical (aβ=-0.83; aβ=-1.15), and lower frequencies of depression (PR=0.91; aPR=0.86). Western score was associated with higher MSWS (aβ=+3.07; aβ=+3.21), higher MSIS-Physical (aβ=+1.89; aβ=+2.43), and higher frequencies of fatigue (aPR=1.09; aPR=1.09), depression (aPR=1.20; aPR=1.26), and anxiety (aPR=1.10; aPR=1.15). 

Conclusion: These findings suggest a role for diet in symptom management in pwMS; however, prospective studies are needed to confirm these relationships. 

Funding: This project is supported by Multiple Sclerosis Australia (22-2-089) and UK MS Society catalyst award (B001-22.2).  

Keywords: multiple sclerosis; diet; principal components analysis; progression 

Authors: Steve Simpson-Yap (1,2,3), Shelly Coe (4), Athanasios Tektonidis (4), Sandra Neate (1), Lucinda Black (5), Nupur Nag (1), Yasmine Probst (6,7), Rod Middleton (8), Richard Nicholas (9), Jeanette Reece (1), 

Author affiliations:
1. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Australia; 
2. CORe, School of Medicine, The University of Melbourne, Australia; 
3. Menzies Institute for Medical Research, University of Tasmania, Australia;  
4. Department of Sport, Health Sciences and Social Work, Oxford Brookes University, United Kingdom; 
5. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Australia; 
6. School of Medical, Indigenous and Health Sciences, University of Wollongong, Australia; 
7. Illawarra Health and Medical Research Institute, Australia; 
8. Population Data Science, FHMLS, Swansea University, United Kingdom; 
9. Imperial College London, United Kingdom. 

Longitudinal trends in multiple sclerosis epidemiology in eastern Australia, 1951 to 2022.

Background: The MS latitudinal gradient in Australia has been well demonstrated, with frequencies of MS in Hobart (43˚S) roughly 7-times that of tropical Queensland (19˚S) and twice that of Newcastle (23˚S). 

Objectives: To describe the longitudinal variation in MS prevalence and incidence across these three sites from the historical surveys in 1961 to our current surveys.  

Methods: Prevalence and incidence estimates were extracted from these previous publications or from our own data for the recent timepoints. Where age/sex-specific data were available from publications or current data, all prevalence estimates were age-standardised to the 1961 Greater Hobart population and the 2022 Australian population. Differences in prevalence and incidence were assessed by Poisson regression. 

Results: Prevalence ratios decreased since 1961: Hobart:Newcastle decreased from 2.0 to 1.0 in 2019/2021 and Hobart:Townsville from 4.9 to 1.9 in 2019/2022, while that between Newcastle:Townsville was more stable (2.5 in 1961 to 1.9 in 2021/2022). Incidence rate ratios since 1971-81 between Hobart:Newcastle were stable (1.9 in 1971-81 and 1.7 in 2011-2021), while that between Hobart:Townsville decreased from 5.8 to 1.7 in 2012-2022 and Newcastle:Townsville from 3.1 to 1.1 in 2012-2022. 

Discussion: The prevalence latitudinal gradient in eastern Australia has markedly attenuated, a consequence of significantly increasing incidence in Townsville, alongside proportional increases in incidence in Hobart and Newcastle, and changed population structures over time. Potential factors underlying these dynamics may include changes in environmental/behavioural exposures.  

Keywords: multiple sclerosis; epidemiology, prevalence, incidence, latitude 

Authors: Steve Simpson-Yap (1,2,3), Bruce Taylor (3), Jeannette Lechner-Scott (4,5,6), Mike Boggild (7), Cameron Shaw (8), Anneke van der Walt (9), Tomas Kalincik (1,10) 

Author affiliations:
1. CORe, Department of Medicine, The University of Melbourne, Parkville, Australia; 
2. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia; 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 
4. Department of Neurology, John Hunter Hospital, New Lambton, Australia; 
5. Hunter Medical Research Institute, New Lambton, Australia; 
6. School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, Australia. 
7. Department of Neurology, Townsville University Hospital, Douglas, Australia; 
8. Geelong Clinical School, School of Medicine, Deakin University, Geelong, Australia; 
9. Department of Neuroscience, Monash University, Melbourne, Australia;  
10. Neuroimmunology Centre, The Royal Melbourne Hospital, Melbourne, Australia; 

Longitudinal epidemiology of multiple sclerosis in Townsville, Queensland, Australia 2012-2022.

Background: Tropical Queensland, of which Townsville is the largest city, is in a region defined as a low-prevalence area. However, the previous estimate of MS prevalence in this region was only undertaken in 1981. The modern epidemiology of MS in this region is thus unknown.  

Aims: To undertake a study of the prevalence, incidence, mortality, and descriptive characteristics of MS in Townsville, Queensland, over 2012-22.  

Methods: Demographic/clinical data extracted from medical records of MS cases identified by public and private clinicians. Cases were identified from a review of medical records at the sole tertiary referral hospital in the region, extracting information about demographics, MS diagnosis and onset dates, and current MS phenotype. Prevalence, and incidence and mortality rates estimated for 2012 and 2022 and age-standardised to the 2022 Australian population. Statistical comparisons by Poisson regression. 

Results: Females and relapsing-remitting MS comprised most cases. The 2012 prevalence was 45.0/100,000 (50.4/100,000 age-standardised, F/M sex ratio=2.0). Prevalence increased by 188% in 2022, with a crude prevalence of 86.9/100,000 (91.7/100,000 age-standardised, F/M sex ratio=2.7). 2012-22 MS onset incidence rate was 3.8/100,000 person-years (age-standardised 3.5/100,000, F/M sex ratio=2.7). Mean age increased from 49.4 to 57.3 years. Age-standardised mortality rate was 0.9/100,000 person-years, with standardised mortality ratio=1.0.  

Conclusion: These results show that Townsville is a high-frequency region for MS, with prevalence and incidence on par with that seen at higher latitudes in Australia. These results have implications for clinical practice in the region and for organisational resource allocation.   

Funding: This project was supported by an Incubator Grant from MS Australia (22-0148). 

Keywords: multiple sclerosis; epidemiology, prevalence, incidence, mortality 

Authors: Steve Simpson-Yap (1,2,3,9), Duncan Maddox (4), Jeanette Reece (2), Jeannette Lechner-Scott (5,6,7), Cameron Shaw (8), Bruce Taylor (3), Tomas Kalincik (1,9), Anneke van der Walt (10), Mike Boggild (4) 

Author affiliations:
1. CORe, Department of Medicine, The University of Melbourne, Parkville, Australia; 
2. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia; 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 
4. Department of Neurology, Townsville University Hospital, Douglas, Australia; 
5. Department of Neurology, John Hunter Hospital, New Lambton, Australia; 
6. Hunter Medical Research Institute, New Lambton, Australia; 
7. School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, Australia;  
8. Geelong Clinical School, School of Medicine, Deakin University, Geelong, Australia. 
9. Neuroimmunology Centre, The Royal Melbourne Hospital, Melbourne, Australia 
10. Department of Neuroscience, Monash University, Melbourne, Australia.  

