Explore 2018 Research

RA-related information, in addition to standardised measures of RA symptom severity, the physical and psychological impact of RA, difficulty associated with parenting activities due to RA, parenting stress, and health-related quality of life.  Twenty women were also purposively sampled across child age and RA severity (using standardised measures) to participate in in-depth one-to-one interviews. The interviews covered how RA had influenced the women’s experiences of motherhood and caring for children; self-care practices in which the women engaged; and experiences of support.

In the analysis of quantitative survey data, we found that regardless of whether children were younger or older, greater difficulty with parenting activities contributed to lower health-related quality of life in mothers with RA, in addition to higher RA symptom severity and greater impact on physical and psychological functioning. In qualitative interviews, women gave accounts of additional burden and complexity in their mothering role due to RA. Reports of distress were also given across child age that were associated with accounts of loss of control over mothering practices due to RA. This included reports of feelings of failure at not being able to be the kind of mother the women wished to be. In contrast, accounts of adjusting mothering practices and relinquishing control were associated with reports of wellbeing. Some women also reported experiencing greater ease as a mother due to the increased independence of older children compared to when they were younger. Across the qualitative interviews, social support was described as reducing burden and distress, while the absence of support exacerbated the burden of RA on mothering. It is suggested that healthcare practitioners and community organisations can support mothers with RA by addressing feelings of failure, acknowledging coping strategies of adjusting and letting go, and encouraging greater access to social support. The findings from this study extend those from previous research on the psychosocial impact of RA by suggesting it is important to consider motherhood in understanding women’s experiences of wellbeing while living with RA.

There has been a lack of research which has addressed women’s experiences of wellbeing as mothers while living with RA. In addition, few studies have included mothers with children across a range of ages. Previous research has focused on early motherhood and women’s decision to become a mother. Furthermore, mothering practices and identities are influenced by a woman’s social context that informs experiences of mothering. In previous research, women have reported accommodating actions of limiting contact or withdrawing from children because of RA, which are at odds with cultural expectations that women take up intensive styles of motherhood, including spending time with their children. Few studies have examined the impact of RA on mothers’ wellbeing. In addition, there is little evidence examining how women subjectively experience motherhood when living with RA, including how they negotiate coping strategies in relation to social expectations of mothering. The aim of this research was:

1. To examine the experience of health-related quality of life amongst mothers who are living with rheumatoid arthritis
2. To identify how women with rheumatoid arthritis subjectively experience motherhood and their concerns and unmet needs.

This study is important for providing an evidence base for understanding how rheumatoid arthritis can impact on women’s experiences of motherhood across a range of child ages.

Over the course of the research we found that mothers’ health-related quality of life was associated with reports of greater difficulties with parenting activities, in addition to higher RA symptoms and higher psychological and physical impact from RA. This finding was identified across women with children of all ages. This means that it is important to consider motherhood in understanding the impact of RA on women’s health-related quality of life.

In qualitative interviews, women described experiencing considerable burden and additional complexity as a mother due to RA. Reports of distress were also given across child age that were associated with accounts where there was a loss of control over mothering practices due to RA. This included reports of feelings of failure at not being able to be the kind of mother the women wished to be. In contrast, accounts of adjusting mothering practices and relinquishing control were associated with reports of wellbeing. This meant developing a ‘new normal’ in how parenting activities were carried out, as well as letting go of some standards, such as cleanliness or assuming primary responsibility for the raising of children without support. Some women with older children also reported experiencing greater ease as a mother due to the increased independence of their children compared to when they were young. Social support was described as reducing burden and distress, while the absence of support exacerbated the burden of RA on mothering.

The findings from this study will inform future research and support for mothers with RA in the following ways:

1. By providing evidence for the importance of considering the influence of motherhood in shaping women’s experiences of wellbeing while living with RA.
2. The findings suggest that it is important to consider women’s feelings of failure and associated experiences of distress when unable to be a mother as they would like due to RA.
3. It is important to acknowledge the coping strategies that women are using to adjust their mothering practices and let go over some aspects of their role, such as doing it all by one’s self.
4. The study provides preliminary evidence which suggests that addressing social support, may assist women in coping by alleviating the burden of mothering with RA.
5. The use of qualitative methods, as part of a mixed method design, can provide critical in-depth knowledge of subjective experiences of motherhood amongst women with RA.

Funding is currently being sought to examine women’s experiences of social support as mothers with RA. An emerging theme of social support was identified in qualitative accounts, in which support was described as alleviating the burden of RA on mothering. This was associated with reports of greater wellbeing. However, there exists an outstanding need for research that examines in detail the relationship between support and wellbeing amongst mothers with RA. This includes the different types of support that are beneficial to wellbeing, and the unique challenges experienced by mothers with RA to accessing that support. New research has been planned to address this gap. Findings will identify how women can further leverage support from their networks to facilitate their coping and wellbeing. These findings can be used by heath care professionals and support organisations to encourage and normalise access to effective and appropriate forms of support for mothers with RA.

Shoulder disorders are a leading cause of pain and disability in our society with one in three people experiencing shoulder pain at some stage in their lives. Recurrence is common and symptoms are often persistent. The rotator cuff muscles are considered the prime source of symptoms with a diagnosis of rotator cuff tendinopathy/subacromial pain syndrome (SPS) accounting for approximately 30% of all diagnoses made by GPs. SPS is associated with substantial economic costs at both the individual and societal level.

Despite widespread use of injection therapies and increasing resort to surgical procedures, evidence suggests that physiotherapy involving a structured exercise program is the most efficacious in the management of patients with this disorder, associated with fewer risks and lower health costs. It is therefore increasingly advocated that a course of physiotherapy be undertaken before surgery is considered. Within this, exercises that address movement patterns about the shoulder complex as well as strengthening the rotator cuff muscles, have been suggested to be the most effective in this disorder. However, there remains limited evidence on the specifics of this, particularly in terms of the type of rotator cuff strengthening exercises used.

The funding made available from Arthritis Australia (Zimmer Biomet Award) was used to design and implement the SPaRC trial. The purpose of this pilot study was to compare the effects of three different rehabilitation programs in patients diagnosed with SPS to see whether one or other produced faster gains in pain and strength and therefore return to function, for patients diagnosed with this painful and often debilitating disorder. The three groups undertook a similar exercise program except the specific mode of rotator cuff strengthening exercises varied between the three groups.

