Explore 2020 Research

Defining the burden of disease for JIA in WA - a longitudinal population-based cohort study.
Funded by: Australian Rheumatology Association (ARA)
Recipient: Prof Johannes C Nossent
Intended Department University of WA- Sir Charles Gairdner Hospital
Project: Defining the burden of disease for JIA in WA – a longitudinal population-based cohort study.

Since receiving the Arthritis Australia Project Grant in 2021 to study the epidemiological characteristics of Juvenile Arthritis in Western Australia we have undertaken a number of research activities.

Firstly, we utilised the Western Australian Rheumatic Disease Epidemiological Registry (WARDER) to identify unique patients aged 15 years and younger with a (first) hospital admission for JIA between 1990 and 2012 to produce measures of JIA hospitalisation rates and admission characteristics (ie for joint injection, infections or disease activity) for that period. Secondly, we used these data to estimate a minimum (ie hospital based) prevalence of JIA in WA. Thirdly we used WA specific PBS prescription data for the TNF inhibiting drugs Enbrel and Adalimumab to quantify the number of JIA patients requiring treatment with TNFi biologicals (the newest disease modifying drugs) in WA since 2003. Fourthly, data on JIA outcomes (need for repeat admissions, joint surgery, mortality and development of comorbid conditions such as diabetes or kidney disease) are currently being extracted/cleaned/analysed. Finally, we have also started the process of data acquisition from another WA health data source to study the association between maternal pregnancy and early life risk factors and JIA development. Results so far are that we have identified 786 unique cases of JIA in WA hospital records with an average age at index hospitalization of 7.6 (±4.4) years, the majority of which were girls (n=465, 59.2%) with 18% % of patients from rural regions and 6.1% (n=48) identified as Aboriginal. JIA was the primary diagnosis in 90.2% (n=709) with approximately 45 % of these admissions required for joint injections. The average annual hospitalisation rate for JIA patients was 7.9 per 100,000 with the rate for boys (6.3) approximately half of the rate in girls 11.2) per 100,000. Surprisingly and despite the advances made in treating JIA since 2000, the JIA admission rate did not change significantly over the study period (annual percentage change (APC): 1.3, p=0.10). Based on these admission data, the average prevalence of JIA over the study period overall was 59.9 per 100,000 children with the rate in girls (89.4) twice the rate in boys (44.5).The prevalence of JIA at the end of the study period was 72.7 overall (52.9 in boys and 114.5 per 100,000 in girls). Data from the PBS database for TNFi use in WA indicated that the use of Enbrel/Adalimumab for JIA increased almost linearly from 2003 and based on the WHO definition of daily dose per 1000 population per day (DDD) TNFi usage reached 0.37 in 2012, indicating TNFi usage by 1 in 2700 children. When combined with the minimum prevalence data form hospital admission this indicates TNFi use by at least 1 in 3 children with JIA.These findings will be presented at national and international scientific meetings in 2022 and a scientific paper is currently being written. With the bulk of the other data collection has been completed, we are aiming to write two more papers on JIA risk factors and outcomes over the next 6 months.

What questions did the grant set out to answer? What problems did you try to solve, or gaps in knowledge did you try to fill? Why is this important?
This grant was to investigate disease characteristics, potential triggers and long-term consequences for children registered with JIA in the Western Australia Rheumatic Disease Epidemiology Registry over the period 1980-2015. The main reasoning behind this is the very limited Australian data available for these areas with our knowledge mainly extrapolated from overseas studies. Having Australia specific data will allow for better insight and planning of JIA service in (Western) Australia. Particular outcomes of interest for this longitudinal observational cohort were to fill in gaps in our knowledge about the disease prevalence as well as the rates and reasons for hospital admission for JIA and potential changes over time given 2 advances in disease management. services for children with JIA. More specifically, we aim to provide specific data on the rate of joint injections, joint surgery, serious infections, pregnancy frequency and outcomes, cancer development, mental health problems, mortality and direct health care costs seen with JIA. While our research is descriptive and epidemiological in nature, this will provide important Australian first data.

What did you discover during the course of the grant?
1) The minimum prevalence of JIA in Western Australia is 0.12% for girls and 0.05% for boys. While this aligns with data from other countries, it is lower than reported in a study of school children in Perth (0.4%) and Belgium (0.16%).
2) Despite the significant use of biological therapy (at least 1 in 3) by JIA patients, the rate of first hospital admissions for JIA has not decreased since. The reasons behind this discrepancy require further study.
3) Preliminary data suggest that history of rheumatic disease in first degree family members and early life infection are risk factors for JIA development.

Have the findings of the research already benefitted people with musculoskeletal disease? How might the findings inform further research to help sufferers in the future?
Given that our findings are descriptive and epidemiological we have filled a number of knowledge gaps in scientific literature for the Australian setting of JIA. This will benefit patients over time as it can serve to underwrite further research into the clinical, serological and/or laboratory-based aspects of the disease.