Consumer and Community Involvement (CCI) in Research - policy and strategy development using a consumer consultation process.

Background: The regulatory framework in Australia that governs consumer and community involvement in research requires medical research institutes to have a policy for involving consumers in research. 

Objectives: The objectives of this work will outline the consumer and researcher consultation process used to develop a policy and strategy for consumer and community involvement (CCI) in research for the Menzies Institute for Medical Research, University of Tasmania. 

Method: 1. Scoping review of the literature focussing on the regulatory framework in Australia. 2. Invitation to the Australian Association of Medical Research (AAMRI) strategy group to discuss 3. Consultation workshop with researchers, consumers and partners (n=30).  4. Survey to define shared values and principles of involvement. 5. Break out groups discussed the key barriers and enablers for CCI.  6. Reimbursement guidelines were discussed and endorsed. 

Results: The survey conducted with the researchers and consumers formed the basis of the shared values and principles for involvement which were used to develop the core policy document for the institute. The key barriers and enablers for CCI identified in the consultation workshop were used to develop our core strategies for involvement; 1. Establish a governance structure, 2. Promote diversity and accessibility 3. Build capacity and capability 4. Create engagement and impact. 

Conclusion: Medical research institutes are regulatory obligated to develop a CCI policy. However, it is important that consumers are actively involved in the development of institute CCI policies and strategies to ensure the needs of consumers are considered and appropriate strategies that enable involvement are implemented. 

Keywords: consumer, community, research, policy, consultation 

Investigating microglial miRNAs as novel pro-remyelination therapeutics in multiple sclerosis.

Background: In multiple sclerosis (MS) loss of CNS myelin leads to progressive disability. New therapeutics are needed to prevent accumulation of CNS damage and promote remyelination and axon protection. Microglia regulate a multitude of physiological and pathophysiological CNS processes and have the capacity to promote remyelination. 

Objective: Control of microglial function occurs on many levels including regulation by miRNAs. However, the miRNAs that control microglial identity and function have yet to be fully elucidated. This study aims to identify and assess microglial miRNA with roles in demyelination and remyelination. 

Methods: Due to the fundamental role of microglia in MS we have generated a unique dataset of microglia enriched miRNA throughout ontogeny in both humans and mice, allowing us to identify microglial enriched miRNA with human relevance. These datasets were used to identify candidate miRNA that may have roles in remyelination. We employed the cuprizone model to investigate the expression of these miRNA during demyelination and remyelination.  

Results: We identified temporally enriched as well as constantly microglial enriched miRNA. We did not observe sex dependent miRNA expression. Assessment of differential miRNA expression, miRNA-mRNA interactions, and gene ontology analysis identified candidate miRNA that may have roles in remyelination. Using the cuprizone model we have observed how the expression of these candidate miRNA changes during demyelination and remyelination, allowing for the prioritisation of our candidates for functional testing. 

Conclusion: This project will identify microglial miRNA that can modulate microglial function to promote myelin repair. The long-term aim of this project is the development of novel miRNA-based treatments that promote remyelination, prevent the accumulation of axon, and neuron loss that leads to long term disability in MS.  

Keywords: Microglia, miRNA, myelin, remyelination, multiple sclerosis 

Authors: Sarrabeth Stone (1), Alexander D. Walsh (1), Richard J. Leventer (2), Trevor J. Kilpatrick (1), Paul J. Lockhart (3), Brendan R.E. Ansell (4), Michele D. Binder (1) 

Author affiliations:
1. The Florey Institute of Neuroscience and Mental Health 
2. Royal Children’s Hospital 
3. Murdoch Children’s Research Institute 
4.Walter and Eliza Hall Institute of Medical Research 

Neurotoxic kynurenine pathway metabolite quinolinic acid preferentially accumulates in the CSF of progressive MS patients, and localises to cortical neurons, astrocytes, and microglia.

Background: The kynurenine pathway metabolises tryptophan, producing metabolites including neuroprotective kynurenic and picolinic acid, and neurotoxic quinolinic acid (QUIN). MS serum metabolomics show dysregulation towards QUIN accumulation. Neurodegeneration predominates in progressive MS, but understanding CSF dysregulation in active/inactive subtypes and QUIN localisation in tissue is unknown.

Objective: Kynurenine pathway dysregulation is observed in progressive MS serum, but to date, limited studies have compared active/inactive forms. We analysed metabolite concentrations in CSF from different MS subtypes, and histologically-localised QUIN in post-mortem MS patient brain tissue (Human Brain and Spinal Fluid Resource Centre, USA).

Methodology: 36 CSF and 12 post-mortem cortical tissue samples were obtained, comprising age-matched healthy controls, inactive relapsing-remitting MS (RRMS), and active and nonactive secondary progressive MS (SPMS). Kynurenine pathway metabolites were measured analytically. Chromogenic immunohistochemistry localised QUIN, glial fibrillary acid protein (GFAP+) astrocytes, and ionised calcium-binding adaptor molecule-1 (IBA1-positive) microglia in healthy controls and MS tissue. CSF and IHC statistics used a Kruskal-Wallis ANOVA with Dunn’s pairwise comparison; significance of p<0.05.

Results: MS patient CSF had a significantly higher kynurenine/tryptophan ratio than controls (p<0.001). QUIN/kynurenic acid and QUIN/picolinic acid ratios, and QUIN were significantly higher in active-SPMS  (62.96nM, p<0.001) or remitting-RRMS (45.47nM, p<0.05) than controls (36.32nM). QUIN/picolinic acid levels were higher in active-SPMS than non-active-SPMS (p=0.013). We’ve undertaken the first QUIN immunostaining in human MS brain tissue, finding it localises to IBA1-positive macrophages/microglia, GFAP-positive astrocytes, and in the grey matter, presumed neurons.

Conclusions: Kynurenine pathway CSF activation/dysregulation confirmed; favours QUIN production to neurotoxic levels »2-fold>controls (SPMS), versus picolinic acid (decreased). Microglial QUIN production could occur during neuroinflammation, secretion contributing toward cell death in progressive MS. QUIN localisation, possibly to reactive astrocytes in the lesion/border, is under ongoing analysis. 

Funding: We acknowledge the funding of the Peter Duncan Neurosciences Research Unit at St. Vincent’s Centre for Applied Medical Research. 