It was considered important to establish feasibility using a pilot trial design before undertaking a large full-scale study. Therefore, the primary aim of the pilot RCT was to evaluate key study feasibility parameters relating to ease of recruitment, adherence and compliance with the various components of the study, dropout rates and, (serious) adverse events. The secondary aim was to offer insights into any potential trends in treatment effects observed between the groups, to explore whether faster gains in pain, strength and therefore function were achieved from either of the three exercise interventions being investigated.

Diagnosis of this disorder is difficult with no one test able to differentiate SPS from other common shoulder conditions such as frozen shoulder or instability. A specific algorithm was developed, in an attempt to ensure appropriate participants were included, with both telephone and face-to-face assessments undertaken. To date, out of a possible 34 participants screened, 12 participants have been randomised to the study. Recruitment has therefore been slower than hoped. However, adherence to the study has been excellent, with all participants to date, completing all study protocols.

The intervention involved 5-8 face to face treatment sessions with the physiotherapist, primarily using an exercise-based approach. Participants were assessed at baseline, week 6, week 12 and 6 months to observe any differences in change scores between the groups. The effects on the entire cohort as a group were also observed. Participants were required to complete questionnaires relating to pain and function, and physical measures were undertaken including shoulder strength testing.

The SPaRC trial is on-going, with just over a third of participants recruited to date.

Preliminary results are promising and although it is too soon to determine between-group differences, there is a definite trend that the participants to date have benefited from the intervention, with improvements in pain and function well above the established minimal clinically important differences for the patient reported outcomes used. Of the 10 participants who have so far undertaken the 3 month post-treatment assessment, median change scores for the Shoulder Pain and Disability Index (SPADI), the Western Ontario Rotator Cuff Index (WORC) and Numerical Rating Scale for Pain (average pain, night pain and pain on shoulder activity) were significantly improved from baseline and eight out of the ten reported feeling “much better” on the Global Rating of Change Scale (GRCS) than prior to the start of the treatment.

Further recruitment drives will ensure that full participant recruitment is achieved with final analysis providing further direction for the implementation of a larger scale trial.

Since commencement, recruitment has been ahead of schedule, with 37 participants randomised into study, and no losses to follow-up to date. Hip pain is a common in active young and middle-aged people, and has a large impact on their quality of life. Femoroacetabular impingement (FAI) is a leading cause of activity-related hip and groin pain in young and middle-aged people, and increases the risk for end-stage hip osteoarthritis (OA). It is possible that treatments targeted to young adults with FAI, could reduce hip symptom severity, and slow symptomatic disease progression. Interventions like physiotherapy have the potential to reduce the substantive individual and social costs of hip OA. However, there has been an absence of efficacy supporting physiotherapy (i.e. non-surgical) management for FAI. Physiotherapy treatment is used clinically, but no randomised controlled trial (RCT) evidence has evaluated this approach in hip pain. Interventions using exercise-science principals, which resulted in greater improvements in knee osteoarthritis than “traditional” physiotherapy exercises, have potential to optimise benefits for patients.

We aimed to evaluate the effectiveness of an exercise-based physiotherapy intervention on reducing pain and improving quality of life in young and middle-aged people with hip pain. We planned a full-scale randomised controlled trial evaluating the effectiveness of our exercise-based physiotherapy program on hip pain. We aimed to recruit 80 people who were aged 18 to 50 years with hip and groin pain (FAI) to participate in our trial. In order to be eligible, people needed to have hip pain for at least 6 weeks that was at least 3 out of 10 intensity. They also needed to fulfil some clinical and x-ray-based criteria. Our intervention was six months duration, and participants needed to be able to commit the time needed to this. To date, 40 people have entered our study. We aim to have recruited all people into our study by the end of 2018. We will have full 6-month follow-up on 80 participants by the middle of 2019.

Young and middle-aged adults with hip pain (FAI) are up to 10 times more likely to develop advanced hip osteoarthritis and undergo total hip arthroplasty in later life. In addition, they experience significantly reduced function, sports participation and poor quality of life at a time in life when they have peak occupational and family commitments. Non-surgical treatments like physiotherapy have the potential to improve function, sports participation and quality of life in this patient group, as well as slow arthritis progression, however the effectiveness of such interventions had not been tested in a clinical trial. This project aimed to provide unique high-level knowledge regarding the benefit of exercise-based physiotherapy interventions in this important patient group. The findings of this study could provide an effective treatment option for these affected individuals, improving their quality of life, as well as participation in physical activity and work activity. It also could reduce the substantive societal burden of hip arthritis over time.

As the project is not yet complete, the results addressing our primary and secondary aims are not yet known. However, a number of achievements have occurred in spite of this. The study protocol was presented at an international conference on hip pain (Warwick Sporting Hip Conference) in July 2018. At this meeting we confirmed that this trial is currently the only trial internationally looking at physiotherapy treatment of hip pain in young and middle-aged adults. As such, we anticipate the results of this study will be published in a very high impact medical journal. We have trained over 10 physiotherapists located in 4 physiotherapy clinics in Melbourne and Regional Victoria, to be able to implement the study protocol. During this process, we discovered that physiotherapy knowledge of exercise-based interventions for hip pain is poor, and the results of this study will make a large impact on physiotherapy practice for hip pain. Finally, to date one-third of the community of adults aged 18-50 years with hip pain, who responded to our study advertisements, fulfilled the inclusion criteria. This suggests that FAI is a common cause of hip pain, and affected individuals are seeking effective treatments for their condition.

As this study is not yet complete, the findings of the research have not yet benefitted people with musculoskeletal disease. However, once complete, the findings of this study will conclusively show whether an exercise-based physiotherapy treatment is an effective option to reduce pain, improve quality of life and physical activity participation in people aged 18-50 years with hip pain. In addition, longer-term follow-up (beyond the scope of this grant) is planned, in particular progression of arthritis and progression to hip surgery will be documented. This additional information will provide valuable information about the effectiveness of the exercise-based physiotherapy intervention in slowing disease progression and preventing expensive hip surgery. We are planning to continue this research.