Are you planning to continue the research? 
The grant was used to support a part time Research Associate for collection/extraction and cleaning of WARDER data to obtain a full dataset of longitudinal health data for JIA patients. We now have a fully functional JIA database from which the first results are being produced (posters, presentations, draft manuscript). We will continue investigating a range of health outcomes for patients with JIA in Western Australia and expect this research expected to produce at least 3 more manuscripts on various health outcomes for patients with JIA over a 2-year period.

Effect of self-monitoring urate levels of adherence to allopurinol with people with gout.
Funded by: Australian Rheumatology Association (ARA)
Recipient: Prof Richard Day
Intended Department Department of Clinical Pharmacology & Toxicology- St Vincent’s Hospital
Project: Effect of self-monitoring urate levels of adherence to allopurinol with people with gout.

 

Using the Arthritis Australia 2021 National Research Program Grant, our research study is examining why people with gout do not take their allopurinol as prescribed by their doctor, as well as investigating novel methods of improving allopurinol medication-taking behaviour.

Gout is caused by elevated urate concentrations in the blood, and allopurinol helps to control gout by reducing the production of urate. An increase in urate concentrations in the blood results in a build-up of urate in the joints, triggering painful gout flares. Consistently taking allopurinol prevents this build-up from happening by keeping urate concentrations below a target (<0.36 mmol/L), and therefore reduces the occurance of painful gout flares. Allopurinol is a safe and effective medication; however, many people with gout struggle to take their allopurinol every day. This leads to poor patient outcomes in the gout community.

Our study consists of two phases. Phase 1 is observational, whereby people with gout are provided a self-testing device to measure their urate concentrations for 12 months. The device is similar to glucose meters used by people with diabetes. The study explores how empowering pa-]tients to track their own urate concentrations influences the way they take their allopurinol. We are also evaluating how the collection of their own urate concentrations can help facilitate discus-sions with their doctor regarding their gout management, specifically allopurinol dosing decisions. Phase 2 consists of semi-structured interviews with people with gout, including people who are either currently or previously prescribed allopurinol. This aims to learn more about the lived experiences of people with gout, including what factors influence their allopurinol taking behaviour. Both Phases recruited people with gout across Australia, including in rural and remote regions. This is the first time that self-testing devices have been used by people with gout to monitor their urate concentrations as a way to improve their medication-taking behaviour.

For Phase 1, we have recruited 32 people with gout. Only one participant has withdrawn, due to conflicting time commitments. Most participants are male (93.8%), with half living in metropolitan areas (53.1%). Most participants are approaching the 9-month milestone with three more months until their exit interview is conducted. To date, the average adherence rate is 85.5% (95% CI 76.4,91.6), with urate concentrations decreasing on average by 0.17 mmol/L (95% CI 0.15, 0.20). Most participants now have urate concentrations within the target range (0.33 mmol/L, 95% CI 0.31,0.35). Additionally, in response to sharing the urate concentration data obtained with the de-vice with their general practitioner, four participants have had their dose of allopurinol increased. The exit interview will further explore patient perspectives on using the self-testing device to manage their gout over the year.

Phase 2 is complete, with 26 participants interviewed. Participants were mainly male (92.3%), over 60 years old (53.8%), living in metropolitan areas (65.4%), who had gout for over 10 years (88.5%), and have never seen a rheumatologist/gout specialist (80.8%). These interviews identified that doc-tor-patient relationships, an accurate understanding of how allopurinol works, and gout flare experiences influence the gout medication taking behaviour of people with gout.

Phase 2 results have been submitted to a peer-reviewed journal as an invited publication.

Gout is the most common inflammatory arthritis in men, affecting up to 6.8% of Australians.1

Owing to its substantial prevalence, gout represents a significant musculoskeletal disease burden, with the cost of gout to the Australian healthcare is $202 million per year which is 1.5% of total musculoskeletal disease expenditure.2 Given how effective allopurinol is in eliminating the cause of gout (elevated urate concentrations), improving how people with gout take allopurinol represents an achievable means of reducing musculoskeletal disease burden in Australia. This research into patient-led models of care to manage gout informs the design of health services to better manage gout. The ability to self-monitor urate concentrations has improved our participant’s gout health literacy, facilitated discussions with their primary healthcare team to optimise their gout medications, improved their urate control and reduced the frequency of gout flares. In light of the impressive improvements in gout control with this patient-led model-of-care, findings from this research provided the pilot data for a recent MRFF application designed to rollout this service in rural and remote regions of NSW and VIC. Arthritis Australia was also a partner in this MRFF application. The funding outcome will be known in May, 2022.

1. Pisaniello HL, Lester S, Gonzalez-Chica D, Stocks N, Longo M, et al. Gout prevalence and predictors of urate-lowering therapy use: results from a population-based study. Arthritis Res. Ther. 2018;20(1):143.

