Explore 2021 Research

Scientific Summary

What were the main scientific objectives of the grant?

Key Research Question: What are the serum urate lowering effects of empagliflozin, fenofibrate and the combination of these two treatments in people with type 2 diabetes and a raised serum urate concentration?

Aim: To examine serum urate responses in hyperuricaemic people with type 2 diabetes treated with a sodium-glucose co-transporter-2 inhibitor (SGLT2i) and/or fibrate.

Hypotheses to be tested: Empagliflozin, fenofibrate and combination therapy will reduce the serum urate by ≥0.04 mmol/L, ≥0.06 mmol/L and ≥0.10 mmol/L, respectively.

What were the main scientific achievements of the grant?

In a sample of eight people with type 2 diabetes who participated in a crossover study, empagliflozin (a medication for type 2 diabetes which also promotes uric acid excretion) and fenofibrate (a lipid modifying drug which also lowers serum urate) monotherapies reduced fasting serum urate concentrations to levels at least as much as hypothesized based on previous studies, but their effects appeared additive when given in combination. This was a novel finding. The mean reduction in serum urate (0.14 mmol/L) with recommended maximum daily doses of combination therapy (empagliflozin 25 mg plus fenofibrate 145 mg) was associated with three quarters of the participants achieving a serum urate <0.36 mmol/L after all had started the study above this level.

There was, however, evidence that the combination was synergistic in its effect on kidney function. Although neither drug is nephrotoxic and neither had a statistically significant effect on the estimated glomerular filtration rate (eGFR) when given alone in our study, the significant mean eGFR reduction of 10.2 mL/min/1.73m² with combination therapy may have clinical implications. These would include the need for close monitoring of renal function if the combination were used for their usual indications with or without the additional potential benefits of urate lowering, and consideration of dose modification of other therapies used in people with diabetes that are affected by changes in renal function such as the widely used drug metformin.

What problems, if any, did you encounter in achieving the project’s objectives, and how did you address them?

Recruitment for the study proved difficult since many people with type 2 diabetes are now receiving treatment with an SGT2i such as empagliflozin, while other exclusion criteria (such as renal impairment) are also relatively common. In addition, the duration of the study and the need for regular blood sampling over 6 weeks were factors that influenced participation.

Have you disseminated, or plan to disseminate, the results of this research? Please tell us about it:

The study report has been accepted for publication in the well regarded diabetes-related journal Diabetes Obesity and Metabolism (a copy of accepted version is attached). The corrected proofs of the article were returned to the journal recently which means it will appear in press shortly.

Plain language summary (Lay report)

Tactile acuity is the ability to precisely feel the location and quality of touch on the body. This ability has shown to be diminished in several persistent pain conditions, including chronic neck, back, and knee pain. This sensory

impairment has shown to correspond to changes in the area of the brain that processes information from the body. This finding has led to the search for sensory training interventions that might restore normal sensory function and reduce pain. After building a semi-automatic sensory training device, we set out with the support of an Arthritis Australia grant to conduct a proof-of-concept trial to assess its feasibility in a population of people with persistent neck

pain. Our first achievement was to publish a trial protocol (Harvie et. al 2021), overcome recruitment barriers, and begin data collection. During the trial, quantitative and qualitative feedback on the intervention was garnered that is informing the devices further development. What was clear in the data however, was that for neck pain participants in particular the intervention is not feasible in its current form. That is, because the training required prolonged training in a sustained posture, a significant proportion of participants found the training uncomfortable. Given that any overall group-level treatment benefit would be clearly offset by the numbers of participants reporting discomfort with use, we determined it was no longer ethical to continue the study. The findings are awaiting peer reviewed publication. In the meantime, we have pivoted to using the device for other promising conditions and applications. For example, we have been testing the device as a way to test for (rather than train) sensory impairments (Olthof et al., 2021a; Olthof et al., 2021b) and we have been piloting it as a way to treat the debilitating and very difficult problem of spinal cord injury-related pain (pilot data also in process for publication). As such, the project has made a significant contribution to the line of research investigating sensory training for persistent pain.

Harvie, D. S., Olthof, N., Hams, A., Thomson, H., & Coppieters, M. W. (2021). The iSTOPP study: Protocol for a proof-of-concept randomised clinical trial of sensory discrimination training in people with persistent neck pain. Contemporary Clinical Trials Communications, 23, 100820.

Olthof, N. A., Harvie, D. S., Henderson, C., Thompson, B., Sharp, R., Craig-Ward, L., … & Coppieters, M. W. (2021). Description and psychometric properties of a prototype to test tactile acuity in the neck. Musculoskeletal Science and Practice, 51, 102259.

Olthof, N. A., Coppieters, M. W., Moseley, G. L., Sterling, M., Chippindall, D. J., & Harvie, D. S. (2021). Modernising tactile acuity assessment; clinimetrics of semi-automated tests and effects of age, sex and anthropometry on performance. PeerJ, 9, e12192.

We gained valuable feedback to improve the intervention before further testing, but ultimately we withdrew the study before completion because the training required prolonged training in a sustained posture that participants found uncomfortable. An important outcome of the study, is that it has caused us to trial the device for other conditions that might benefit, but not have the same problem encountered by people with neck pain. For example, we have been testing the device as a way to treat the debilitating and very difficult problem of spinal cord injury-related pain.

Plain language summary (Lay report)

Osteoarthritis (OA) is a multifactorial, slow-progressive disease of the whole joint and the most common single cause of pain and disability in adults after 45 years of age. Because the underlying causes of OA are not understood, the current treatment strategies are limited to pharmacological pain management and, when those are not sufficient, costly and invasive joint replacement surgery.

Recent research, including our own, strongly suggests that structural, cellular, and molecular changes within the subchondral bone (bone beneath the articular cartilage) are causal of osteoarthritis initiation and progression. Despite osteocytes being the most abundant cell type within bone, their association with OA pathogenesis remains unknown. Overall, the osteocyte viability, density, and connectivity in human OA are largely unexplored.

The overall aim of this project was to comprehensively characterise the osteocyte morphology and function, and its association with specific subchondral bone pathologies in human OA.