Since receiving funding from Arthritis Australia, our recruitment starting date was delayed by a number of factors. These included a delay in the commencement of the project as Dr Kemp moved from Federation University to La Trobe University. There were subsequent delays in the approval of the human research ethics application, in confirmation of engagement of physiotherapy clinicians, and subsequent delay in physiotherapist training. We also extended the treatment period of the study from 3-months to 6-months, based on new evidence demonstrating a possible increase in improvement with a longer intervention, with additional university funding to pay for additional treatment over a longer treatment time. Furthermore, we consulted
additional statisticians for advice regarding the required number of participants for the six-month follow-up, and cost-effectiveness analyses. The additional advice indicated that the required number of participants required to achieve these aims was 164, not 80 as originally planned. Over the next 12months, we will complete recruitment of the revised target number of participants, and then subsequently complete the 6-month follow-up. We have also applied for additional NHMRC project grant funding to include these additional participants.

The Allan and Beryl Stephens Grant provided scholarship funds for me to undertake my second year in PhD studies at the Australian National University. In all chronic diseases, patients are said to take around 50% of the medications they are prescribed. In rheumatic conditions such as rheumatoid arthritis (RA) and spondyloarthritis (SpA), there is evidence of suboptimal medication adherence, and increased arthritis flares and disability as a result. I aimed to understand the patients’ and caregivers’ perspectives around difficulties of medication taking in Rheumatology and improve the strategies that are designed to help support patients with their medications. I have 6 studies planned for my PhD. The studies have taken a slightly different direction from what was originally planned. I have now included research with populations outside of RA and SpA including transitional care patients in Rheumatology, gout patients and osteoporosis patients. Rather than the planned pilot intervention study, I have formed a medication adherence special interest group in OMERACT (Outcome Measures in Rheumatology), which is an international organisation focusing on standardising outcomes across trials in Rheumatology. My studies also focus on standardising outcomes in trials that test strategies to improve medication adherence in Rheumatology.

The studies that will be included and their progress are summarised below:

• Systematic review of interview (qualitative) studies of RA and SpA patients, on their perspectives on disease modifying anti-rheumatic drugs – published in a medical journal
• Cross sectional (questionnaire study at one period of time) study, to determine medication adherence rates and factors associated with adherence in RA and SpA patients at Canberra Hospital – completed, draft manuscript written and ready to submit for publication shortly
• Clinician interview study – interviews with rheumatologists from Australia and around the world on ideas on how to better support RA and SpA patients with their medication taking – all interviews completed, ready for data analysis and write up
• Systematic review of interview (qualitative) studies of transitional care patients in Rheumatology, on their perspectives and needs during transition, and in particular how this relates to medication adherence – ready for final data analysis and write up.
• Focus group study with ranking exercise (nominal group technique) with gout, RA and osteoporosis patients and their caregivers – 8 focus groups complete, 4 more focus groups planned in Australia in September 2018.
• Systematic review of adherence related outcomes and measures in trials of interventions aimed to improve medication adherence in Rheumatology – underway.

The grant set out to understand medication adherence from a patients’ and caregivers’ perspective and suggest solutions that can be employed by a rheumatologist. It also aims to improve the quality of adherence intervention research by standardising the outcomes used. This is important as many adherence interventions are not successful in improving adherence, and those that are successful have modest effects at best. My studies focus on creating solutions for medication non-adherence by understanding patients’ needs, and making sure that interventions that are designed and tested for medication adherence are aiming to improve things that matter to patients’ and caregivers. A broad range of patient populations were included so that solutions can be applicable to a larger group of Rheumatology patients. Interviews with rheumatologists aimed to see what strategies clinicians from around the world employ to help support their patients with their medication taking, and to ensure that new strategies that are suggested would be practical and could be used to improve clinical care. During the course of the grant, it has become clear that medication adherence is a complex topic. Over 200 reasons have been reported in research papers to exist that influence medication adherence. My studies have demonstrated many factors that influence medication taking.

The systematic review of 56 studies in RA and SpA including 1383 participants found that patients can equate their mediations with intensifying disease identify and distressing uncertainties and consequences. A trustworthy, confident and knowledgeable physician can help negotiate treatment expectations and improve medication acceptance and adherence. Patients wish to maintain control, can be swayed by social influences and appreciate privileged access to biologic agents.

The cross-sectional study of 48 RA and 43 SpA patients from Canberra hospital found high rates of medication adherence using a self-report questionnaire and by looking at pharmacy refill records. However, low participation rates and limitations of the measures of adherence highlighted the need for more accurate, objective data to determine levels of adherence in this population. Multiple factors were tested in questionnaires for an association with adherence, and none were found to be significantly associated. Further work is needed to assess the reasons for non-adherence in rheumatology.

In our focus groups with gout, RA and osteoporosis patients and their caregivers, 46 participants identified more than 40 factors to influence adherence. The five top ranked factors were: trust in doctor, medication effectiveness, medication side effects, doctor’s knowledge and disease knowledge. These factors were amongst the top ten factors in subgroup analyses of patient/caregiver, condition and gender. Caregivers ranked medication side effects higher, and trust in doctor lower than patients.

The systematic review of qualitative (interview type) studies on transitional care in Rheumatology showed that there were limited studies (18 studies, predominantly with juvenile idiopathic arthritis patients). A synthesis of the studies found that successful transition can be nurtured by building trust in familiarity, creating a sense of belonging and facilitating an adolescent’s quest for autonomy. However some patients feel de-personalised, abandoned, ill prepared and out of control of the transition process. Patients wanted to be supported with issues they faced in work, education, relationships and with self –esteem. However, they felt that their health care providers focused on their clinical outcomes and medications rather than the issues that were most important to them. 14 Australian rheumatologists and 15 international rheumatologists from Canada, France, Germany, Japan, The Netherlands, Norway, Portugal, Singapore, Spain and Switzerland have participated in the clinician interview study. Many clinicians emphasised the importance of good patient-physician communication and relationship as being key to supporting medication adherence. In addition, participants valued working collaboratively with other health professionals such as social workers and pharmacists. The systematic review of outcomes in adherence trials showed the disconnection between strategies used to improve medication adherence and what is important to patients and caregivers to from our studies. From the 25 studies analysed in this systematic review so far, the top 5 reported outcome domains were; adherence (25 [100%] trials), medication knowledge (4 [16%]), then medication beliefs, medication necessity, and self-efficacy all reported in 3 [12%] trials. In addition, 31 unique ways of measuring adherence were identified. Medication adherence research in Rheumatology would benefit from better standardisation of adherence measures and ensuring the strategies used match patient and caregiver priorities. I have presented the findings of the studies outlined above at multiple international and national meetings to rheumatologists, nurses and other health care professionals, patient research partners and other researchers. This has helped me as a rheumatologist, and hopefully other clinicians in understanding what our patients experience with their medications. The research helps to think of solutions to better support patients’ needs around their medication taking, and overall care. I think that in the future it will help improve communication and trust between doctor and patient, and lead to better patient-focused solutions to improve support for medication taking. I will complete the six studies for my PhD in the next year. After this I plan to continue doing research with the OMERACT-Adherence special interest group to improve the quality of the interventions designed to support medication adherence in Rheumatology, and incorporate outcomes that are important to all stakeholders, especially patients.