Keywords: Kynurenine pathway, multiple sclerosis, quinolinic acid, astrocytes, microglia. 

Authors: Krishan Gondal (1,2), Chai K Lim (3),  Dan Hemphill (1,2), Benjamin S. Summers (1,2), Gayathri Sundaram (1,2) Michael D. Lovelace (1,2),  Bruce Brew (1,2,4). 

Author affiliations:
1. Peter Duncan Neurosciences Unit, St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia 
2. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia 
3. Faculty of Medicine, Macquarie University, Sydney, NSW, Australia  
4. Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia  

Rate of wordfinding difficulties in MS as an isolated language problem and association with cognition, fatigue, disability and depression.

Background: Persons with MS often reported word-finding difficulties even in the early stages.  In literature, language weaknesses involving acquisition and word retrieval are mainly attributed to cognitive impairment (CI). 

Objectives: To determine the associations between CI, fatigue, disability (EDSS), and depression word-finding difficulties (WFD) using a standardised naming task as part of a computerised cognitive assessment battery (CAB) (NeuroTrax©) with age- and education-adjusted cognitive domain scores. 

Methods: 586 PwMS (137 males and 449 females, mean age 47.1 (SD+10.34) with a median EDSS-score of 2.0 (var=2.0) completed the CAB and the Fatigue Severity Score and Beck Depression Inventory. The rate of CI was 43% in all PwMS. On the naming test, a score of 85 (i.e. 100 – 1 SD) was considered an abnormal score. 

Results: The average score for naming in the CI group was 83.9 (SD±24.2) compared to 100.6 (SD±13.2) in the group without CI (p<.001). In the CI group, 41% of PwMS had an abnormal score on the naming task, whereas, in the non-CI group, 14% scored abnormal (p<.001). No correlation between naming scores and disease duration, EDSS-score, fatigue scores and depression scores were found in both groups. 

Conclusion: Although the rate of WFD in PwMS is higher with CI, a large group of PwMS without CI (14%) has WFD. No correlation with EDSS status, fatigue or depression scores was found. Results suggest that WFD may occur as an isolated language disturbance in PwMS. 

Keywords: Multiple Sclerosis, Wordfinding Difficulties, Cognitive Impairment, Speech Pathology 

Authors: Mildred Tan, Stacie Attrill, Mark Gudesblatt, Hans Bogaardt 

Complex variations within the complement component 4 gene contribute to risk of developing multiple sclerosis.

Background: Complement component 4 (C4) is an important part of complement cascade mediating inflammation and neuronal damage. C4 gene is located within major histocompatibility complex locus that consistently shows strongest genetic association with multiple sclerosis (MS), though the role of C4 variations in MS remains unclear.  

Objective: To investigate C4 genetic variations in MS risk and gain better understanding of how the major histocompatibility complex region influences MS susceptibility.  

Methods: We used an established protocol to impute C4 alleles into the available single nucleotide polymorphism genotyping data from a case-control cohort of European-ancestry (n= 3,252 MS cases and 5,725 controls). We performed logistic regression analysis to explore the association between MS risk and C4 gene isotypes, with considerations of different copy numbers of C4A, C4B, and long/short versions of C4. 

Results: We found evidence that higher total C4 copy number was associated with a reduced risk of MS (odds ratio (OR) =0.93, P=0.028). Regarding C4 isotypes, an increased copy number of C4A (OR=0.91, P=1.62x10-3) and short version of C4 (OR=0.90, P=8.18x10-5) were both significantly associated with the reduced MS risk. We are currently analyzing C4 alleles in larger cohorts, as well as incorporating transcriptomics data to further understand the role of C4 variations in MS development. 

Conclusion: The preliminary analysis shed important light on the significance of C4 genes in MS development, and this will add insights into a potentially important genetic risk locus in MS. 

Funding: This work was supported by funding from the Medical Research Future Fund (B.V.T., EPCD000008), and the Australian National Health and Medical Research Council (B.V.T., 2009389 & Y.Z., 1173155). 

Keywords: multiple sclerosis, complement component 4, copy number polymorphism, major histocompatibility complex 

Authors: Dongdong Tang (1,4), Xin Lin (1,4), Yuanhao Yang (2,3), Bruce V Taylor (1), Yuan Zhou (1) 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia 
2. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia 
3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia 
4. These authors contributed equally to this work. 

Evaluation of BAFF signalling after demonstrating that B cells exhibit a globally decreased expression of BAFF-receptor in early Multiple Sclerosis.

Background: B cells contribute to MS pathology through antibody-dependent and independent processes. We have previously demonstrated that the phenotype of circulating B cells is altered in patients with early MS including a significant reduction in BAFF receptor expression.  

Objectives: The aim of the current study is to evaluate the functional outcomes of reduced BAFF receptor expression and further assess the immunophenotype of B cell subpopulations in MS.  

Methods: Peripheral blood mononuclear cells from patients with established MS (n=28) and healthy controls (n=17) were included in the forerunner study. Additional MS patients (n=20) and controls (n=10) will be included in this extended analysis. Extensive B cell phenotyping, using spectral flow cytometry, short term cultures and phosphorylation analysis will be employed to evaluate the impact of BAFF signalling on MS-specific B cell profiles. 

Results: Preliminary analysis suggests that IgA+ memory B cells area increased in patients with early MS. In addition, a global decrease in expression of the BAFF receptor was observed. We have now established several novel assays in our laboratory to further evaluate the impact of BAFF exposure on B cell activation, including the molecular signalling pathways involved. 

Conclusions: This study will provide novel insights into the pathogenic role of B cells in patients with MS, including changes to immunophenotype of specific B cell subpopulations. It may also provide insights into why therapies targeting BAFF may have been unsuccessful in the past. 

Funding: This work was supported by grants from Multiple Sclerosis WA. Some participants were recruited through the Pho-CIS phototherapy trial, which was supported by the National Health and Medical Research Council of Australia (ID 1067209).  

Keywords: Multiple Sclerosis, B cells, BAFF, Flow cytometry 

Authors: Jonatan Leffler (1), Stephanie Trend (1,2), Jordana Sheahan (1), Isabelle Coenen (1), Georges E Grau (3), Simon Hawke (3), Scott N Byrne (3,4), Allan G Kermode (2,5), Martyn A French (6), Prue H Hart (1) 

Author affiliation:
1. Telethon Kids Institute, University of Western Australia, Perth, WA, Australia 
2. Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, University of Western Australia, Perth, WA, Australia 
3. The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia 
4. Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW Australia 
5. Institute for Immunology and Infectious Disease, Murdoch University, Perth, WA, Australia 
6. UWA Medical School and School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia 

No association between consumption of ultra-processed foods and symptoms of depression, anxiety, and fatigue in people with multiple sclerosis.