To achieve this, we collected post-joint replacement tissue (femoral head after hip replacement and tibial plateau after knee replacement) and control/cadaveric tissue.

Samples were imaged by high-power synchrotron micro-CT to obtain parameters describing bone microstructure, osteocyte-lacunar network, and bone matrix vascularity, and processed for histological determination of osteocyte density, viability, and connectivity.

Our findings demonstrate that osteocyte viability and connectivity are compromised within OA subchondral bone implicating a direct role for osteocytes in human OA pathogenesis. Furthermore, the results indicated that hip and knee OA have different structural phenotypes and different aetiologies and that potentially different risk factors might influence the progression of OA in different joints.

The Arthritis Australia Fellowship has permitted me to build my track record, such that I was able to secure future funding such as 2022 Arthritis Australia Project grant “Cellular senescence as a therapeutic target for knee osteoarthritis” CIA Kuliwaba J, CIB Muratovic Dz, CIC Atkins G, CID Findlay D and 2021-2022 Bone Health Foundation Research Grant; The Osteocyte as an Orchestrator of Bone Quality in Osteoarthritis b Dz. This funding supported my ongoing interest in the investigation of the involvement of subchondral bone in the progression of human osteoarthritis and as a future treatment target.

A list of the manuscripts and awards awarded over the funding period are listed below:

Original research publications:

Muratovic, D., Findlay, D. M., Quinn, M. J., Quarrington, R. D., Solomon, L. B., & Atkins, G. J. (2023). Microstructural and cellular characterisation of the subchondral trabecular bone in human knee and hip osteoarthritis using synchrotron tomography. Osteoarthritis and Cartilage, 31(9), S1063-4584(23)00791-4. doi:10.1016/j.joca.2023.05.005

Le, T. N., Muratovic, D., & Linacre, A. (2022). Recording and analysing DNA from osteocytes in resin-embedded bone samples. Forensic Science, Medicine, and Pathology, 19(2), 160-168. doi:10.1007/s12024-022-00559-1

Dorraki, M., Muratovic, D., Fouladzadeh, A., Verjans, J. W., Allison, A., Findlay, D. M., & Abbott, D. (2022). Hip osteoarthritis: A novel network analysis of subchondral trabecular bone structures. PNAS Nexus, 1(5), pgac258-1-pgac258-11. doi:10.1093/pnasnexus/pgac258

Le, T. N., Muratovic, D., Handt, O., Henry, J., & Linacre, A. (2022). DNA profiling from human bone cells in the absence of decalcification and DNA extraction. Journal of Forensic Sciences, 67(4), 1690-1696. doi:10.1111/1556-4029.15033

Muratovic, D., Findlay, D. M., Quarrington, R. D., Cao, X., Solomon, L. B., Atkins, G. J., & Kuliwaba, J. S. (2022). Elevated levels of active Transforming Growth Factor β1 in the subchondral bone relate spatially to cartilage loss and impaired bone quality in human knee osteoarthritis. Osteoarthritis and Cartilage, 30(6), 896-907. doi:10.1016/j.joca.2022.03.004

Awards:

1. “The Best Basic Science Poster” Australian Rheumatology Association 2021.
2. “The New Investigator Award” European Calcified Tissue Society (ECTS) 2021.
3. “The Best Bone Biology Image”, International Society of Bone Morphometry (ISBM), 2020

Lay Report

Research Team This research was conducted by a multidisciplinary team including Associate Professor Nicola Burton (Clinical Health Psychologist, Griffith University), Professor Ranjeny Thomas (Rheumatologist, The University of Queensland), Professor Jeff Coombes (Exercise Physiologist, The University of Queensland), Dr Hannah Mayr (Accredited Practising Dietitian, Princess Alexandra Hospital), Dr Veronique Chachay (Accredited Practising Dietitian, The University of Queensland), Associate Professor Coral Gartner (Tobacco Cessation Specialist, The University of Queensland) and Dr Helen Benham (Rheumatologist, Princess Alexandra Hospital).

Overview of Goals & Actualities

This project aimed to evaluate a wellbeing and healthy lifestyle program for adults with rheumatoid arthritis (RA). The project was originally designed as a study with 30 participants to compare the program with usual care. However, the project was delayed and constrained by hospital- and university-based clinical research restrictions because of COVID19. We also found patients were reluctant to engage with the study if they did not receive the intervention program. We therefore did a smaller study in which all participants received the program and there was no comparison group.

The program was initially designed with a total duration of five months including eight weeks of resilience training (2 x 1hour/week) followed by eight weeks of concurrent group supervised exercise training (2 x 40 mins/week), individual nutrition counselling (4 x 30mins/fortnight), individual smoking cessation (4 x 30mins/fortnight) and group behaviour change counselling (1 x 2hours followed by 3 x 1 hour/fortnight). During the initial stage of the project, participants indicated they were not available to attend a second in person exercise training session. In response to this and the smaller study design, the program was revised to a total duration of four months including six weeks of resilience training, one hour supervised exercise training session per week, five sessions of nutrition counselling, and four sessions of behaviour change counselling. The smoking cessation component was not delivered as no participants were current smokers.

The assessment was done as planned, with participant-reported indicators of wellbeing, quality of life, physical activity, sitting time and diet composition; and staff measures of participants’ physical functioning, weight and hip/waist circumference, session attendance and safety. We obtained feedback on the program from the participants and from the staff who delivered the program.

Research Questions & Importance

Research questions were

• What is the impact of this program on patient wellbeing, physical activity, sitting time, physical function, diet composition, and perceived competence for regular exercise and healthy eating?
• Is it possible to deliver the program as intended?
• Is the program acceptable to, and safe for, patients?

This research is important to enable effective self-management of RA, which is a key predictor of RA severity and progression. People with arthritis report little support for emotional wellbeing and self-management, as well as limited and fragmented multidisciplinary care. This research addressed these issues by demonstrating a new multidisciplinary program integrating wellbeing and healthy lifestyle support. Good wellbeing and healthy lifestyles among people with RA will reduce the burden of RA associated with distress, reduced function, medical and allied health consultations, and long-term complications.