With the support of Arthritis Australia, the Australian Rheumatology Association and Roche, I have completed a 12 month fellowship as an honorary fellow in the Department of Rheumatology and Connective Tissue Diseases, University College London (UCL) Division of Medicine, Royal Free Hospital, under the supervision of Professor Christopher Denton. The Royal Free Hospital (RFH) is a large University Teaching Hospital in the National Health Service (NHS), and a major European centre for the management of systemic sclerosis and related connective tissue diseases. Systemic sclerosis (SSc) commonly known as ‘scleroderma’ is an autoimmune condition that affects blood vessels and connective tissues. It causes hardening of the skin and can result in scarring of internal organs. Systemic Sclerosis is divided into two major subtypes; diffuse and limited disease. These subtypes are differentiated based on the distribution and amount of skin that is involved. These subtypes have different clinical manifestations and outlooks. It is important to identify which form of scleroderma a patient has in order to ensure optimal monitoring and management. Scleroderma is a condition that to date has no cure and unfortunately can cause significant functional impairment and a reduction in life expectancy. My research has focussed on this condition and I have been involved in both basic science and clinical research during my fellowship. My main area of investigation while completing my fellowship was to look into any relationships between a protein called: Interleukin-7 (IL7) and scleroderma. IL7 is a cytokine, these are small proteins produced and released by cells in the body that act as messengers between cells. IL7 was chosen to study as it plays a role in the functioning of the immune system, and has been shown in recent studies to be implicated in autoimmune diseases.

As a first step in introducing myself to this project I assisted in the genetic analysis of a group of scleroderma patients for differences in IL7 and IL7 receptor genes in a candidate gene association study. Genes are the building blocks of everyone’s individual genetic code (or DNA). Candidate gene association studies target a selection of genes that have been identified by previous research as being potentially implicated in a particular disease. We aimed to identify if specific changes within genes known as single nucleotide polymorphisms (SNPs) where related to scleroderma disease features.

The initial part of the study included 728 scleroderma patients and 260 without scleroderma. This study found a significant difference between scleroderma patients who had an antibody usually associated with the diffuse form of the disease (known as anti-topoisomerase I antibody [ATA]) versus those that did not have this antibody, in five areas (four SNPs in the IL7 receptor region and one in IL7 gene). We wished to see if these findings held true in a second, different genetic group of patients. We tested a further 256 scleroderma patients and 106 healthy people for the SNPs that were significant in the first stage. The association with the antibody ATA remained present for two SNPs when both groups were combined. Association of one SNP with pulmonary arterial hypertension, a disease characteristic affecting some scleroderma sufferers, was found in the second stage. These results are important in suggesting a potential genetic significance of IL7 in determining how scleroderma patients will present. We wished to look further for any associations between IL7 and the subtype of scleroderma (limited or diffuse), other disease characteristics and its profile over the disease time course. Our aim was to explore if IL7 was associated with the subtype of scleroderma that people develop, and could be a useful test for discriminating between the forms.

We looked at the levels of IL7 in the blood of 153 patients with scleroderma and 47 people without. We included patients with up to five blood samples available, representing different times in their disease. IL7 levels did not significantly change across time. We found a meaningful association between pulmonary arterial hypertension and mean IL7 levels. We also discovered that IL7 levels were significantly higher in scleroderma patients compared with patients who didn’t have scleroderma. There was no significant difference in IL7 levels across all scleroderma subtypes, although levels were numerically higher in diffuse scleroderma and levels in limited scleroderma remained significantly higher compared with people without scleroderma. This project represents the largest cohort in this area to date. We have shown increased IL7 levels in scleroderma patients. In addition, IL7 levels are elevated in scleroderma patients developing pulmonary arterial hypertension. However, IL7 levels did not change significantly over time and we did not identify a difference in IL7 levels when analysed across all scleroderma subtypes. The importance of this suggests that IL7 levels may be a marker of someone’s susceptibility to scleroderma, or a factor in which type of scleroderma you develop, rather than having a role in causing the disease itself.  The implications of these findings are that IL7 would therefore not likely be a good test in scleroderma for differentiating disease subtype, nor would it be a good target for drug trials in scleroderma. This research is important for scleroderma sufferers as it has largely excluded IL7 as a causative cytokine in scleroderma and thus further research should be directed towards other potential targets. Finally, I had the opportunity to explore a potential link between exposure to proton pump inhibitors (PPIs), medications used for the treatment of reflux, and calcinosis in scleroderma sufferers. Calcinosis is the deposition of calcium hydroxyapatite in the skin and subcutaneous tissues and occurs in around 25% of patients with scleroderma. The cause remains unclear and to date there are no proven effective treatments. Calcinosis can be a source of much distress for scleroderma patients. We assessed PPI exposure and the presence and extent of calcinosis in 216 patients seen at our clinic. We found an association of calcinosis with disease duration and antibody profile. The most striking finding from this study was that that even after correcting for disease duration and antibody status, we found that higher exposure to PPI (> 10 years) remained a significant predictor of calcinosis. To our knowledge work from our centre is the first to identify an association between PPI use and calcinosis in scleroderma patients. Given the clinical impact of calcinosis on scleroderma sufferers, and the lack of available efficacious treatments, this finding of a potentially adjustable risk factor is very important and warrants further investigation. As demonstrated above, we have answered all research questions set out during my fellowship. There will be further publications forthcoming from this research. I am confident that the research that I have been involved in, particularly my work in PPI and calcinosis, will lead the way for further studies.  Furthermore, through my fellowship I have gained laboratory skills, experience in research methodology including formation of research questions and implementation of studies, practice in writing abstracts for submission for international conferences, and producing and presenting posters at international conferences. Most importantly I have gained much knowledge in the management of patients with connective tissue diseases and learnt many skills that will benefit not only my career, but the patients I am to care for in the future.