Background: Higher-quality diets may be associated with better mental health outcomes in people with multiple sclerosis (MS). Ultra-processed foods (UPFs) are energy-dense and low in nutrients; however, it is unclear whether higher consumption of UPFs is associated with adverse mental health outcomes in people with MS. 

Objective: We used data from the AusLong Study, a longitudinal cohort of people followed since clinically isolated syndrome. We tested associations between consumption of UPFs and symptoms of depression, anxiety, and fatigue over ten years.
 

Methods: Dietary intake data were collected using food frequency questionnaires at baseline, five- and ten-year reviews. Anxiety, depression, and fatigue symptoms were measured using the Hospital Anxiety (HADS-A), Depression (HADS-D) Scale, and Fatigue Severity Scale (FSS), respectively, at five- and ten-year reviews. We used bootstrapped multivariable mixed effects analysis, stratified by sex, to examine associations between a ten-point increase in UPF consumption (servings/day) and HADS and FSS scores.

Results: Consumption of UPFs was not significantly associated with HADS-D score (males: coeff. 0.06, 95%CI [-0.08, 0.20], p = 0.379; females: coeff. 0.05, 95%CI [-0.07, 0.17], p = 0.426), HADS-A score (males: coeff. 0.11, 95%CI [-0.04, 0.26], p = 0.157; females: coeff. 0.06, 95%CI [-0.08, 0.19], p = 0.401) or FSS score (males: coeff. 0.18, 95%CI [-0.69, 0.06], p = 0.685; females: coeff. 0.11, 95%CI [-0.16, 0.39], p = 0.427). 

Conclusion: Consumption of UPFs was not significantly associated with symptoms of depression, anxiety, or fatigue over a ten-year period in males or females with MS. It is unknown whether UPFs are associated with other health outcomes, such as markers of disease progression, in people with MS. 

Funding: Funding for the AusLong Study was provided by the National MS Society of the United States of America, the National Health and Medical Research Council of Australia and MS Australia. ED is supported by an MS Australia Postdoctoral Fellowship. AD is supported by MSWA. LJB is supported by MSWA and an MS Australia Postdoctoral Fellowship. 

Authors: Shane van Bueren (a), Lucinda J Black (a,b), Alison Daly (a), Daniel Rudaizky (a), Ausimmune/AusLong Investigator Group, Eleanor Dunlop (a) 

Author affiliations:
a. Curtin School of Population Health, Curtin University 
b. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University 

Understanding the Microbiome in Autologous Haematopoietic Stem Cell Transplant (AHSCT) in Multiple Sclerosis (MS).

Background: Multiple Sclerosis is an inflammatory neurodegenerative disease affecting the central nervous system. The gut microbiome’s role in immunity has been implicated in MS. Natalizumab is a monoclonal antibody that blocks lymphocyte trafficking to the CNS and gut. AHSCT has sustained therapeutic benefit to arrest MS. 

Objective: This cross-sectional pilot study aimed to analyse the oral and stool microbiome of two MS cohorts, consisting of stable subjects on Natalizumab and commence sample collection in individuals undergoing AHSCT, and compare this to a healthy control cohort.  

Methods: An MS cohort (n=11) of Natalizumab (n=9) and AHSCT (n=2) subjects was compared to a healthy control cohort (n=11).  Amplicon sequencing of the 16S ribosomal RNA V4 region (Illumina MiSeq) from saliva and stool was used to evaluate alpha and beta diversity, oral-stool microbiota distances, and relative taxa abundances. 

Results: All participants in the MS Natalizumab cohort had relapse-remitting MS with an increased female proportion (1M:10F). There were differences in richness (p<0.0001), diversity (p=0.0431) and overall microbial composition (p=0.0001) of oral samples in MS participants compared to controls. Oral samples of people with MS showed increased relative abundances of Prevotella but decreased Haemophilus compared to healthy controls. Stool samples showed increased Turisibacter and Clostridium in MS.  

Conclusion: Our findings suggest distinct changes in the oral and stool microbiome can be identified in people with MS compared to a control cohort. Future longitudinal studies will analyse the microbiome in larger cohorts with MS undergoing AHSCT to identify changes as a result of treatment. 

Funding: by St Vincent’s Hospital, Sydney 

Keywords: multiple sclerosis; gut microbiome 

Targeting Acid-Sensing Ion Channels in the Pathophysiology of Multiple Sclerosis.

Background: Certain pathophysiological conditions can cause a rapid drop in pH and activate acid sensing ion channels (ASICs). Their dominant subtype in the central nervous system, ASIC1a, has been shown to have increased expression in post-mortem human tissues and animal models of multiple sclerosis.

Objective: Our study has used an ASIC1a selective peptide inhibitor ‘Hi1a’ in the Experimental autoimmune encephalomyelitis (EAE) model to understand the role of this target in the pathophysiology of MS, as well as to ascertain the potency of the peptide as a therapeutic for MS.
 

Methods: 10–12-week-old female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) to develop the experimental autoimmune encephalomyelitis model. Following onset of disease, mice were randomized to intraperitoneally receive either Hi1a (50ug/kg) or PBS and observed for disease progression and twice weekly on rotarod to assess motor deficits. Post-mortem tissues were analyzed for changes in ASIC1a expression, immune cell infiltration and neurodegeneration to compare after Hi1a treatment.
 

Results: Our data has shown that Hi1a is protective with significant improvement in symptoms such as motor deficits and paralysis. Post-mortem analysis of tissues shows marked decrease of immune cell infiltration and neurodegeneration, with immunohistochemistry of spinal cord tissues showing preservation of myelin and neuronal damage in treated vs untreated. Immune cell assays show decrease in monocytes and neutrophils and markers of inflammation post Hi1a treatment.

Conclusion: These findings will contribute to better understanding of the MS pathology and help in developing better potential therapeutics for clinical MS patients.  
 

Keywords: Multiple Sclerosis; neurodegeneration; Acid Sensing Ion Channels. 


Authors: Maleeha Waqar (1), Nemat Khan (1), Neville Butcher (1), Lachlan Rash (1) 

Author affiliations:
1. School of Biomedical Sciences, The University of Queensland. 

Role of the multidisciplinary MS team in supporting behaviour change among people with MS: A qualitative study of clinician perspectives.

Background: Healthcare professionals have an important duty to support the adoption of a brain-healthy lifestyle as an essential target for MS care. Therefore, clinicians need to consider addressing lifestyle behaviour change during routine consultations. Nonetheless, studies to date mainly focussed on the consumer perspective. 

Objective: To explore current practices of how MS speciality nurses and healthcare professionals support lifestyle behaviour change among people living with MS (plwMS) and the perspectives of their professional roles. 