Discoveries

Six people completed the program. Participants had an average age of 59 years, and included both men and women, and people born in Australia and people born overseas. The program had positive impact, and was acceptable and safe. There were some feasibility issues.

There were significant improvements in sitting time, diet composition (Mediterranean diet, sugar, monounsaturated fatty acids, olive oil) and physical function (neuromuscular strength, strength endurance, exercise capacity). There were improvement trends for general wellbeing, mental and physical quality of life, physical activity, other dietary intake (fish, legumes, unsaturated lipids) and body mass index.

Average attendance across the four components was 77%-86%. Participants liked the program duration and frequency. There were feasibility issues regarding staff availability when participants wanted weekend sessions. Participants were not available to attend two in person exercise training sessions per week. There were no adverse safety events.

All participants strongly agreed they would recommend the program to others. They rated the program very highly in terms of helpfulness for managing RA, resilience and wellbeing, physical activity and healthy eating. Participants liked starting with the resilience training, the specialist interventionists, the exercise equipment provided (mat, fitball, therabands), in-person and small group sessions, gym orientation sessions, interactions with and learning from other patients, individualisation, and the non-medical focus on RA management. Participants said the program was helpful for people with a new or ongoing diagnosis of RA.

Patient Benefits & Directions for Future Research

Patient benefits were improvements in key components of RA self-management including wellbeing, physical activity and healthy eating. The program provided an integrated approach to RA care and reduced the need for patients to negotiate and coordinate appointments across multiple healthcare professionals and locations. It provided both emotional and healthy lifestyle support.

Directions for future patient research involve refining the program in response to participant and program staff feedback. Participant suggestions included more time for activities during the resilience training (which was reduced from the initially planned 8 weeks), having at least one group or in person session with the dietician, having a “booster” follow up 2-3 months after the program, strategies to accommodate when participants missed sessions, and having significant others attend. Participants wanted a more consistent communication system across program components. Staff feedback included a group physical activity education session with the exercise physiologist, support for exercise adjustments/queries outside of training sessions (e.g., email/online sessions), more exercise resources (e.g., technique videos), an online booking session for nutrition counselling and tools for participant self-monitoring. There may be scope for some of the resilience training to be done online.

Future Practice/Research Intentions of the Team

The next stage in our research is to refine our program and conduct a larger evaluation study. We have written a proposal in collaboration with Arthritis Queensland to build on their successful online exercise training programs and also provide our resilience training and nutrition counselling components as separate programs, with a “health coordinator” for improved program administration and communication support. We are also considering variations of specific components of our program (e.g., online vs in person resilience training). We are developing an international collaboration with a senior scientist at Arthritis Research Canada to access an ehealth self monitoring tool for people with arthritis and want to evaluate this in Australia.

Scientific Report

Research Team

This research was conducted by a multidisciplinary team : Associate Professor Nicola Burton (Clinical Health Psychologist, Griffith University), Professor Ranjeny Thomas (Rheumatologist, The University of Queensland), Professor Jeff Coombes (Exercise Physiologist, The University of Queensland), Dr Hannah Mayr (Accredited Practising Dietitian, Princess Alexandra Hospital), Dr Veronique Chachay (Accredited Practising Dietitian, The University of Queensland), Associate Professor Coral Gartner (Tobacco Cessation Specialist, The University of Queensland), Dr Helen Benham (Rheumatologist, Princess Alexandra Hospital).

Scientific Objectives

This study aimed to evaluate the impact, feasibility, acceptability, safety and fidelity of a person-centered multicomponent wellbeing and healthy lifestyle program for adults with rheumatoid arthritis (RA). It was hypothesized that the intervention would
• have a positive impact on wellbeing, physical activity and function, diet quality, and (where indicated) smoking cessation/confidence
• be feasible, acceptable and safe for participants
• have demonstrated fidelity in terms of being delivered as intended

Scientific Achievements

During recruitment, 24 people were provided with study information. Of these, 54% (n=14) completed baseline assessment, 37% (n=9) agreed to commence the program, 25% (n=6) commenced the program and 25% (n=6) completed the program. The average age of the participants who completed the program was 59 years (SD = 10.7) and there was an equal proportion of women and men, and people born in Australia and outside of Australia.
The program had positive impact and was acceptable and safe. There were some issues with feasibility and fidelity.

Impact Measures

Between baseline and post intervention, there were statistically significant improvements in self-reported sitting time on a weekday (p=0.017) and weekend (p=0.001), and objective measures of neuromuscular strength (dominant hand grip strength p=0.023; non dominant hand grip strength p=0.031), exercise capacity (six minute walk test, p=0.016) and strength endurance (sit to stand test, p=0.040). The reduction of 0.5 kg/m2 in BMI approached statistical significance (p=0.058). There were trends towards improvements in self-reported measures of psychological well-being, physical and mental quality of life, time per week spent in physical activity and perceived exercise competence.

Food diary data demonstrated a statistically significant increase in adherence with mediterranean diet principles (p=0.020). There was a statistically significant favourable reduction in daily intake of dairy foods (p=0.036), grams of total carbohydrates (p=0.023) and total sugar (p=0.050), and a favourable increase in monounsaturated fatty acids (p=0.026) and olive oil (p=0.024). Other trends towards improvement included increased intake of fish and seafood, legumes, unsaturated oils and docosahexaenoic acid; and decreased intake of processed meat, solid fats, grams of protein, total energy, added sugars and saturated fatty acids.

Participant Feasibility, Acceptability and Safety

Average attendance was 86% for the resilience training (six sessions), 77% for the exercise training (eight sessions), 83% for the nutrition counselling (five sessions) and 77% for the behaviour change counselling (four sessions).

All participants said they would recommend the program, and described it as helpful for people with a new diagnosis of RA and people with RA for a long period. Very high scores (>4.5 on a scale with 5 as the upper limit) were obtained for the perceived helpfulness of the program for managing RA, managing resilience and wellbeing, being more physically active and doing more healthy eating. Participant liked starting with the resilience training, the resilience training, the specialist interventionists, the exercise equipment provided, the in person and small group-based sessions, interactions with and learning from other participants, individualised exercise tailoring, gym orientation sessions, and the non-medical focus on RA management.