The aim of this randomised, placebo controlled trial is to determine whether a low dose of colchicine is tolerated, and improves pain and function scores amongst participants with osteoarthritis (OA) of the hand, over three months. This pilot study is the first to investigate the use of colchicine in treating hand OA. Colchicine is a medication used to treat joint pain during episodes of gout, working as an anti-inflammatory. Colchicine may provide the first cost-effective pharmaceutical treatment option of participants with hand OA. Participants enrolled in this study are randomly placed into the placebo group, or the colchicine group. Both groups take two identical white tablets per day, one in the morning and one at night. The placebo tablets contain only non-active carbohydrate, while the colchicine tablets provide 1 mg colchicine per day in total. At the beginning and end of the study, participants report their hand pain and function via questionnaires. We assess fluid levels via ultrasound and perform a tender and swollen joint count on both hands. We monitor side-effects throughout the 3 month study. Participants can come off the medication if the side-effects are too severe. We hope that participants will be able to tolerate the medication without side effects, while receiving some benefit in their hand OA symptoms. So far we have 23 participants enrolled in the study, of a required minimum 62. Recruitment has been slower than expected, however is ongoing. As the participants and staff do not know which group each participant is in, we cannot analyse the results until un-blinding occurs. Two participants have stopped the medication due to suspected side effects, while several have reported a perceived benefit over 3 months.

Osteoarthritis of the hand affects roughly 20% of older adults, and has a negative impact on quality of life. There are no proven drug therapies to help prevent hand OA, or to delay progression. Pain killers and topical anti-inflammatory creams can provide temporary relief only. Some pain-killers have undesirable side effects if used in excess, thus are not a viable option for long term or daily use. Due to its anti-inflammatory properties, theoretically colchicine may help those with inflammation of the joints caused by osteoarthritis. Some previous research has suggested that colchicine may benefit those with knee OA, although it has never been studied for hand OA. This pilot study is the first to try colchicine in the treatment of hand OA. As an anti-inflammatory medication, long term use of colchicine in hand OA may help to reduce not only symptoms such as pain and loss of function, but also reduce the progression of the disease, prolonging quality of life. As the population of Australia ages, treatments for osteoarthritis will become increasingly important to prolong quality of life and reduce costs. The study has been recruiting for approximately 12 months, and we have so far enrolled 23 participants, with several more in screening. The target is 62 participants. As the study is double-blinded, that is, neither the participant nor the research staff knows whether the participant is in the placebo group or the active treatment group, analysis of results is impossible until the group allocation is revealed. This is scheduled to happen once the last participant has completed the study.

Although any formal results analysis is impossible at this time, some data can be presented. The average age of the participants currently enrolled is 67 years. We have 6 males and 17 females enrolled. At the half-way point, 7 of a possible 18 have reported a perceived benefit. Two participants reported side effects within 3 weeks of starting the medication and ceased immediately. Otherwise no side effects have been reported. This study may or may not directly benefit participants. If colchicine is effective as a treatment, participants allocated to the colchicine group may benefit directly from being part of the study. If the participants feel they have benefitted from the medication during the study, it can be made available to them at the conclusion of the 16 weeks, through either hospital staff or their GP. If a significant number of participants continue to perceive a benefit after 3 months, we may do an interim analysis to determine whether those participants were receiving colchicine. If there is a suspected benefit, the study will be terminated and colchicine will be made available to all participants. If participants are in the placebo group they will not benefit directly from the study, unless interim analysis suggests a clear benefit of colchicine. If there is a clear distinction between the two groups after the data has been analysed, this pilot study will be strong grounds to perform a larger, longer term study to determine the effects of colchicine on symptoms and progression of hand OA. Further questions will need to be answered, such as the ideal dose of colchicine, whether progression of the disease can be slowed, and whether there are gender or age differences in response. Colchicine may prove to be a cost-effective, low risk drug for sufferers of hand OA, in which case it will be the first pharmaceutical option to help treat OA, beyond pain killers. This research is ongoing. Recruitment will continue until the target of 62 enrolled participants is met. Efforts to recruit, including advertisements in local newspapers/magazines and via web channels will continue. If positive results are found, we will aim to submit for a grant to perform a larger randomised controlled trial over a longer term to confirm the results of the pilot study.

Low back pain is a major cause of disability and a common symptom for people with arthritis. People with low back pain commonly seek help from their community pharmacist.

This project, supported by Arthritis Australia through the Zimmer Biomet Australia Grant, aims to assist pharmacists to provide high quality care and information for patients who present with low back pain, through creation of customised evidence-based advice. This will be achieved using a decision support tool.

An Apple iPad App has been designed for use in community pharmacy, and is undergoing assessment prior to testing within pharmacies across the Sydney metropolitan area. Sufferers of low back pain in the community often do not receive the best advice to manage their pain effectively. Community pharmacists can play an important role for patients as pharmacists are easily accessible and are well placed to provide effective care for low back pain. However, a recent study found that pharmacists offered inadequate self-care advice, or failed to identify what types of low back pain presentations may require prompt medical review. The aims of this pilot research are to test the acceptability, and potential impact of the latest evidence-based advice as generated by a custom iPad App to assist pharmacists manage low back pain.