2. AIHW 2019b. Disease expenditure in Australia. Cat. no. HWE 76. Canberra: AIHW. Viewed 12 April 2022.

A novel regenerative therapy for treating Osteoarthritis
Funded by: Suzette Gately
Recipient: Dr Jiao Jiao Li
Intended Department Kolling Institute, Faculty of Medicine and Health, University of Sydney
Project: A novel regenerative therapy for treating Osteoarthritis

 

Osteoarthritis is a leading cause of chronic pain and disability, and the most common musculoskeletal reason for hospitalisation in Australia. There is no cure for this disease. A range of non-surgical treatments are used clinically, but only to manage symptoms until joint deterioration proceeds to the extent that a total joint replacement surgery is needed. However, the surgery brings increased risk of complications, and the implant usually last for less than 20 years. An alternative therapy that can provide a cure is urgently needed.

Mesenchymal stem cells have recently brought new hope for treating osteoarthritis. They are a type of stem cell that can be found in the adult bone marrow, which can produce many types of beneficial factors that reduce inflammation and promote the ability of damaged tissues to self-repair. However, direct injection of mesenchymal stem cells into osteoarthritic joints in early-stage clinical trials have not shown consistent benefits or any ability to ‘cure’ osteoarthritis. Our preliminary investigations suggested that mesenchymal stem cells can ‘respond’ to a diseased environment, essentially adopting the diseased state of surrounding joint structures when injected into an osteoarthritic joint, and losing their ability to produce beneficial factors.

To solve this problem, in this project we set out to grow mesenchymal stem cells in the laboratory and extract the beneficial factors they secrete, which are housed in nanoscale particles called ‘extracellular vesicles’. We created different types of conditions for the mesenchymal stem cells to produce these extracellular vesicles and tested them in an experimental model of a human osteoarthritic joint. We found that when mesenchymal stem cells were grown under different types of conditions, their extracellular vesicles had different types of therapeutic benefits on human osteoarthritic cells. These exciting findings have broad implications on our path to developing a new, effective, and off-the-shelf solution for treating osteoarthritis.

Research questions answered and their importance
Our team’s survey of the literature indicates that the current international landscape of using extracellular vesicles derived from stem cells as a treatment for osteoarthritis is limited to less than 20 studies, all in experimental models (cells or small animals) of osteoarthritis. Importantly, all existing studies in this space are limited by a critical challenge: the extracellular vesicles were generated from stem cells grown under randomly selected conditions, and the effects of changing the culture environment of stem cells on the therapeutic efficacy of the resultant extracellular vesicles have never been investigated. Currently, these non-optimal stem cell-derived extracellular vesicles need to be injected at high concentration and frequency in experimental animals to demonstrate a beneficial effect on osteoarthritis, on the order of 100 μg of extracellular vesicles weekly or several times weekly in mice. Putting this in context for human therapy, we need to use 60 million stem cells to produce enough extracellular vesicles for a single injection in the human knee joint. This is nowhere near viable for clinical application. This project set out to test whether growing the stem cells in different culture conditions might improve the therapeutic benefits of their extracellular vesicles on osteoarthritic cells, to essentially ‘optimise’ the production of extracellular vesicles from stem cells and increase their potential of being used in the future as a clinically viable therapy.

Findings of the study
The key finding from our pilot study was that when different groups of extracellular vesicles derived from mesenchymal stem cells were applied to human osteoarthritic cells, each group of extracellular vesicles had different effects on the osteoarthritic cells. The nature of the effects depended on the culture environment of the mesenchymal stem cells. For instance, extracellular vesicles from mesenchymal stem cells grown in an environment that encouraged cell survival induced anti-inflammatory behaviour in osteoarthritic cells. In contrast, extracellular vesicles from mesenchymal stem cells grown in an environment that encouraged cartilage formation induced osteoarthritic cells to produce signals relevant to cartilage repair. These were very exciting results suggesting that this line of research would potentially not only allow us to produce extracellular vesicles from stem cells that had improved therapeutic benefits on osteoarthritic cells, but also to tailor the culture environment of stem cells so we can produce extracellular vesicles with specific and possibly
personalised functions
.

During the course of the project, we also made a number of methodological advances. First, we were able to formulate our own in-house culture medium for growing mesenchymal stem cells, which removed our reliance on commercial culture medium. Second, we optimised the method of isolating extracellular vesicles from the culture medium that has been used to grow mesenchymal stem cells, and we can now produce the extracellular vesicles as purified preparations. Third, we found that the biological activity of extracellular vesicles does not diminish after freezing and thawing, which enables their potential future application as an off-the-shelf therapy. All of these findings have important implications in our further work along this line of research, towards developing a new regenerative therapy for osteoarthritis from stem cell-derived extracellular vesicles.