Participant suggestions for the program included better communication and consistency of communication mode (ie email, phone) across components, tighter session organisation and timetabling, more time for discussion and activities during the resilience training, reducing the focus on the Mediterranean diet given the cosmopolitan world, having at least one group or in person session with the dietician, having a follow up 2-3 months after the program, strategies to make up content when participants missed sessions, and having significant others attend.

No adverse events were recorded during the program.

Intervention Feasibility and Fidelity

Of the a priori target of 10, 14 people (140%) were recruited. Among the 14 people who completed the baseline assessment and were invited to start the program, 43% (n=6) commenced the resilience training. Of the eight people who did not commence, two were too busy, two were unable to attend at the scheduled time, three had current illness/injury (unrelated to RA), and one was unable to be contacted. Ten participants were invited to attend the lifestyle component and 60% (n=6) commenced. The four others were unable to attend because of unsuitable timing and current illness/injury (unrelated to RA).

There were some initial feasibility issues regarding staff availability when participants wanted after hours and weekend sessions.

The resilience training was delivered as intended in terms of session frequency, duration and content. Although participants were initially hesitant about the in-person group format, there was a high level of engagement with sharing and normalisation of experiences as well as mutual support, and after the program participants feedback they wanted time for more discussion, activities and interactions during the group sessions. Participants strongly supported the in person delivery and thought online delivery would be less engaging and constrain interactions. The participant manual of session notes was seen as a useful permanent resource.

Exercise training sessions were delivered as intended in terms of duration and (revised) frequency, but there were challenges with content delivery. Participants’ exercise goals changed as their perceived and actual capabilities changed, and this required frequent exercise advice and adjustments which limited time for exercise training. The interventionist suggested that this component could be revised to commence with a group education session, have additional resources such as demonstration exercise videos, and to provide adhoc support between training sessions (eg email, online drop in sessions). There was a high level of social interaction during the group sessions which contributed strongly to engagement and motivation. Participants were described by the interventionist as often self-directing exercise at a lower intensity than when directly advised and/or supervised by the interventionist.

The nutrition counselling sessions were delivered as intended in terms of frequency, duration and content. Processes that worked well included the flexible scheduling of individual sessions including times after hours, using telephone and or videoconferencing for counselling delivery, using email between sessions to answer ad hoc questions, and having core resources for participants – in particular to compare current eating to the Mediterranean diet principles. Interventionist suggestions for program improvement included using online booking for sessions and providing tools for participant self-monitoring and check in between counselling sessions.

The behaviour change counselling sessions were delivered as intended in terms of duration, frequency, and content. The fortnightly sessions were conducted between the small group exercise sessions which reduced participant travel burden. Processes that worked well were the strong person-centred focus with participants initiating session content, and having the same person deliver the resilience training and behaviour change counselling, which enabled cross referencing of content.

Problems in Achieving Objectives and How These Were Addressed

The project was originally designed as a randomised controlled trial (RCT) with 30 participants to compare the program with usual care. However, the project was delayed and constrained by hospital- and university-based restrictions against clinical research because of COVID19. During the restrictions on in person recruitment, we obtained ethical clearance to recruit people by phone instead of at the hospital clinics. During recruitment, we found that patients were reluctant to engage because they wanted to be allocated to the intervention condition. Given both these difficulties, the project was redesigned as a small single group pilot study without a comparison group. To address the lack of a comparison group, we are extending our research beyond the scope of the original grant to access data from the A3BC project which records 6-monthly clinical measures along with biobanking of blood samples (DOI: 10.1089/bio.2021.0098). We will access physiological data from our study participants, who are already enrolled in A3BC, as well as data from matched (by gender and age) A3BC participants.

The program was initially designed with a total duration of five months including eight weeks of resilience training (2 x 1hour/week) followed by eight weeks of concurrent group supervised exercise training (2 x 40 mins/week), individual nutrition counselling (4 x 30mins/fortnight), individual smoking cessation (4 x 30mins/fortnight) and group behaviour change counselling (1 x 2hours followed by 3 x 1 hour/fortnight). Hospital- and university-based covid19 restrictions against research delayed the project start, and participants indicated they were not available to attend in person exercise training sessions twice per week (because of employment commitments and/or fatigue). The program was therefore revised to four months duration, including six weeks of resilience training, one hour of exercise training session per week, five sessions of nutrition counselling, and four one hour sessions of behaviour change counselling. The smoking cessation component was not delivered as no participants were current smokers.

Participants wanted the program to be delivered after hours, which was difficult for staff availability. To address this, we used casual staff to provide the exercise training and nutrition counselling, and one of the investigator team delivered the resilience training and behaviour change counselling on a weekend day.

Dissemination of Results Done and Intended

Jean Lee, Rheumatology Registrar with team investigator Professor Ranjeny Thomas, presented an overview of the project at the Australian Rheumatology Association (Queensland) meeting in October 2021.

The full investigator team delivered an online presentation at the 2022 Australian Rheumatology Association conference (May, 2022). This provided a background rationale for each of the discipline components and the protocol of our program, and we used a real time online survey to obtain feedback. More than 90% of practitioner respondents said they would refer always/often if such a comprehensive lifestyle intervention program combined with behaviour change support were available, and 100% of consumer respondents said they would join such a program.

The investigator team has submitted an abstract of the study results to the 2023 Australian Rheumatology Association conference. If accepted, team investigator Professor Ranjeny Thomas (Rheumatologist) will deliver the presentation at the conference in Hobart, Tasmania (May, 2023).

We are currently writing up the project as a manuscript to be submitted to a relevant journal e.g., Arthritis Care Research, BMJ Open. The team may also present select results at relevant forums within their professional networks.

A written summary of project results will be provided to participants when the results are finalised.