To create a decision support tool for pharmacists, multiple and sometimes contrasting design goals had to be met simultaneously. We needed to balance the competing aims of gathering enough information from the patient to provide high quality customised advice, while also ensuring the process was quick enough to be practical for pharmacists to use. The key questions needed to gather the critical information were: have you already consulted a pharmacist for this episode of back pain, what is the pain duration, is the pain is getting better or worse, what current medications are being taken and, questions relating to the possibility of serious disease. As a result, we designed the iPad App to work within the normal flow of a pharmacist-patient interaction. The iPad App has been designed to help pharmacists make the best decisions, not be a substitute for thinking or be overly prescriptive with advice. Finding the right balance has required multiple phases of consultation between health researchers, pharmacists, consumer representatives, and our computer programmer. We also discovered the need to be very careful in language used, in order to optimise patient understanding of the advice generated by the App. The final App has been designed so most of the output advice is generated automatically based on the patient’s responses but the pharmacist can override or modify this advice as they choose. Key messages such as staying active, avoiding bed rest, and using a heat wrap can be conveyed simply and effectively to improve symptoms, empower patients, and potentially decrease medication use. Development and refinement of computer coding has been completed, and the design of the interface for the iPad is in the final stages of usability testing. We will then test the App in the community pharmacy setting. A key barrier to improving the health of patients with musculoskeletal disease is how to offer evidence-based advice that is both accurate and easy to follow. Our research supports the pharmacist to deliver the latest evidence-based advice regarding self-care strategies, medicine choice, and referral advice within a single visit. Empowering patients with this advice will help to reduce the burden of low back pain in society. We will be continuing this project, and will use the results from the current study to further refine the iPad App whilst testing within community pharmacy. Future research can include clinical trials to test the effectiveness of the advice generated by the App, compared to other types of care, when patients present with low back pain.

Hip arthritis patients are known to suffer significant pain and loss of function during activities such as normal walking (gait). The loss of function has been related to atrophy of the gluteal muscles that stabilise the hip. Previous studies have shown limited benefits from rehabilitation programs that have been designed to improve hip muscle function. This research project is a randomised controlled trial (RCT) that aims to compare a new targeted gluteal exercise program to a sham exercise program to see if the targeted program can successfully improve hip muscle function and therefore improve activity levels of people with hip arthritis.

Both of the programs involve 12 weekly visits to specifically trained physiotherapists and home exercises. The targeted program targets not only particular muscles, but particular parts of those muscles with high intensity exercises should increase muscle size (hypertrophy). This program also involves gait retraining in an attempt to correct uneven gait (limping) and pelvic stability exercises to increase stability of the hip joint. In contrast, the sham program involves similar duration of exercise but not targeting particular muscles around the hip and usually non-weight-bearing exercises so is therefore less likely to result in improvements in muscle structure and function. Random allocation of participants to the two groups ensures that there is no bias in the study and checks whether any apparent benefits at the end of the study are in fact due to the targeted program or could be due to co-called placebo effect, whereby participation in even a sham program brings about benefits in the affected group.

The project is running across three sites; La Trobe University Bendigo, La Trobe University Melbourne and Otago University in New Zealand. Participants will have their hip muscle structure and function and their activity levels assessed prior to and after the 12-week rehabilitation program.

The major question that the grant set out to answer is whether the targeted program, in contrast to the sham program, results in improved gluteal muscle structure and function and whether the activity levels of the participants are improved as a consequence of any improved function. Our hypothesis is that previous rehabilitation programs for hip arthritis, unlike knee arthritis program, have not been adequately targeted at the affected muscle segments and that is why they have not been shown to be successful in improving patient outcomes. If the program is successful, this should improve function, and potentially delay hip replacement surgery, for hip arthritis patients. Because data collection is still underway we have no outcomes to report at this stage. However in this interim report we can outline progress as follows:

• Ethics approval was obtained at all 4 sites (initially one site was at the University of Queensland, but one of our Chief Investigators, Dr Adam Semciw, has relocated to La Trobe University in Melbourne during the course of the grant so this site was abandoned.
• The Bendigo site currently has 9 (of intended 30) participants that have completed the rehabilitation with all data collected and a further 5 participants that have commenced the program (baseline data collected). Recruitment is continuing in the hands of Zac Rostron, a new PhD student on this project and we hope to complete data collection by the end of 2018.
• The Otago site currently has 13 (of intended 20) participants that have commenced the program (baseline data collected) and recruitment is continuing in the hands of Steph Woodley and Pete Lawrenson, a research assistant being employed under complementary funding through Arthritis New Zealand is conducting the data collection. Again it is hoped that data collection will be completed by the end of 2018.
• The Melbourne site has been delayed but training of the physiotherapy staff has been completed and Belinda Pacella has been employed as a research assistant to undertake recruitment and data collection activities. Belinda is being employed using Arthritis Australia funding from this grant. We hope that data collection for the intended 40 participants (20 transferred from University of Queensland site) will proceed more efficiently now that Adam Semciw will also be present at this site to assist.
• If necessary, we may recruit additional participants at each of the Bendigo and Otago sites if their numbers are reached before Bundoora site reaches target numbers.

Rheumatoid arthritis is a chronic systemic destructive inflammatory disorder characterised by joint inflammation, synovia hyperplasia and associated destruction of bone and cartilage impacting on joint function. Additionally, nociceptive pain, attributed to the damage to body tissue causes significant morbidity. There is a recognised decrease in the threshold of the sensory nervous system’s response to certain harmful or potentially harmful stimuli threshold (hypernociception) that also
impacts on joint function. Currently, there are few effective treatments that target inflammation, bone loss and hypernociception. Many disease modifying anti-rheumatic drugs (such as methotrexate) target inflammation, allowing chronic bone erosion to progress. The overarching aim of the project was to investigate the immunomodulatory and anti-inflammatory properties of parthenolide on local bone loss and inflammation and the associated hypernociception in an animal model of collagen antibody induced inflammatory arthritis. Clinical Paw Induction of CAIA resulted in significant redness, tenderness and inflammation in the front and rear paws following LPS administration on day 3. From day 8-10 CAIA mice treated with 4mg/kg PAR had significantly lower paw scores compared to CAIA untreated mice (p<0.05). On day 10 CAIA mice treated with 1mg/kg PAR also had significantly lower paw scores compared to CAIA untreated mice (p=0.03). Micro-CT BV and PV: Control CAIA CAIA+PAR 1mg/kg CAIA+PAR 4mg/kg
BV measured in the radiocarpal joints was significantly greater in control mice compared to all disease and treatment mice (p<0.0001). Similar to BV, control mice also had a significantly lower PV compared to all disease and treatment groups (p<0.001). Consistent with inflammation present on day 10, CAIA mice treated with 1mg/kg and 4mg/kg PAR showed lower PV measurements compared to CAIA mice.