Methods: This qualitative study recruited Australian MS healthcare professionals with experience seeing plwMS. Eligible clinicians underwent one online semi-structured interview between April and August 2023. An inductive, data-driven analysis using a realist research epistemology was undertaken before thematic categorisation of quotes from all transcripts. Data analysis was guided by the methods of Braun and Clark. 

Results: Ten MS nurses, five neurologists, one general practitioner and 20 allied health professionals were interviewed. Four primary themes emerged from the data: patient empowerment, provision of tailored support, multidisciplinary collaboration and navigators of the healthcare system. External pressures underpinning current practices/provision of advice included organisational factors, personal values, professional experience, scope of practice and patient readiness and self-efficacy. MS nurses appeared to be key drivers of behaviour change. 

Conclusion: Person-centred behaviour change coaching is becoming an integral role in professional scope of practice for MS care. However, results emphasise that a greater focus on clearer and consistent lifestyle messaging, between and across disciplines, is needed.  

 
Keywords: Brain health; lifestyle; holistic; management; behaviour change 
 

Authors: Olivia Wills (1), Anne McMahon (1), Yasmine Probst (1) 

Author affiliations:
1. School of Medical, Indigenous and Health Sciences, University of Wollongong, Wollongong NSW 2522, Australia. 

Towards new perspectives: A systematic scoping review to redefine brain health in multiple sclerosis.

Background: Brain health is a multidimensional concept and while consensus of a comprehensive definition is still debated, increasing interest has aligned with how lifestyle or behaviour change modifications, adjunct to pharmacologic intervention, can maximise lifelong brain health for people living with MS (plwMS). 

Objective: To map topics relevant to brain health for plwMS by creating a repository of definitions, brain-healthy lifestyle elements and measures of brain health, to challenge or inform the holistic management of MS. 

Methods: This systematic scoping review followed the methodological framework of the Joanna Briggs Institute and reported as per the PRISMA-ScR checklist. Eligible studies explored the concept of brain health or a brain-healthy lifestyle among plwMS. Quantitative analysis of study characteristics and frequencies of outcome measures were calculated, and content analysis was used to generate codes presented as key themes. Lifestyle elements of brain-health were graphically summarised. 

Results: Fifty-nine evidence sources (30 peer-reviewed, 29 grey literature) were eligible for inclusion. Of these, only 34 (58%) defined ‘brain health.’ The most common definition (n=18, 53%) encompassed a biomedical model of neurological reserve, a self-remodelling theory of functional reorganisation. Twenty-six types of brain health measures were identified, the most frequent being magnetic resonance imaging metrics (n=22, 85%). Physical activity was the most common lifestyle element to a brain-healthy lifestyle (n=36).  

Conclusion: Despite increasing interest in brain health, the evidence base remains in its infancy. In efforts for plwMS to adopt a brain-healthy lifestyle, an explicit definition encapsulating a biopsychosocial model of brain health may contribute to a greater understanding and consistent use of the term.  

Keywords: Brain health, definition, review, management  

Authors: Olivia Wills (1), Yasmine Probst (1) 

Author affiliations:
1. School of Medical, Indigenous and Health Sciences, University of Wollongong, Wollongong NSW 2522, Australia. 

An epigenetic signature is associated with Multiple Sclerosis independently of known genetic risk and is a more accurate classifier.

Background: DNA methylation is an epigenetic mechanism influenced by both genotype and environment, making it an important molecular interface to study disease etiology and progression. Methylation can be used as a biomarker for various diseases but is not yet used in MS. 

Objective: The objective of this study was to determine if epigenetic signatures can discriminate between people with  MS (pwMS) and controls independently of known MS genetic risk. 

Methods: Whole blood DNA from 208 people with MS and 401 controls was hybridized to Illumina EPIC arrays. We performed an epigenome-wide association study to identify differentially methylation probes between pwMS and non-MS controls, correcting for known MS risk genotype: HLA-DRB1*15:01 haplotype and a polygenic risk score (PRS) based on 202 known risk variants. We then constructed a Methylation Risk Score (MRS) to assess its discriminating power. 

Results: We identified an MRS for MS that occurs independently of known genetic risk loci and show this more strongly differentiates disease than known genetic risk loci. MRS (AUC=0.85, 95%CI: 0.82-0.89) vs PRS (AUC=0.72, 95%CI: 0.66-0.76).  Combining MRS , PRS and HLA-DRB1*15:01 haplotype marginally improved accuracy (AUC=0.87, 95%CI: 0.84-0.91) as did the addition of other covariates such as cell proportions, sex and age (AUC=0.89, 95%CI: 0.86-0.92). 

Conclusion: This study shows that an MRS, derived from epigenetic profiling, after correction for known genetic risk, outperforms a variant-based PRS when discriminating between MS and non-MS individuals. This provides evidence that dynamic/modifiable epigenetic factors play a larger role in MS onset than known genetic factors. 

Funding sources: Funding sources for this work include the National Health and Medical Research Council of Australia, MS Research Australia, and the National Multiple Sclerosis Society of the United States of America.  

Keywords: multiple sclerosis, methylation, HLA-DRB1*1501, classification, genetic risk 

Authors: Alexandre Xavier (1), Vicki E. Maltby (2,3), Ewoud Ewing (4), Maria Pia Campagna (5), Sean M. Burnard (1), Jesper N Tegner (6,7,8,9), Mark Slee (10), Helmut Butzkueven (5,11), Ingrid Kockum (4), Lara Kular (4), Ausimmune/AusLong Investigators Group, Vilija G. Jokubaitis (5), Trevor Kilpatrick (12), Lars Alfredsson (4), Maja Jagodic (4), Anne-Louise Ponsonby (12,13), Bruce Taylor (14), Rodney J. Scott (1,15), Rodney A. Lea (2,16), Jeannette Lechner-Scott (2,3) 

Author affiliations:
1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Hunter Medical Research Institute, Newcastle, NSW, Australia 
2. School of Medicine and Public Health, University of Newcastle, Hunter Medical Research Institute, Newcastle, NSW, Australia 
3. Department of Neurology, John Hunter Hospital, New Lambton Heights, NSW, Australia. 
4. Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, 171 76, Stockholm, Sweden 
5. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia 
6. Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia. 
7. Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia. 
8. Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, L8:05, SE-171 76, Stockholm, Sweden
9. Science for Life Laboratory, Tomtebodavagen 23A, SE-17165, Solna, Sweden 
10. College of Medicine and Public Health, Flinders University South Australia. 
11. Director, MSBase Foundation, Melbourne, Victoria, Australia 
12. Florey Institute of Neuroscience and Mental Health, The University of Melbourne; Melbourne, Victoria, Australia 
13. National Centre for Epidemiology and Public Health, Australian National University, Canberra, ACT, Australia 
14. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia 
15. Department of Molecular Genetics, Pathology North, John Hunter Hospital, New Lambton Heights, NSW, Australia 
16. Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Kelvin Grove, QLD, Australia. 