Implications for further research
I presented the project idea and a snapshot of our preliminary findings as part of an invited National Science Week talk “Regenerate and Cure” in 2021. This virtual seminar attracted >50 audience members from across Australia and internationally, many of whom were patients with osteoarthritis or their family members. Although this new therapy will not be immediately available, understanding the drawbacks of current clinical therapies including stem cell injections for osteoarthritis, and seeing hope that there is a promising therapy in development on the horizon, spiked immense interest in the audience and great community engagement. The results from our pilot study provide a pioneering finding in the field that the key to producing efficacious and clinically viable treatment for osteoarthritis perhaps lies in optimising the production of stem cell-derived extracellular vesicles. With further research to test a wider range of conditions for growing stem cells, performing detailed analyses to understand the molecular mechanisms underlying their therapeutic benefits, and testing them in experimental animals with osteoarthritis, we will understand more about the properties of stem cell-derived extracellular vesicles and be able to build them towards a possibly curative clinical therapy for osteoarthritis.

Future directions
Thanks to this pilot project, I have convened an extensive project team consisting of researchers in basic science (across cell and molecular biology, materials science, nanotechnology, and data science),clinicians, and an industry partner to carry our idea forward. This pilot project has built up essential preliminary data to allow us to proceed with nationally competitive grant applications, as well as partnership with industry, to performed more detailed analyses as well as to set up a therapeutic development platform. Pitching the idea underlying our research, I was the national winner of Falling Walls Lab Australia 2021. I am excited to be leading a multidisciplinary team to carry this research forward, with the hope of bringing a cure for patients with osteoarthritis in the future.

Gait Retraining for reducing pain in people with medial knee osteoarthritis
Funded by: Arthritis WA
Recipient: Laura Hutchison
Intended Department Faculty of Medicine and Health, The University of Sydney
Project: Gait Retraining for reducing pain in people with medial knee osteoarthritis

 

My research project aimed to determine whether gait retraining (changing the participants regular walking pattern) reduces knee pain and the forces inside the knee during walking in people with knee osteoarthritis. Unfortunately, our clinical trial was impacted by the relocation of the Sydney Biomechanics Laboratory and COVID-19. After our new laboratory was installed, we enrolled nine participants into our clinical trial before COVID-19 lockdowns prevented further face-to-face therapy sessions. We ran telehealth sessions with participants already enrolled, however, were unable to enrol new participants into the study as an initial face to face assessment was required. Our original trial has therefore become a pilot trial, which will provide preliminary evidence to inform a larger study commencing shortly.

As we were unable to run our study as planned in 2021, we further refined our upcoming clinical trial protocol based on emerging research. I have also been able to focus on other chapters of my PhD thesis, including the introduction, conducting a systematic review and meta-analysis, finalisation of a pilot study testing a new gait retraining intervention, and write up of our randomised controlled trial protocol manuscript. I have also been able to collaborate with other student research projects in closely related areas and have presented our research at an international conference.

What questions did the grant set out to answer? What problems did you try to solve, or gaps in knowledge did you try to fill? Why is this important?

An aspect of my thesis I could work on in 2021 was a systematic review and meta-analysis (a large, systematic analysis of existing literature) on the relationship between knee biomechanics (the way the knee moves and forces it experiences during walking) and knee pain in people with knee osteoarthritis. This is important as pain is often the motivating factor for people with knee osteoarthritis to seek health care, and various biomechanical devices, such as braces, foot orthoses and footwear are used as part of clinical management. However, the relationship between knee biomechanics and pain in people with knee osteoarthritis is unknown with conflicting findings reported in the literature.

I also worked on another systematic review and meta-analysis with a student colleague, which is now published. This study investigated the association between biomechanics during gait with the disease onset and progression of lower limb osteoarthritis. As osteoarthritis has no cure, research is focussing on strategies to slow or stop disease progression, which has potential to delay or prevent costly joint replacement surgeries. Some knee biomechanics are potentially modifiable using devices such as braces, or gait retraining. It may be that by changing knee biomechanics, the disease course of osteoarthritis could be changed.

We also developed and piloted a new gait retraining strategy to be included in our clinical trial that is commencing shortly.

What did you discover during the course of the grant?

Our systematic review and meta-analysis on the relationship between knee biomechanics and pain found that people with varus thrust presence (an abrupt outwards “thrust” of the knee during walking) are almost four times as likely to experience pain compared to people without varus thrust. This indicates that in people with knee osteoarthritis, varus thrust should be screened for early in clinical assessment. We also found that the relationship between the load on the inside of the knee during walking and pain varies depending on body mass index (BMI). Therefore, it is important for researchers and clinicians to consider the impact of BMI when using certain interventions that target knee load. I presented these findings recently at an international conference (Osteoarthritis Research Society International 2022 World Congress) and our paper is currently under peer-review.