However, this was not significantly different. Histological evaluation of sagittal sections of the radiocarpal joint and ankle joint showed that CAIA untreated mice had significantly greater scores for cellular infiltration, cartilage and bone degradation and pannus formation compared to non-diseased mice (p<0.0001). Although CAIA mice treated with either 1mg/kg or 4mg/kg PAR exhibited reduced scores for cellular infiltration, cartilage and bone degradation and pannus formation compared to untreated CAIA mice, this was not statistically significant: All CAIA groups had a significantly greater number of TRAP-positive multinucleated cells on the bone surface and within the surrounding soft tissue compared to control mice (p<0.0001 and p=0.0002, respectively). CAIA mice treated with 4mg/kg PAR had a significantly lower number of TRAP-positive multinucleated cells on the bone surface compared to untreated CAIA mice (p<0.05). These mice also had reduced TRAP-positive multinucleated cells within the surrounding soft tissue, however this was not statistically significant. In the rear paws, a significantly greater number of TRAP-positive multinucleated cells was also observed on the bone surface and in the surrounding soft tissue of all disease and treatment groups compared to control mice (p<0.0001). Similar to the front paws, CAIA mice treated with 4mg/kg PAR had a lower number of TRAP-positive multinucleated cells on the bone surface, however this was not statistically significant. Within the surrounding soft tissue CAIA mice treated with both 1mg/kg and 4mg/kg PAR had significantly lower TRAP-positive multinucleated cells compared to CAIA mice (p-0.025 and p-0.0057, respectively). However, there was no significant difference between the two treatment groups. We are currently finalizing immune histochemical analysis of glial activation (astrocyte and microglial) in the brain and spinal cord. This will enable us to determine central involvement of the inflammatory pathway by measuring astroglyosis/microgliosis observed as cellular morphological changes. Glial fibrillary acidic protein (GFAP) as a marker of astrocytes in the mouse CNS and Iba-1as a marker of activated microglia. Current results were presented at the European Calcified Tissue Society PhD Workshop in September 2018. An abstract will also be submitted to the State Australian Rheumatology Association Conference to be held in November 2018. A manuscript is in preparation and will be submitted once the analysis of the CNS has been finalized.

We are grateful to the Australian Rheumatology Association and the Estate of the Late Marion Alice Simpson for support of our project.

The immune system protects us from harmful infections and tumours but, in some instances, also attacks healthy tissues in our own bodies resulting in autoimmune diseases. Ankylosing spondylitis (AS) is one such disease. It is a chronic inflammatory disorder that mainly affects the spine and pelvis. It is a severely disabling disease that normally first presents in the second decade of life. There is no cure for AS but powerful anti-inflammatory drugs relieve some of the symptoms of disease telling us that inflammation is an important part of the disease process. AS is an inherited disease and our group has led large genetic studies in the last decade to define genes that increase the likelihood of developing AS. We have now discovered over one hundred of these so called AS-associated genes, many of which are involved in control of the immune system. Our ongoing research program aims to understand how these change functions of immune system in AS patients. Our ultimate goal is to identify specific parts of the immune response in AS patients that may be useful targets for novel drug development.

Our studies have shown that a protein called T-bet plays an important role in the immune system of AS patients and contributes to some of the inflammation seen in patients. In mouse models of AS, mice that lack the T-bet gene do not develop disease. T-bet is a protein that is capable of controlling many different types of immune responses. Of importance to AS, one of the immune responses it controls involves one of the critical proteins in AS inflammation, IL-17. Immune cells in AS patients make a lot more IL-17 than immune cells in healthy people. In turn, this increased amount of IL-17 plays a big part in the inflammation and subsequent pain experienced by AS patients. In clinical trials, patients who receive drugs that block the effects of IL-17 have their inflammation significantly reduced and experience reduced levels of pain. Since T-bet plays an important part in controlling how much IL-17 is made by immune cells, understanding more about T-bet in AS patients provides an opportunity to know more about the immunological basis disease and may highlight new drug targets.

T-bet controls the function of other genes by directly attaching to parts of those genes. A lot is known about what genes T-bet controls in mice and mouse models of disease but very little is known about its function in humans. Almost nothing is known about its function in human diseases. The goal of our studies was to determine precisely what aspects of the immune response T-bet controls in AS patients. We planned to do this in two ways: (i) by purifying T-bet from cells and studying what genes were attached to T-bet which would give us a precise list of genes that T-bet controls in humans; (ii) by studying in detail the function of immune cells in which T-bet is found compared with cells in which there is little or no T-bet.

This was a challenging and ambitious project and we have had to develop new methods to purify T-bet from cells. This method development has taken considerable effort and time. As of July 2018 we are very close to finalising the method development and will be able to study T-bet in great detail before the end of 2018. Analysis of cells is part of a larger study and has also taken considerable time to complete. The challenge here has been recruitment of patients and healthy controls that carry the necessary set of genes (known as a genotype). This has taken longer than anticipated because finding healthy controls carrying the main AS-associated genes has required recruiting and screening a large number of people. In this regard we have collaborated widely to access biobanks and blood collections in order to expedite our recruitment.

 This work is ongoing and remains a priority within our group. To date, we have developed methods for reliable isolation of T-bet (and attached genes) from human immune cells called CD8 T cells and NK cells. While methods for T-bet isolation have been described in the scientific literature none of these worked reliably for CD8 T cells or NK cells. The methods we have now optimised work reliably and reproducibly. Furthermore, we have generated the raw materials to perform next-generation sequencing on CD8 T cells and NK cells from AS patients and healthy controls and will commence sequencing these samples before the end of 2018.

The real strength of our study will be realised towards the end of 2018 as we perform ‘next generation sequencing’ of T-bet associated genes and of the immune cell subsets in which T-bet is found. This sequencing effort will generate very large and complex datasets that will be require specialist analysis. We have in house experts in this type of analysis ready to go once the data is generated. At a simple level we will be able to define what genes T-bet controls and how T-bet changes the function of particular immune cells. However, based on our experiences with similar projects the datasets generated will provide new and important knowledge for many years as our ways of interrogating the data becomes more refined and sophisticated.

The long term potential of the data we are generating is great. We are producing very large datasets containing a lot of complex data that will be analysed for many years to come. This dataset will be a rich resource for our lab in the first instance but will also be made publicly available to the wider AS research community in time and will therefore provide a resource beyond the scope of our own studies.