Genetically Modified Macrophages with NgR(310)ecto-Fc Expression: Enhanced Myelin Phagocytosis and Phenotypic Shifts.

Background: Macrophage and microglia play a pivotal role in myelin phagocytosis, ensuring timely debris clearance essential for remyelination during experimental autoimmune encephalomyelitis (EAE). Genetic modification might promote the phagocytic activities and affect macrophage activation dynamics. 
 

Objective: Examine whether macrophages expressing NgR(310)ecto-Fc improve the phagocytic efficiency of microglia towards myelin in vitro and elucidate the functional consequences of such phenotypic shifts 

Methods: Macrophages were genetically modified to express NgR(310)ecto-Fc. The efficiency of myelin engulfment was assessed in macrophages and microglia by flow cytometry, along with live imaging visualization. Underlying mechanism, particular Fc receptor (FcR)-associated endocytosis, were investigated by gene expression analysis of bulk RNA sequencing data.
 

Results: Activated genetically modified macrophages exhibited elevated engulfment of myelin fragments compared to control groups. Myelin uptake was facilitated through FcR-associated endocytosis, potentially inducing a phenotypic transition from a proinflammatory to an anti-inflammatory state hightented by the secretion of cytokine and chemokines. 
 

Conclusion: Macrophages expressing NgR(310)ecto-Fc demonstrated increased myelin phagocytosis efficiency, prompting beneficial phenotypic alterations. This finding unveils potential therapeutic prospects for addressing myelin debris clearance and ameliorating neuroinflammation. 

Keywords: Myelin fragments, Phagocytosis, NgR(310)ecto-Fc, Microglia, Genetic modification  

Demyelination reversibly alters dendritic spine morphology and dynamics in the mouse cortex.

Background: Myelination regulates glutamatergic and GABAergic neuron function.  As demyelination alters glutamate levels and action potential conduction it could significantly affect synaptic efficacy.   

Objective: To evaluate the impact of demyelination and remyelination on excitatory synapses and interneuron activity. 

Methods: We used Thy1-YFPH mice in which a subset of layer V pyramidal neurons express the yellow fluorescent protein (YFP).  P65 male and female Thy1-YFPH mice received normal chow (controls), 0.2% cuprizone for 5 weeks (demyelination), or 5 weeks cuprizone + 2 weeks normal chow (remyelination).  We performed immunohistochemistry and tissue imaging, as well as live two-photon imaging of the mouse cortex.

Results: Demyelination significantly increased the proportion of mature, mushroom spines and decreased the proportion of immature, thin spines on apical dendrites but did not change total dendritic spine density.  Demyelination increased the number of parvalbumin+ interneurons in layers IV (input layer) and V (output layer) of the parietal cortex, suggesting they are more active.  Remyelination reversed these changes.  Acute demyelination also increased the rate of dendritic spine turnover in vivo. 

Conclusions: Demyelination rapidly alters cortical circuitry in a way that could make neurons more responsive to glutamate and vulnerable to excitotoxic injury.  As this effect is “reversed” by remyelination, our data support the need for early remyelinating therapies for people with multiple sclerosis.   

Keywords: Demyelination, remyelination, synapses, glutamate, interneurons 

Self-efficacy of people living with multiple sclerosis enrolled in an online multimodal lifestyle course: cross-sectional associations with lifestyle behaviours.

Background: Self-efficacy, that is, a person’s belief in their capacity to execute behaviours required to achieve specific goals, is strongly linked with self-management and behaviour change. As such, we developed an online intervention course [Multiple Sclerosis Online Course (MSOC)] to facilitate self-efficacy and effect lifestyle behaviour change in people with MS (pwMS). 

Objectives: We performed a randomised controlled trial (RCT) to examine the effectiveness of the MSOC on modifiable lifestyle factors in improving self-efficacy and health outcomes in pwMS. We examined cross-sectional associations between participants’ lifestyle behaviours and self-efficacy at baseline, and mediation effects of fatigue and depression. 

Methods: RCT participants completed a self-reported online survey at baseline. Lifestyle behaviours measured included diet quality (Diet Habits Questionnaire), physical activity (International Physical activity Questionnaire), vitamin D and omega-3 supplementation, smoking, and meditation practice. Self-efficacy was measured by the MS-validated University of Washington Self-Efficacy Scale. We performed multivariable regression to examine associations between individual lifestyle behaviours and self-efficacy, and examined whether depression, and fatigue mediated these associations.

Results: Amongst 665 RCT participants, higher diet quality, vitamin D supplementation, and greater physical activity were associated with higher self-efficacy at baseline. After adjusting for other lifestyle behaviours, physical activity was the only lifestyle behaviour independently associated with greater self-efficacy (aβ=2.00, 95%: CI 0.12, 3.17). Moreover, the relationship between physical activity and self-efficacy was mediated by fatigue (indirect effect: aβ=0.22 [95%CI: 0.15, 0.28) and depression (indirect effect: aβ=0.18 [95%CI: 0.12, 0.25).  

Conclusions: Physical activity was independently associated with self-efficacy at baseline, with fatigue and depression mediating this association. These findings help increase our understanding of the relationship between physical activity and self-efficacy, which in turn may help develop strategies to promote self-efficacy in pwMS.  

Key words: Self-efficacy, lifestyle behaviours, physical activity, health outcomes, digital health education 

Trial registration: This trial was registered prospectively with the Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, identifier ACTRN12621001605886 Date of registration: 25 November 2021. 

Authors: Maggie Yu (1), Sandra Neate (1), William Bevens (1), Rebekah A. Davenport (2), Steve Simpson-Yap (1,3,4), George Jelinek (1), Nupur Nag (1), Jeanette Reece (1) 

Author affiliations: 
1. Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia 
2. Melbourne School of Psychological Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, VIC, Australia 
3. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia 
4.CORe, School of Medicine, The University of Melbourne, Melbourne, VIC, Australia 

Long-term disability trajectories in multiple sclerosis: a group-based trajectory analysis of the AusLong cohort.

Background: Previous natural history studies highlighted a consistent heterogeneity of disability trajectories among patients with primary or secondary progressive multiple sclerosis (MS). However, evidence on disability progression in relapsing onset MS (ROMS) is scarce.  

Objective: To investigate heterogeneity in disability accumulation over 10 years following a first clinical diagnosis of CNS demyelination (FCD) and identify clinical and demographic factors associated with these trajectories.  
 