The systematic review and meta-analysis on the association between biomechanics and the disease onset and progression of lower limb osteoarthritis found that certain gait biomechanics are associated with increased odds of osteoarthritis onset and progression in the knee, and progression in the hip. In particular, there was almost two times increased odds of medial knee osteoarthritis disease progression if participants had varus thrust presence, or higher load on the inside of the knee at baseline. This study was presented at the Congress of the International Society of Biomechanics in 2021 and published in Osteoarthritis and Cartilage.

Have the findings of the research already benefitted people with musculoskeletal disease?

Although we only had nine people enrolled in our pilot study conducted in 2021, we have received positive feedback from participants regarding the study. Participants average knee pain intensity scores for walking over the past 48 hours reduced by an average of 23 points on a 101-point scale (0 = no pain, 100 = worse pain imaginable) (average 42% pain improvement) at short-term (approximately six weeks) follow-up, and 27 points (average 50% improvement) at long-term (approximately six months) follow-up. Additionally, as we have published and presented our systematic review and meta-analysis findings at international conferences, clinicians and researchers worldwide may be more aware of biomechanical factors to screen for that are associated with pain and disease progression in people with knee osteoarthritis.

How might the findings inform further research to help sufferers in the future?

Both systematic reviews highlighted the importance of varus thrust as a biomechanical factor of interest in knee osteoarthritis as it is associated with both pain and disease progression. This finding is significant, as varus thrust can be screened for and potentially modified in the clinical setting. However, currently, there is minimal research addressing varus thrust presence clinically, and most biomechanical research regarding knee osteoarthritis has been focussed on medial knee joint load. Therefore, this would be an area for further investigation informed by our findings.

Are you planning to continue the research? Please provide details.

As this research forms part of my PhD thesis, it will continue into at least 2023. We are soon commencing our large (postponed) clinical trial to determine whether gait retraining reduces pain and the forces at the inside of the knee during walking. In the future, I also hope to conduct projects regarding gait retraining research translation, and investigation into the effect of gait retraining on osteoarthritis disease progression outcomes using imaging. I am also interested in exploring ways to address varus thrust presence clinically.

Spondyloarthropathy- Evaluating responses to infection and inflammation
Funded by: Australian Rheumatology Association (ARA)
Recipient: Assoc Prof Meilang Xue
Intended Department Sutton Arthritis Research Laboratory, Royal North Shore Hospital
Project: Association of EPCR gene polymorphism with Rheumatoid Arthritis

 

Rheumatoid arthritis (RA) is currently not curable. Identification of RA at initial presentation and treatment at an earlier stage can greatly reduce long‐term disability and joint damage, even exert a curative effect for a proportion of patients. However, current diagnostic criteria are not sensitive enough to identify early RA, and although a number of treatments are available, each of them shows a significant non-response rate in patients. Research in RA is increasingly focused on the discovery of biomarkers that can lead to RA early diagnosis and reduction of non-response rates. Therefore, predicting the likelihood of treatment response and RA severity based on DNA/protein testing would be of great patient benefit. Specific gene mutations in an anticoagulant factor, endothelial protein C receptor (EPCR), have been identified as risk factors for cardiovascular diseases. Cardiovascular diseases have been recognized as the main cause of mortality among RA patients with the risk of these diseases estimated at least 50 % greater than that in general population. But what is the status of mutation and expression of this gene in RA has never been investigated. In this project, by identifying specific gene mutations and expression of EPCR in a RA cohort we may be able to provide a new predictive marker for RA and its complications. This biomarker may be used by clinicians for better disease management. In addition, innovative therapeutic interventions to prevent disease progression and improve the overall mobility of RA patients may be developed.

In this study, we found that when compared to normal healthy individuals, RA patients showed a lower frequency of a specific EPCR gene mutation, immune cells from the patients with RA expressed higher levels of EPCR. Due to small numbers of patients, we did not find the correlation between EPCR mutation and cardiovascular disease in these patients.

How might the findings inform further research to help sufferers in the future?

The knowledge gained from this project will likely lead to improved therapies to patients with rheumatoid arthritis by facilitating the diagnostic/predictive markers or novel target in RA, improve the overall outcomes of RA patients.

Are you planning to continue the research?

Yes, we are continuing this line of research, by recruiting a large cohort of RA patients to validate the current data, and investigate other mutations associated with this gene, and whether these mutations or the expression of this gene can be used a predictive/early diagnostic marker in RA.

Immune reconstitution following Autologous Haematopoietic Stem Cell Transplantation for Systemic Sclerosis (Scleroderma)
Funded by: Australian Rheumatology Association (ARA)
Recipient: Dr Ross Penglase
Intended Department Sutton Arthritis Research Laboratory, Royal North Shore Hospital
Project: Immune reconstitution following Autologous Haematopoietic Stem Cell Transplantation for Systemic Sclerosis (Scleroderma)

 

The generous grant from Arthritis Australia enabled an in-depth description of immune system recovery after autologous haematopoietic stem cell transplantation for Systemic Sclerosis, using two 18 colour flow cytometry panels.