We have established a collaboration with Arthritis Queensland and a consumer representative and written a proposal which builds on Arthritis Queensland’s successful online exercise training programs to also provide our resilience training and nutrition counselling components, with a “health coordinator” for program administration and communication support. As part of this collaboration, we have provided our consumer representative with a written summary of the current study results and will provide more detailed information to Arthritis Queensland Chief Executive Officer and Health Promotion Manager.

Plain language summary (Lay report)

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We ask that you pay special attention to placing the research in its wider context – how the research contributes to the understanding of disease and why this is important, or how it contributes to the development of a solution to a clinical problem. Although challenging, this is particularly important for basic laboratory research.

1. Give a brief overview of the research you have undertaken, what you hoped to achieve and what you have achieved.

Chronic musculoskeletal conditions commonly lead to impairments in body function, impacting an individual’s ability to perform daily activities and limiting social and workforce participation. Because of this, an important part of healthcare for this population is the measurement of function over time. This helps clinicians evaluate treatment response and adjust treatment if required. Numerous ‘performance-based tests’ of physical function, balance, and strength exist and are commonly used in clinical practice. These tests include things like measuring how fast someone can walk, how quickly they can get up from, or sit down in, a chair, and how quickly they can raise up and down on their toes while standing – as a couple of examples.

Physiotherapists, who commonly provide care to people with musculoskeletal pain, traditionally provide care in-person. However, uptake of telehealth has surged since the start of the COVID-19 pandemic. The reliability of administering performance-based tests of function via videoconferencing is unclear. Therefore, the aims of our study was to investigate how reliable these tests are for use via telehealth. Specifically, this involved evaluating the: i) reliability of performance-based tests via telehealth over time, and ii) the agreement between scores obtained via telehealth and in-person for people with chronic lower limb musculoskeletal pain.

To do this, we recruited 57 adults aged 45 years or over with chronic lower limb musculoskeletal pain. Participants underwent testing, including the 30 second chair stand, 5 metre fast-paced walk, stair climb, timed up and go, step test, timed single-leg stance, and calf raises. We found that the reliability of test scores over time was good-excellent. Agreement between telehealth and in-person scores was also good-excellent for many tests. Overall, we found that the stair climb, timed up and go, right leg timed single-leg stance, and calf raise tests have acceptable reliability for use via telehealth in research and clinical practice. If re-testing via a different mode (telehealth/in-person), clinicians and researchers should consider using the 30 second chair stand test, left leg timed single-leg stance, and calf raise tests.

1. 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?

Chronic musculoskeletal conditions commonly lead to impairments in body function, impacting an individual’s ability to perform daily activities and limiting social and workforce participation. Because of this, an important part of healthcare for this population is the measurement of function over time. This helps clinicians evaluate treatment response and adjust treatment if required. Numerous ‘performance-based tests’ of physical function, balance, and strength exist and are commonly used in clinical practice. These tests include things like measuring how fast someone can walk, how quickly they can get up from, or sit down in, a chair, and how quickly they can raise up and down on their toes while standing – as a couple of examples.

Physiotherapists, who commonly provide care to people with musculoskeletal pain, traditionally provide care in-person. However, uptake of telehealth has surged since the start of the COVID-19 pandemic. The reliability of administering performance-based tests of function via videoconferencing is unclear. Therefore, the aims of our study was to investigate how reliable these tests are for use via telehealth. Specifically, this involved evaluating the: i) reliability of performance-based tests via telehealth over time, and ii) the agreement between scores obtained via telehealth and in-person for people with chronic lower limb musculoskeletal pain.

1. What did you discover during the course of the grant? 

We recruited 57 adults aged ≥45 years with chronic lower limb musculoskeletal pain. Participants underwent testing, including the 30 second chair stand, 5 metre fast-paced walk, stair climb, timed up and go, step test, timed single-leg stance, and calf raises. We found that the reliability of test scores over time was good-excellent. Agreement between telehealth and in-person scores was also good-excellent for many tests. Overall, we found that the stair climb, timed up and go, right leg timed single-leg stance, and calf raise tests have acceptable reliability for use via telehealth in research and clinical practice. If re-testing via a different mode (telehealth/in-person), clinicians and researchers should consider using the 30 second chair stand test, left leg timed single-leg stance, and calf raise tests.

Participant satisfaction with our telehealth testing sessions was high, indicating people with chronic musculoskeletal conditions feel confident, comfortable and safe performing tests via telehealth, and that test requirements were not perceived as difficult to complete. However, telehealth did present some challenges. Participant’s home environments often lacked appropriate space or stairs which meant that some tests could not be performed (e.g. stair climb and 5 metre walk test). Although no adverse events were reported, some participants (2-11% of participants) were unable to complete some of the single-leg tests on account of safety/balance concerns. Finally, our first telehealth assessment sessions took approximately 10 minutes longer than the in-person assessment sessions, which has implications for the viability of administering the full suite of our performance-based tests via telehealth in some healthcare settings (e.g. private physiotherapy clinics that may have limited consultation time). This was likely because physiotherapists were required to guide the participant through the set up and procedure for each test, as well as instruct the participant on the necessary camera angles to ensure they had an appropriate view. However, our second telehealth session was shorter, and of a similar duration to the in-person session, suggesting that experience can help reduce the time required. Our physiotherapists followed a detailed testing manual (freely available online), which was vital to help them adapt each test to a telehealth setting and instruct patients from afar.

1. 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 findings from our study have led to the development of a clinician testing manual for performing tests of physical function via telehealth. This has likely already benefitted people with musculoskeletal pain by ensuring that their clinicians have access to an evidence-informed tool that will help them improve the quality of care that they provide.

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

No, the study is complete.

Scientific summary (Scientific report) 

1. What were the main scientific objectives of the grant?

The aims of this study were to investigate the: i) test-retest reliability of clinician-administered performance-based tests via telehealth, and ii) agreement between scores obtained via telehealth and in-person for people with chronic lower limb musculoskeletal pain

1. What were the main scientific achievements of the grant

Fifty-seven participants were recruited. The estimated ICC for test-retest reliability for four tests were good to excellent (ICC=0.84-0.91) and above the pre-specified acceptable lower 95% CI threshold of 0.7 (95% CI lower limit=0.71-0.79), including the stair climb, timed up and go, right leg timed single-leg stance, and calf raise tests. The estimated ICC for test-retest reliability for four tests were moderate to good (ICC=0.69-0.81), however the lower 95% CI did not reach acceptable levels (95% CI lower limit=0.52-0.69), including the 30 second chair stand, 5 metre fast-paced walk, step test, and left leg timed single-leg stance.