Methods: We used group-based trajectory models (GBTM) to identify distinct trajectories of Longitudinal Expanded Disability Status Scale (EDSS) scores in a prospectively assessed cohort of 263 participants. Factors associated with trajectory membership were explored using generalized linear models. 

Results: We identified three distinct clinically meaningful disability trajectories: no or mild (minimal), moderate, and severe in the FCD cohort (n=263). For the ROMS subgroup (n=201), we identified a very similar pattern of three distinct disability trajectories: no/minimal (minimal) (20.1%; 95% CI: 12.0-28.2), moderate (65.3%; 95% CI: 56.5-74.0)  and severe (14.5%; 95%CI: 8.7-20.3) disability. Those in the minimal disability trajectory showed no appreciable progression of disability (median EDSS ~ 1 at 10-year review), while those in the moderate and severe disability trajectories experienced disability worsening (median 10-year EDSS~ 2.5 and 6, respectively). Number of relapses within the first five-years post-FCD, having a shorter interval between the first two attacks of MS, having a higher body mass index, were consistently associated with a higher likelihood of being in a severe disability trajectory compared with minimal and moderate groups.  

Conclusion: Utilising the GBTM in our FCD cohort allowed us to identify heterogeneities in prognosis from the onset of disease. Those at higher risk of faster MS disability progression can be identified based on their early clinical characteristics with potential therapeutic implications for early intervention and escalation of MS treatments. 

Keywords: Multiple sclerosis, longitudinal studies, risk factors, disease progression, disability 

Authors: Amin Zarghami (1*), Mohammad Akhtar Hussain (1), Ingrid van der Mei (1), Anne-Louise Ponsonby (2,3), Simon Broadley (4), Steve Simpson-Yap (1,5), Yuan Zhou (1), Ausimmune/AusLong Investigator Group, Bruce V. Taylor (1) 
 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 
2. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia. 
3. Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Australia. 
4. Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. 
5. Melbourne School of Population and Global Health, The University of Melbourne, Australia. 

The disease modifying therapy utilisation and costs trends for multiple sclerosis in Australia from 2013 to 2022.

Background: Disease modifying therapies (DMTs) are commonly used to reduce the rate of relapses and disease progression in people with multiple sclerosis (MS). The MS DMT prescribing landscape in Australia has substantially changed over time due to changes in reimbursement policy, particularly in the last decade. 

Objectives: This study evaluated the utilisation and cost trends of MS-related DMTs in Australia in the last 10 years and investigated the differences between Australian States/Territories.  

Methods: The prescription and costs of 16 DMTs were extracted from the Pharmaceutical Benefits Scheme Reports for 01.2013-12.2022. DMTs were categorised into three groups: G1-classical injectables; G2-moderate efficacy; and G3-higher efficacy. Descriptive approaches were used to analyse the total numbers of DMT prescriptions/costs per 10,000 population and proportions of prescriptions/costs by DMT subgroups over the 10 years period. All estimates were produced for Australia and stratified by States/Territories. 

Results: DMT prescription/costs recorded significant growth between 2013 and 2022: 125%/197% for Australia, and 94%–251%/129%–373% for the Australian States/Territories. G3 accounted for 54% of total prescriptions in 2013 and 75% in 2022. Fingolimod was the most popular DMT until 2020, which was then dominated by Ocrelizumab. The trends of individual DMT prescriptions and costs were similar in ACT, NSW, Victoria, Queensland and SA, but differed in WA, Tasmania, and NT. 
 

Conclusions: MS-related DMT prescription and costs continuously increased over the last decade, particularly for G3 DMTs. The trends of DMT prescriptions and costs differed between some States/Territories. Understanding the drivers of such differences may help to standardise the use of DMTs across Australia. 

Keywords: Multiple sclerosis, DMTs, PBS prescriptions/costs 
 

Authors: Ting Zhao (1), Bruce Taylor (1), Julie Campbell (1), Andrew J Palmer (1) 

Author affiliations:  
1. Menzies Institute for Medical Research, University of Tasmania, Medical Sciences 2. Precinct, 17 Liverpool Street, Hobart, Tasmania, Australia 7000 

Updated health economics simulation model of the lifetime progression of multiple sclerosis in an Australian setting.

Background: Multiple sclerosis (MS) is a progressive disease leading to increasing disability over time, with subsequent profound human and economic consequences. Our previous MS simulation model relied on transition probability data from a relatively small cohort (n=330) necessitating simplified approaches. 
 

Objective: We sought to improve our existing model by incorporating more granular disease states, improving the accuracy of input data based on a large MS cohort (n=6,360), and including contemporary transition probabilities, cost and health state utility (HSU) inputs that match the more granular health states. 

Methods: A four-state Markov model simulated MS progression from no disability to mild, moderate and severe disability and death.  Costs, HSUs and transition probabilities were defined by distributions, allowing second order Monte Carlo simulation. State-specific probabilities, costs, HSUs, and relapse rates/disutilities were considered. Life expectancy (LE), quality-adjusted life years (QALYs) and lifetime total (direct+indirect) costs were calculated and compared with Australian norms. Costs and QALYs were discounted at 5% annually. 

Results: A typical MS cohort of females aged 35 years had: future LE of 43.7 years (95%CI: 43.5-43.9), 10.4 QALYs (7.6-12.9); and lifetime costs (AUD 2021 values) $1,263,875 ($1,183,486-$1,345,598), respectively. Compared with the Australian general population, people with MS had 6.3 years lower LE, 3.5 less QALYs, and $1.1M higher costs. Compared with our previous model, LE and costs were higher, while QALYs were lower for a variety of reasons. 

Conclusions: Our more detailed model with updated cost, HSU and probability inputs from a much larger cohort allows nuanced and contemporary evaluations of the impacts of MS on lifetime disease outcomes and costs. It will be used for cost-effectiveness analyses of current and future MS interventions. 

Keywords: Health economics, microsimulation model, lifetime costs, life expectancy, quality adjusted life years, multiple sclerosis  

Characterizing up to 2 years of ofatumumab onboarding and utilization among real-world relapsing multiple sclerosis patients in Australia - EAFToS

Background: 
Ofatumumab is approved in Australia for the treatment of adults with relapsing forms of multiple sclerosis (RMS). This Real-World Evidence study will analyze the onboarding data and identify the ofatumumab patient profile, through secondary use of data (SUD) from integrated digital patient support program MSGo.

Objective: The primary objective is to characterize the onboarding experience and utilization of ofatumumab in RMS patients in Australia. Secondary objectives are to describe the profile of patients initiating ofatumumab, evaluate patient demographics and prior therapy. 