Systemic sclerosis is a severe and potentially lethal autoimmune disease that causes considerable disability. The main organ involved is the skin, presenting as progressive hardening and thickening of the skin. Patients may also develop severe heart and vascular disease, joint and muscle disease, gastrointestinal problems and fibrosis or scarring of the lungs. To date, there have been few treatment options, however stem cell transplantation has recently been shown to be effective and can result in long term remission from disease. Stem cells are taken from a patient’s own blood (autologous stem cells) and used to ‘grow’ a new immune system. It is hypothesised that this new immune system will no longer ‘attack’ a patient’s own body.

We set out to describe some of the changes in the immune system after stem cell transplantation, using a method called flow cytometry. This involves labelling a cell with up to 18 different cell-surface markers and then passing these cells through a machine to identify which markers are present on each cell. This permitted identification of 10+ primary cell types with many more subpopulations of such cells. Immune cells were drawn from each patient before and up to two years post transplantation. The generous grant from Arthritis Australia covered the reagents and materials required to perform these experiments.

Firstly, we wanted to see if the thymus gland reactivated post-transplantion. This gland sits in the chest and is involved in the ‘schooling’ of T cells. We hypothesised that reactivation of the thymus is involved in long term remission. Our results showed that after transplantation, this gland recovers activity and repopulates the immune system with both regular T cells and T cells involved in regulation of the immune cells, termed T regulatory cells. These cells have a key role in dampening immune responses and limiting autoimmune disease. Our study is the first to show renewed production of these cells from the thymus after transplantation.

Secondly, after transplantation, these T regulatory cells carry markers that show an improved ability to suppress and regulate other cells. These cells emerge early after transplantation and persist after two years, particularly in those who respond to treatment. These cells also carry markers that allow them access to the skin and other diseased organs.

The two panels allowed identification of many more cell types. For example, we demonstrated that subsets of natural killer (NK) cells and total B cells expand post-transplantation.

While stem cell transplantation is effective, it is not for all patients with systemic sclerosis; if patients have already suffered too much organ damage, particularly to the heart, lungs or gut, then the treatment is considered too high a risk. Therefore, there is a key unmet need to extend effective but safer therapies to all patients with systemic sclerosis. One answer to this is to try and manipulate immune cells with a modified transplant, or without a transplantation at all. T regulatory cells are an attractive candidate to manipulate with the aim of dampening the autoimmune response. The data gained from this project will be invaluable to develop ways of targeting T regulatory cells.

In the future, these data will be correlated with other clinical and laboratory data collected as part of my PhD. These data will be presented as a thesis and hopefully published in the coming 12-24 months.

Investigating the relationship between autoimmune rheumatic disease and pregnancy outcomes
Funded by: Leanne Stafford Award (funded by Australian Rheumatology Association- ARA)
Recipient: Shi Nan Luong
Intended Department Centre for Rheumatology Research, Division of Medicine, University College of London
Project: Investigating the relationship between autoimmune rheumatic disease and pregnancy outcomes

 

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that occurs when the body’s overactive immune system attacks its own organs.  My research examines the important area of SLE and pregnancy.  SLE tends to affect women of childbearing age, and improvement in treatment has resulted in more women with lupus considering pregnancy.  However, management of these patients during pregnancy can be fraught with complications of their SLE or pregnancy itself.  We do not completely understand the relationship in lupus between the overactive immune system and pregnancy complications and are unable to predict which patients are most likely to improve or get worse in pregnancy.  Consequently, there is often a great deal of uncertainty amongst doctors on how to best manage patients with lupus during pregnancy.  There is also a lack of accurate information for lupus patients regarding the impact of pregnancy on their disease, and effect of their disease on their pregnancy.

My research project aimed to explore this area of unmet need and involved two parts:
1) To perform an combined analysis of existing studies (a systematic review and meta-analysis) on the fertility side effects of the medication cyclophosphamide, and the benefits of using another medication (called gonadotrophin releasing hormone agonists) in preventing cyclophosphamide-induced infertility in women of child-bearing age with SLE.
2) To identify immune cell numbers/markers (using a laboratory technique called flow cytometry) and blood metabolites in pregnant patients with SLE, and the relationship with pregnancy complications and quality of life.

With the support of Arthritis Australia, I was based at University College London/University College London Hospital, which is renowned for its clinical expertise and research in SLE and other autoimmune rheumatic diseases.  During my time in the UK, I published my work on cyclophosphamide and gonadotrophin releasing hormone agonists.  I also presented this research at the British Society of Rheumatology Annual Conference and European League Against Rheumatism Annual European Congress.