The estimated ICC for agreement for three tests was good to excellent (ICC=0.82-0.91) and above the pre-specified acceptable lower 95% CI threshold of 0.7 (95% CI lower limit=0.71-0.85), including the 30 second chair stand, left leg timed single-leg stance, and calf raise tests. The estimated ICC for agreement for four tests ranged between moderate to good (ICC=0.71-0.81), however the lower 95% CI did not reach acceptable levels (95% CI lower limit=0.52-0.69), including the stair climb, timed up and go, step test, and right leg timed single-leg stance. One test did not meet our minimum acceptable ICC and showed poor agreement (95% CI included values <0.5), which was the 5 metre fast-paced walk (ICC=0.55, 95% CI=0.30-0.72).

Participant confidence, comfort, safety, and ease of the performance-based tests were high and similar across telehealth and in-person sessions, ranging from a mean of 8.5-9.8 out of 10 on and 11-point NRS for the in-person session, compared to 8.4-9.4 out of 10 for the telehealth sessions. The in-person testing session was, on average, shorter than the first telehealth session but of similar duration to the second telehealth session.

1. What problems, if any, did you encounter in achieving the project’s objectives, and how did you address them?

Out study was delayed by COVID-19 lockdowns in Melbourne throughout 2021. This meant we were unable to recruit participants or gather data (as participants were not allowed to attend our laboratory in-person). We addressed this by pausing recruitment until lockdowns were over.

1. Have you disseminated, or plan to disseminate, the results of this research? Please tell us about:

• References for peer-reviewed papers that have been published (please provide pdf copies of papers if possible)
• Papers that have been submitted and/or accepted for publication
• Meetings/conferences at which you have presented this research, or are due to present it (please provide abstracts if possible)
• Any other ways in which you may have disseminated the research, including to the public and the media (please provide urls to relevant press releases or media articles)

We have published the paper:

BJ, L., F. Dobson, B. KL, M. Merolli, B. Graham, T. Haber, T. PL, D. Mackenzie, F. J. McManus, K. E. Lamb and H. RS (2022). “Clinician-administered performance-based tests via telehealth in people with chronic lower limb musculoskeletal disorders: test-retest reliability and agreement with in-person assessment.” Journal of telemedicine and telecare Nov 30;1357633X221137387. doi: 10.1177/1357633X221137387. Online ahead of print.

We have also created a clinician testing manual based off the findings of this study. It, along with an infographic of our findings, can be found/downloaded here: https://healthsciences.unimelb.edu.au/departments/physiotherapy/chesm/research-overview/telehealth-administered-performance-based-tests-for-chronic-lower-limb-musculoskeletal-pain

Gout is a common condition, but there is a lot of evidence that it is undertreated and understudied. The burden of gout on the Australian health care is not well known, meaning it is impossible to understand where funding should be directed to improve outcomes for people with gout. We aimed to examine a Western Australian population based dataset of 30 years of admissions to hospital with gout, to determine the health outcomes for people with gout, and what health resources people with gout use.

We have demonstrated that Western Australians admitted to hospital with gout are more likely to die in the next 10 years than patients without gout or the background population. We also identified that people with gout have high rates of hospital presentation and readmission in the years following their admission with gout, and that a large percentage of these admission are preventable. The readmissions are usually for heart problems.

People admitted to hospital with acute gout have a much higher risk of having a heart attack or stroke in the 30 days after their admission, suggesting that acute inflammation may have a role in the heart attacks and strokes that people with gout have.

Our findings suggest that people with gout have poorer short and long term outcomes than hospital based controls, and that this is associated with high, and potentially avoidable health care costs; further work needs to be undertaken to see if interventions can produce better outcomes for people with gout and the health system.

The prevalence of gout in Australia is one of the highest in world second only to New Zealand, and estimated at 16.5% in elderly Australian men. The effects of gout are not limited to the joints, as gout contributes to morbidity and mortality associated with hypertension, chronic kidney disease, and cardiovascular disease and may have role in diabetes and obesity. Whilst the cause of gouty arthritis is relatively well understood, and effective therapy is available, gout remains badly managed and relatively rarely studied. As the population ages and obesity increases, the prevalence of gout, its comorbidities, and burden on the health system is likely to rise. Despite this, the outcomes for people with gout internationally are poor, and the outcomes and costs associated with gout in Australian society are not well understood. We aimed to examine hospital data for people admitted to hospital with gout to understand their health outcomes, the factors that affect these outcomes, and the costs. In doing this, we can start to work on targeting resources where they may make the most difference to health outcomes and health care costs associated with gout.

Our key research question was: What are the epidemiology and longitudinal population-based outcomes with respect to gout in a Western Australian population based sample?

Our specific questions were:

1) What are the overall trends in comorbidities (hospital admission for acute gout/ hospital admissions complicated by acute gout/ cardiovascular events/ renal events/ fracture), mortality and use of hospital resources (ED visits) for patients with gout in WA over the period 1980-2012.

2)  What hospital resources do people with gout use in WA?

3)  What is the relationship between admission to hospital with acute gout in WA and cardiovascular outcomes in WA?

We found that patients admitted to hospital with gout in WA are more likely to have multiple health problems than people without gout. People admitted to hospital with gout are more likely to die over the following 10 years that hospital based controls without gout (or the background population in WA)  due to infection, cancer, heart disease, kidney and bladder disease, hormonal diseases, blood disease, skin disease and arthritis (other than gout). We also found that patients admitted to hospital with gout are highly likely to be re-admitted or attend the emergency department in the following five years. In the five years, there was 22,222 ED attendances with a median cost of $1,826 per patient, and 58,920 hospital admissions, with a median cost of $25,009 per patient. A total of 4,059 (18.3%) ED attendances and 3,834 (6.5%) hospital admissions were deemed potentially preventable.  Most of the reason people represented to hospital were due to diseases other than their gout, such as cardiovascular disease. This information suggests that people admitted to hospital with gout tend to represent to hospital commonly after discharge, and that the presentation is often preventable.