Methods: Retrospective and longitudinal SUD analyses were conducted on data in the MSGo patient digital support program. The primary endpoint was proportion of doses not completed within 3 days of the expected date during initiation and during the first 3 months of maintenance. Key secondary endpoints will assess the patient demographics, prior therapy and whether the treatment administrator influences compliance to treatment. 

Results: Data from 567 de-identified patients were analysed. 25% were treatment naive, 93% self-administered and 9.5% discontinued. 97.6% of patients were adherent during initiation. The proportion of adherent doses during maintenance doses 2 and 3 was 95.6% and 96.9% respectively. Compliance remained high over duration of treatment with 97.7% and 94.1% of the patients remaining at least 80% or 90% compliant to ofatumumab, respectively. 

Conclusion: Ofatumumab patients had high adherence during the first 3 months of treatment and maintained high compliance throughout duration of treatment. Exclusive use of data from MSGo is a novel approach for understanding quality use of medicines in the real world.

Authors: Gina Drake5, Anneke Van der Walt1, Simon Broadley2, Jason Burton3, Todd Hardy4, Clare Kemp5, Rob Walker5, Patricia Berry5, Kate Martel5, Lien Lam5, Morag Nelson5

Addresses: (1) Monash University, Department of Neuroscience, Central Clinical School, Melbourne, Australia, (2) Griffith University, School of Medicine, Gold Coast Campus, Southport, Australia, (3) Nexus Neurology, Murdoch, Australia, (4) Concord Hospital, University of Sydney, Sydney, Australia, (5) Novartis Pharmaceuticals Australia, Sydney, Australia

Keywords: Ofatumumab, Real World Evidence, Clinical Outcomes, Disease modifying therapy, High Efficacy Treatment

Funding Source: Study was funded by Novartis Australia

Disclosures:

Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck and receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.

Simon Broadley has accepted honoraria for attendance at advisory boards, speaker fees and sponsorship to attend scientific meetings from Novartis, Biogen-Idec, Sanofi-Genzyme, Roche, Bayer- Schering, Teva, CSL and Merck Serono and has been a principal investigator for clinical trials sponsored by Biogen-Idec, Novartis, Sanofi-Genzyme and ATARA.

Jason Burton has received speaker honoraria, scientific advisory board fees from Bayer, Biogen-Idec, Novartis, Sanofi-Aventis, Merck, Merck, Sanofi-Genzyme and Roche.

Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Bayer, Biogen, Merck, Teva, Novartis, Roche, Bristol Myers Squibb and Sanofi-Genzyme.

Clare Kemp, Rob Walker, Patricia Berry, Kate Martel, Lien Lam, Gina Drake and Morag Nelson are employees of Novartis Pharmaceuticals Australia.

Employing Novel Indirect Treatment Comparison Methodologies to Differentiate the Efficacy of Ofatumumab versus Orally Administered Therapies for Relapsing Multiple Sclerosis

Background: Emerging evidence challenges whether oral disease modifying therapies (DMTs) achieve similar efficacy to high efficacy therapies (HETs) for relapsing multiple sclerosis (RMS). Without head-to-head randomised controlled trials (RCT), indirect treatment comparisons (ITCs) can be used to estimate relative efficacy between HETs and oral DMT’s. 

Objective: To differentiate HETs from oral therapies based on efficacy measures (annualised relapse rate (ARR), 3 and 6 month confirmed disease progression (3mCDP) (6mCDP)) using different ITC approaches including propensity score (PS) analyses, simulated treatment comparisons (STCs) and network meta-analysis (NMA)

Methods: PS analyses were conducted to compare ofatumumab to fingolimod using inverse probability of treatment weighting to balance the trial populations for both therapies. Unanchored STCs were conducted to compare ofatumumab to each of the oral treatments (cladribine, fingolimod, ozanimod) by fitting a regression model for outcomes of interest. A NMA was also conducted to broadly compare the efficacy of DMTs for RMS, including HETs and oral therapies. 

Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod, and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. 

Conclusion: PS and STC analyses support the therapeutic superiority of ofatumumab over oral therapies with respect to reducing relapses and delaying disease progression. These findings were largely consistent with recently published NMAs that demonstrated mAb therapies to be the most efficacious DMTs for RMS.

Keywords: Ofatumumab, Indirect Treatment Comparison, Health Economics, Disease Modifying Therapy, Relapsing MS 

Authors: Helmut Butzkueven (1), Anja Haltner (2), Chris Drudge (3), Imtiaz Samjoo (3), Michael Barnett (4,5), Simon Broadley (6), Pamela Mccombe (7), Anneke Van der Walt (1), Dee Stoneman (8), Martin Merschhemke (8), Nicholas Adlard (8), Morag Nelson (9), Nicholas Riley (9), Rob Walker (9)

(1) Central Clinical School, Monash University, Department of Neuroscience, Melbourne, Australia, (2) Eversana, Chicago, United States, (3) Eversana, Burlington, Canada, (4) University of Sydney, Brain and Mind Centre, Camperdown, Australia, (5) Royal Prince Alfred Hospital, Camperdown, Australia, (6) Griffith University, School of Medicine, Gold Coast Campus, Southport, Australia, (7) University of Queensland, St Lucia, Australia, (8) Novartis Pharma AG, Basel, Switzerland, (9) Novartis Pharmaceuticals Australia, Sydney, Australia

Funding Source: Study was funded by Novartis Australia

Disclosures:

Helmut Butzkueven institution receives compensation for Advisory Board, Steering Committee and Educational activities from Biogen, Roche, Merck, and Novartis. His institution receives research support from Roche, Novartis, Biogen, NHMRC and MRFF Australia, MS Research Australia. He receives personal compensation from Oxford HPF for serving on the steering group of MS Brain Health.

Anja Haltner, Christopher Drudge, and Imtiaz A Samjoo are employees of EVERSANA™. EVERSANA receives consultancy fees from pharmaceutical and device companies, including Novartis.

Michael Barnett reports research grants from Genzyme-Sanofi, Novartis, Biogen, and Merck outside the submitted work and is a co-founder of RxMx and Research Director for the Sydney Neuroimaging Analysis Centre. 

Simon Broadley has accepted honoraria for attendance at advisory boards, speaker fees and sponsorship to attend scientific meetings from Novartis, Biogen-Idec, Sanofi-Genzyme, Roche, Bayer-Schering, Teva, CSL and Merck Serono and has been a principle investigator for clinical trials sponsored by Biogen-Idec, Novartis, Sanofi-Genzyme and ATARA. 

Pamela McCombe has received sponsorship from Novartis, Teva, Sanofi and Biogen 

Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck and receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.

Dee Stoneman, Martin Merschhemk and Nicholas Adlard are employees of Novartis Pharma AG.

Robert Walker, Nicholas Riley and Morag Nelson are employees of Novartis Pharmaceuticals Australia.