For the second part of my project, I recruited pregnant lupus patients, non-pregnant lupus patients and healthy pregnant patients from University College London Hospital.  Clinical information was collected on lupus disease activity; pregnancy history; pregnancy complications; medications and birth outcomes.  I also asked patients about their health-related quality of life, using questionnaires such as Short-Form 36 and Lupus Quality of Life.

Blood samples were collected for the study of metabolites (called metabolomics) and white blood cells (using the technique flow cytometry).  I performed flow cytometry experiments, looking at specific types of white blood cells called regulatory T cells, which are important in a normal pregnancy as they prevent the mother’s immune system from recognising the foetus as a “foreign body” and rejecting the foetus from her body.  In pregnant women with lupus, there are fewer regulatory T cells, and these T cells do not function normally.  Alterations in these cells may be the reason why miscarriages and premature labour occur more frequently in pregnant patients with lupus.  My work also involved looking at whether blood biomarkers, such as types of cholesterol or proteins, have an impact on pregnancy outcomes or SLE disease activity.

This project is currently in the data analysis stage, and results will be compared between the three patient groups.  Results will also be compared to other patient groups, such as those with rheumatoid arthritis, as part of the larger UK-wide PRINT study (Pregnancy in Rheumatic disease Investigation NeTwork study).

There is lack of knowledge surrounding lupus in pregnancy, and patients value research into the mechanisms underlying lupus.  My research project aims to bridge this information gap by exploring the ways in which the immune and metabolic system breaks down in lupus.  I hope my study will translate into increased understanding for patients, health care professionals, and the public about the relationship between lupus, adverse pregnancy outcomes and quality of life.  This will help improve health outcomes in an area of unmet need.

One outcome of this study would be a greater understanding of the immunometabolic relationship between lupus and pregnancy.  Unlike many other studies, patients with severe lupus who fall pregnant have been included, making it more relevant to everyday clinical practice.  My research will hopefully allow us to predict which patients are more likely to flare or experience complications during pregnancy, and allow us to provide more accurate, individualised treatment to patients.  It will also allow patients to make more informed decisions about the timing and management of their disease in pregnancy.

Patients have been directly involved through exploring quality of life from their perspective.  I hope to gain insight into the impact of lupus and discover what is most important to patients.  This is a novel and significant area to capture in pregnant patients with lupus, as it will allow us to evaluate the effectiveness of treatment.  It provides patients with an opportunity to directly engage in their treatment, and ultimately improve their adherence to management plans.  I am aiming for results of this study to be used to create key educational resources for patients and the public, as patients have expressed a keen desire for more information in this area.

This research will form the basis of my PhD thesis.  My research is being continued through ongoing collaboration with my rheumatology colleagues at University College London.  With the support of Arthritis Australia, I have gained invaluable clinical experience and research skills, particularly in the area of lupus and obstetric medicine.  I hope to apply these skills to my everyday clinical practice, and continue to be involved in research projects with my colleagues both in Australia and in the UK.  In the future, I would like to establish a dedicated rheumatology-obstetric service in Australia.  Lastly, I would like to thank Arthritis Australia for giving me this invaluable career opportunity.

Rheumatology- research on the impact of ongoing medication adherence
Funded by: Australian Rheumatology Association (ARA)
Recipient: Dr Sultana Monira Hussain
Intended Department School of Public Health and Preventive Medicine- Monash University
Project: Topical Corticosteroid and hand osteoarthritis

 

Hand osteoarthritis is very common in the community, causing pain, disability and reduced quality of life. There is no effective treatment for hand osteoarthritis, thus it is an international research priority. Joint swelling (inflammation) is present in 30% of patients with hand osteoarthritis and is associated with pain and joint damage, representing a potential target for reducing pain and improving patient outcomes. Oral corticosteroids are effective in treating inflammation and reducing pain in hand osteoarthritis but are associated with significant side effects including diabetes and osteoporosis. Intra-articular injections of corticosteroids are effective but difficult to administer and their effect lasts for less than a month. Topical corticosteroids are safe, inexpensive and commonly used for skin conditions, with the potential to reduce inflammation; but their effect in hand osteoarthritis has not been examined in a clinical trial. We conducted a clinical trial to test whether topical corticosteroid might reduce pain and improve function in those with painful hand osteoarthritis. If we find that topical corticosteroids are safe and effective, this will provide patients with hand osteoarthritis an effective treatment to relieve pain and improve function.

We have completed enrolment of 106 participants and follow-up assessments. Data analysis is under way and the study findings will be summitted for publication by December 2022 and made available to the study participants after the publication is accepted (likely 2023).

What questions did the grant set out to answer? What problems did you try to solve, or gaps in knowledge did you try to fill? Why is this important? 