Studies need to investigate if managing the health problems of people admitted to hospital with gout can be done better, with the aim of preventing readmissions, and reducing costs, and improving outcomes for people with gout.

We also found that patients admitted with gout are at highest risk of dying from a heart attack or stroke in the 30 days immediately after the admission. This knowledge presents an opportunity to examine why this occurs, and look at potential interventions to improve outcomes for people with gout.

We are using the data to work with the hospital executive to implement care pathways in the hospitals to see if we can improve outcomes for people with gout.

We are also using the information to plan clinical trials on aggressive management of inflammation in acute gout.

We will continue to look at the WA Rheumatic Disease Epidemiological Register with regards to gout to see if information can aid us to understand how to improve outcomes for people with gout and reduce health care costs. For example, can we identify people likely to be admitted with gout, before they get admitted?

We will also undertake further research looking to see if we can institute clinical pathways in the hospital to try and address some of our findings.

For example;

• Can a gout care team in the hospital identify people with gout, manage their gout, and their comorbidities, and prevent readmissions?
• Can aggressive management of acute inflammation in gout prevent heart attacks?

You can read more about this project here: Scientific Summary- Dr Helen Keen

PLAIN LANGUAGE SUMMARY (LAY REPORT)

We would like to start by thanking the generous donors who made this grant possible.

1. Give a brief overview of the research you have undertaken, what you hoped to achieve and what you have achieved.

We completed a pilot feasibility trial to determine whether a treatment involving counselling (motivational interviewing) and access to a multimedia website about the benefits of exercise can increase physical activity in people with knee osteoarthritis. The focus of this study was to determine if a larger clinical trial could be conducted to test our intervention.

Improving physical activity participation in people with knee osteoarthritis is important because this population have lower physical activity participation than people without knee osteoarthritis. Lower physical activity participation places them at risk of developing or worsening other chronic conditions including heart disease, diabetes and dementia.

We planned to recruit 42 people with knee osteoarthritis who had completed an education and exercise program for people with osteoarthritis called Good Life with osteoarthritis Denmark (GLA:D®). Due to impacts of COVID-19 restrictions on people’s ability to attend appointments and engage in exercise, our recruitment was slower than anticipated. However, we were able to recruit 32 participants, and had just 2 of these drop out of the study. Conducting this pilot trial allowed us to test our protocol to assess how successful recruitment, data collection and data analysis might be in a larger trial. Additionally, it provided us guidance on how the intervention might be improved if we tested it in a larger trial.

 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?

 People with knee osteoarthritis are not active enough, meaning they are not getting the known benefits of regularly physical activity. Education and exercise programs have been shown to reduce pain and disability, however the effects of exercise on physical activity participation are variable. Following exercise, many people with knee osteoarthritis remain insufficiently active.

We primarily wanted to determine whether conducting a fully powered trial would be feasible. Our secondary aim was to collect physical activity data using a valid and reliable device (ActivPal) before and after providing participants our counselling and website treatment. Feasibility studies like this are important to ensure a larger trial, which are very costly to run, will be possible, and that the intervention being tested is high quality. This improves the quality of the research and reduces research wastage and costs. Our findings from this pilot trial will also help us to determine which outcome measures are going to be helpful for us to investigate, and provide us with the data and information we need to apply for larger grants to test our treatment.

1. What did you discover during the course of the grant?

Despite difficulties encountered due to COVID-19 restrictions on in-person healthcare and assessments, and exercise, we discovered that a larger trial to test our intervention is feasible. Additionally, we identified improvements for the intervention and study protocol. Planned improvements include:

Intervention

1. Spending more time to orientate participants to the multimedia website to empower them to use it.
2. Improving the multimedia website to be more interactive and including tools such as self-monitoring physical activity trackers.

• Developing stronger processes to link participants with community exercise and physical activity services.

Study protocol

1. Recruiting participants while they are still completing GLA:D®, rather than contacting them following completion.
2. Recruiting participants with clear signs of inadequate physical activity participation, who are most likely to benefit from our intervention.

• Combining physical assessments together, to save participants from having to attend another in-person appointment.

1. Providing participants with a post pack to return their ActivPAL device, to save participants needing to drop them back to our study site.

Our interviews with participants who received our intervention found that i) data collection was acceptable, ii) scheduling and attending motivational interviewing sessions online were convenient and easy, and iii) motivational interviewing was helpful for most participants to identify strategies to increase physical activity participation. Our interview and questionnaire-based findings indicated that the intervention is likely to improve quality of life and physical fitness, and lower blood pressure.

1. 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?

Participants who received our counselling and website intervention in this study reported feeling more confident and positive about being physically active in their everyday life. This is reflected in their higher quality of life scores.

Findings from this research confirm that it is feasible to run a larger study to assess whether counselling and website intervention can increase physical activity in people with knee osteoarthritis. This will include benefits to study participants in the intervention arm. If successful, a larger study may also inform policy to make large-scale changes to improve physical activity and overall health of people with knee osteoarthritis.

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

Now that we have established the feasibility of our intervention and trial, we plan to seek further funding to run a larger trial which to determine if our intervention can increase physical activity in people with knee osteoarthritis.

  SCIENTIFIC SUMMARY (SCIENTIFIC REPORT) 

1. What were the main scientific objectives of the grant?

Our primary aim was to establish the feasibility of conducting a fully powered trial to determine the clinical effectiveness (i.e. increasing physical activity) of a SUpported Motivational InTerviewing (SUMIT) intervention targeting physical activity following completion of a widely adopted exercise-therapy program in people with knee osteoarthritis (OA). Our secondary research aim was to estimate the effects of SUMIT on pain, joint-related quality of life (QoL), and health-related QoL.

1. What were the main scientific achievements of the grant?

Our findings indicate that it is feasible to run a fully powered trial to investigate the clinical effectiveness of SUMIT in people with knee OA, and have informed some quality improvements to the intervention (increasing utilisation of our website, linking participants to existing community groups). Our device measured (ActivPAL) physical activity outcomes indicate within group changes following SUMIT include:

1. Increased average time walking with cadence >100 by 8mins per day (95%confidence interval 3 to 13)
2. Increased average time walking in bouts >1minute by 29mins per day (22 to 25)

Additionally, SUMIT was associated with lower systolic blood pressure, and improved Knee Injury and Osteoarthritis Outcome Score (KOOS) values for all five domains (mean change scores (95% confidence interval)):

• Systolic blood pressure by average = 7mmHg (-13 to -1)
• KOOS symptoms = 9 (3 to 16)
• KOOS pain 12 (4 to 20)
• KOOS function 14 (5 to 23)
• KOOS sport and recreation 14 (6 to 22)
• KOOS quality of life 13 (6 to 19)

1. What problems, if any, did you encounter in achieving the project’s objectives, and how did you address them?

 Our project was significantly impacted by COVID-19 lockdowns, which impacted usual physical activities due to working from home, gymnasium closures, restrictions on time outside, restrictions on number of people doing usual activities such as shopping. Most importantly, we had to delay or repeat physical activity monitoring for several participants due to the imposed pandemic restrictions, particularly in late 2021. The impact of lockdowns also reduced our available recruitment pool due to reduced number of GLA:D® completers (part of our inclusion criteria) in 2020. To address this, we modified our recruitment criteria (i.e. allowing participants to have completed GLA:D® within 2 years instead of 1), and expanded recruitment from metropolitan Melbourne to include two regional clinics. Additionally, we delayed the completion date for recruitment. Despite difficulties with recruitment, our drop-out rate was low (2 participants) and adherence to the intervention was 100%.

1. Have you disseminated, or plan to disseminate, the results of this research? Please tell us about:

• References for peer-reviewed papers that have been published (please provide pdf copies of papers if possible)
• Papers that have been submitted and/or accepted for publication
• Meetings/conferences at which you have presented this research, or are due to present it (please provide abstracts if possible)
• Any other ways in which you may have disseminated the research, including to the public and the media (please provide urls to relevant press releases or media articles)

We are currently drafting a manuscript to submit our findings to peer reviewed journal/s at the beginning of 2023. Once our findings have been peer reviewed, we will create infographics to assist with dissemination to consumers, health professionals and researchers. We intend to submit an abstract to the Australian Physiotherapy Association conference for 2023, subject to abstract submissions opening prior to our manuscript being published. Upon publication or acceptance to present at a conference, we will send through confirmation of these works. We will also tag Arthritis Australia on social media posts where we disseminate our findings. Our preliminary findings will be crucial to support future grant applications to run a fully powered trial.

Lay Report

With the increasing awareness of silica associated lung disease and the development of the silica associated disease registry, increasing attention has been paid to the association of silica exposure and development of autoimmune diseases. The aetiology of systemic sclerosis is unknown, however there is historic data to suggest an association with silica exposure.

The aim of our study was to assess the occupational and environmental exposure history of our systemic sclerosis cohort. We wanted to determine if there was an increased risk of silica exposure (from occupational / environmental exposures) amongst our systemic sclerosis cohort compared with the background general Australian population. In order to do this, we collaborated with the occupational and environmental department at the Alfred Hospital who are involved in the silica associated disease registry.

In our scleroderma cohort of 1,670 persons, we found that 7.5% reported occupational silica exposure. These individuals were more likely to be male and to have worked in mining and construction industries. Those who reported silica exposure were younger at the onset of their skin involvement, of male gender and with more severe inflammatory disease manifested by joint contractures, a higher physical disability and higher mortality. Whilst this was of interest and supported our hypothesis, we feel that we are likely missing a number of systemic sclerosis persons who likely have silica exposure through recreational activities (such as pottery).

These results set the scene for a large collaborative project which we are in the process of setting up and will likely form the basis of a PhD thesis evaluating the development and progression of autoimmune disease in those with silica exposure. We will also endeavour to formally assess the silica exposure amongst our systemic sclerosis cohort to ensure we are capturing all exposures, not just occupational exposures.

This ongoing and important research would not be possible without the generous donations provided by our donors. As such, I want to take this opportunity to thank you for your care and interest, it allows us to dedicate our time to much needed research.

Scientific Report  

With the increasing awareness of silica associated lung disease and the development of the silica associated disease registry, increasing attention has been paid to the association of silica exposure and development of autoimmune diseases. The aetiology of systemic sclerosis is unknown, however there is historic data to suggest an association with silica exposure.

The aim of our study was to assess the occupational and environmental exposure history of our systemic sclerosis cohort. We wanted to determine if there was an increased risk of silica exposure (from occupational / environmental exposures) amongst our systemic sclerosis cohort compared with the background general Australian population. In order to do this, we collaborated with the occupational and environmental department at the Alfred Hospital who are involved in the silica associated disease registry.

In our scleroderma cohort of 1,670 persons, 126 (7.5%) of the cohort reported occupational silica exposure. These individuals were more likely to be male (73 of 231 i.e. 32.6% males exposed) and to have worked in mining and construction industries. Those who reported silica exposure were younger at the onset of SSc skin involvement (OR 0.9, p=0.02), of male gender (OR14.9, p<0.001), have more severe SSc disease manifesting with significant skin involvement, joint contractures (OR 1.8, p=0.05) and higher physical disability as defined by scleroderma health assessment questionnaire (OR1.4,p=0.01).

This data did not allow us to directly make comparison with the background general Australian population nor did it allow us to assess for silica exposure from recreational activities such as pottery. Most people with systemic sclerosis are female and this is not the population which would represent typical occupational exposures related to silica (mining etc). Therefore, we are in the process of formally determining how such recreational and occupational exposures can be appropriately determined and how we can select a control group so our risk of exposure can be standardised.

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.

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.

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.

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.

For further information  – below is the link to a  recently published article:

https://onlinelibrary.wiley.com/doi/abs/10.1002/acr.25001

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.

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.

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.

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.

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.).