This project aims to assess, using a parallel-group randomized controlled design, the effect of topical corticosteroid (Diprosone OV ointment) administered 3 times daily compared to placebo (plain paraffin ointment) in reducing pain and improving function over 6 weeks in participants with hand osteoarthritis.

There is no effective treatment for hand osteoarthritis to reduce symptoms and improve function. Oral corticosteroids have been shown to be effective in pain relief in those with hand osteoarthritis but are associated with significant adverse effects including diabetes and osteoporosis. Intra-articular injections of corticosteroids are effective but the effects often last less than one month and are technically difficult and often performed under ultrasound guidance which adds significantly to the cost, inconvenience and timeliness of treatment. Topical corticosteroids are safe, inexpensive, and have the potential to reduce inflammation, which might provide a potential treatment for hand osteoarthritis. If topical Diprosone OV ointment administered 3 times daily is found to be more effective than placebo in reducing pain and improving function in participants with hand osteoarthritis, this would provide patients with hand osteoarthritis a safe, inexpensive treatment to reduce the burden of disease in the community.

What did you discover during the course of the grant?

We started the clinical trial in October 2020. Due to the COVID-19 pandemic and lockdowns in Melbourne, the study procedures have been significantly affected. Although telehealth has been used for study visits and data collection, the enrolment and having hand x-ray have been challenging and delayed. We have been able to recruit 106 participants and completed follow-up assessment in May 2022. We are now in the stage of establishing database and data analysis. We anticipate to release the study findings to the participants in 2023.

Have the findings of the research already benefitted people with musculoskeletal disease? How might the findings inform further research to help sufferers in the future?

The protocol paper for this project has been published [Topical corticosteroid for treatment of hand osteoarthritis: study protocol for a randomised controlled trial. BMC Musculoskelet Disord. 2021;22:1036]. The research data are currently being analysed and manuscripts of study findings will be submitted for publication in international peer-reviewed journals and presented in international and national conferences so that the findings can be disseminated to the research community. This research provides evidence for the efficacy of topical corticosteroids in hand osteoarthritis. If found effective, this can be immediately translated into clinical practice, providing patients with hand osteoarthritis an effective treatment that relieves pain and improves function. The results will inform clinical guidelines internationally.

Are you planning to continue the research? Please provide details.

Yes. If topical corticosteroid is found to be effective, we plan to examine better methods for delivery of the medication in the affected hand joints. We found that participants were very enthusiastic about the study but found that the ointment was rather messy to use. This work will be done in collaboration with the Monash University School of Pharmacy.

Are Hybrid peptide antigens pathogenic in rheumatoid arthritis
Funded by: Arthritis South Australia
Recipient: Prof Anthony Purcell
Intended Department Department of Biochemistry – Monash University
Project: Are Hybrid peptide antigens pathogenic in rheumatoid arthritis

 

We examined a new class of protein antigens that potentially form pathogenic targets of T cell mediated immunity in rheumatoid arthritis (RA). This stemmed from an extrapolation of studies in type 1 diabetes that have shown that “hybrid peptides” consisting of a piece of insulin and a piece of another protein generate novel and highly reactive antigens for T cells. We hypothesized that similar hybrid peptides are generated from candidate autoantigens in RA forming potent stimulators of T lymphocytes and driving damaging immune responses in RA.

Moreover, we examined their presence in synovial fluid (the fluid that baths the joint) from affect-ed joints. Our hypothesis was directly tested using new tools developed in our laboratory that facilitate the identification of these hybrid peptides using mass spectrometry. A large number of candidate peptides were identified including novel modified peptides, autoantigen derived pep-tides as well as spliced peptides. These peptides are currently being tested for T cell reactivity us-ing blood from healthy volunteers and RA patients. If proven correct this information could revolutionize our understanding of pathogenic T cell responses in RA and provide new avenues for immunotherapeutic development.

What questions did the grant set out to answer? What problems did you try to solve, or gaps in knowledge did you try to fill? Why is this important?

The major question we addressed was if hybrid peptide antigens are presented by RA associated HLA-DR4 molecules and if they are immunogenic. In addition to spliced peptides we also accumu-ated considerable data for other more conventional classes of peptide antigens.

What did you discover during the course of the grant?

We discovered around 2% of HLA-DR4 peptides are spliced in origin – that is they represent hybrid sequences that contain sequences derived from more than 1 protein. A number of these hybrid peptides contain segments from joint specific proteins making them of potential disease relevance. These peptides are now being tested for T cell reactivity using HLA-DR4+ patient and healthy donor derived T cells.

Have the findings of the research already benefitted people with musculoskeletal disease? How might the findings inform further research to help sufferers in the future?

The outcomes of immunogenicity studies may inform future treatment strategies.

Are you planning to continue the research? 

We are planning to finalise the initial immunogenicity screening studies and use this data to apply for additional funding (e.g. NHMRC Ideas grant, Arthritis UK, etc.).