In mouse models of AS we have demonstrated that deletion of the T-bet gene prevents disease developing. Such as strategy is not possible in humans but by defining what genes T-bet controls in AS we have the opportunity to identify new drug targets in the future. The large datasets we are generating will inform basic knowledge of T-bet function in human immune cells. This is fundamental science and will lead to new knowledge of immune function.

This research is ongoing and a very important focus of our group currently. The data generated from this study will be thoroughly interrogated for many years by us and the wider research community.

Treat to Target in Rheumatoid Arthritis (RA TTT) is a way of treating RA where a ‘target’ is set by both the patient and the rheumatologist. This is similar to the approach taken in diabetes and hypertension where a target for treatment is established based on evidence for disease improvement. Using an RA TTT strategy has been shown to significantly improve outcomes for people living with RA. However, implementing RA TTT has many challenges and as a result, an ‘evidence-practice’ gap has emerged. This project is attempting to address this gap via analysis of patient and clinician opinion regarding knowledge, understanding of and use and acceptance of RA TTT in Australia. Additionally a tool (for use on a tablet device) has been designed and is being tested for use by both the patient and rheumatologist at the point of care to allow for an RA TTT shared decision-making process to be instigated.

The research project aimed to investigate patient perspectives and clinicians’ knowledge and acceptance of RA TTT and then address the RA TTT evidence-practice gap through the development of a patient-centred knowledge-translation (KT) tool (on a tablet device) and to determine its effectiveness in ‘real-life’ clinical settings. This is important as addressing the gap will reduce disease activity and therefore reduce pain, improve function and prevent progression of damage. TTT regimens reduce disability, increase quality of life and normalise life expectancy in RA.

We have discovered from the patient surveys that a significant number of patients feel their RA treatment could be improved (48%) and many would like to be more involved in their treatment decisions (28%). Strikingly most patients (91%) have no knowledge of RA TTT but when given education about it they report high levels of agreement and a high level of willingness to try a TTT approach for their RA. Approximately 50% of rheumatologists reported very often or often using RA TTT in daily practice with the barriers including time pressures, concerns around patient acceptance and adherence to medication changes, lack of appointment availability and the lack of a rheumatology nurses in clinics. Given the significant clinician and patient barriers identified we have used this information to further inform the development and testing of the KT tool. This tool has been designed to explain RA TTT to patients before they go in for an appointment (in the waiting room) and then for it to be used during the consultation. The usability testing before and during 40 patient-rheumatologist appointments has just been completed and the data is being analyzed at present.

This research actively continues with the analysis of the usability study and we expect the results to further improve our understanding of the patient’s perspective on RA TTT and to demonstrate that a patient-centred KT tool is acceptable, feasible and effective in real-life clinical settings. The next step is to consider a pragmatic multi-centre randomised controlled trial (RCT) comparing the effectiveness of a patient-centred RA TTT approach using the tool with existing standard care. This innovative project will be one of the first implementation projects undertaken in Australia within RA TTT and we believe that it will provide important data demonstrating the importance of translating research into practice and the value in a patient-orientated approach to care of RA. This initial funding has allowed us to establish this program of research and we are very grateful to Arthritis Australia and The Ride for Arthritis Grant in Aid funded by Chris Barrie and team.

Falls are among the most common cause of injury and hospital admissions in older people in Australia. The number of falls experienced by people who have knee osteoarthritis is almost double the number experienced by people who have no osteoarthritis in their joints. In our previous research work, we found that when simulating a forward fall those with knee osteoarthritis demonstrated slower step responses and impaired ability by the knee joint to absorb impact forces and slow down the body forward momentum to arrest a fall. The inability of the muscle to respond quickly might be related to loss of muscle power (the ability to produce force rapidly), especially in the quadriceps, which are the most commonly affected muscles in those who suffer from knee osteoarthritis. Therefore training the ability to generate force quickly specific to daily living tasks might help to maintain muscle function and effective stepping responses, which also has the potential to prevent falls. Exercise interventions that focus on balance exercises have been shown to be effective in reducing falls for older people. However, there is no evidence to suggest that using current fall prevention programs will be also effective for people with knee OA. Moreover, existing exercise-based fall prevention programs mainly focus on maintenance of balance and do not focus on training the ability of the muscle to produce force rapidly (known as muscle power), which is required to arrest a fall when losing balance. The questions that were aimed to be answered by the grant: In this study we examined the feasibility and safety of eight weeks high speed resistance training programs with and without balance exercises for people with knee osteoarthritis. The effect of the exercise programs on strength, balance, physical function, pain and executive function was also examined. The results of this study aimed to assist us to understand what type of exercise is safe and beneficial for people with knee osteoarthritis to reduce their risk of falling and hence to inform the development of a future large research trial.  To address the research questions three groups were involved and compared in the study: a control group (received no intervention), a high speed resistance training program and a high speed resistance training plus balance exercises program. Participants from all groups were examined at the beginning and after 8 weeks. The pain level during and after each exercise sessions was recorded. Attendance was also recorded as well as any drop out due to reasons associated with the exercise program. Comparison between the groups also took place to determine any improvements in strength, function, balance and mobility.

Twenty-eight participants, average age 67.8 years, took part in the study. Our results demonstrated that the high speed resistance trainings with and without balance exercises were safe and feasible interventions for people with knee osteoarthritis. We reported no drop-outs associated with the exercise programs or adverse events. Both exercise programs resulted in high adherence, satisfaction and overall pain reduction during and after the exercise sessions throughout the eight week exercise program. Both groups also showed improvement in function and lower limb strength. The study incorporated weight bearing functional exercises (e.g. sit to stand, squat) in addition to dynamic and static balance exercises (in the combined group), which resulted in improved muscle performance measures as well as functional power task. Consequently, the combination of the high speed functional movements and the balance exercises might provide beneficial effect on muscle coordination and integration that are more likely to translate into daily activities. Given the pain associated with knee osteoarthritis, it was important to monitor pain during and after exercise sessions to determine the effect of the rapid and powerful movements had on knee pain. Throughout the exercise programs, there were several instances of substantial pain during or after the exercise program. In most instances, the pain subsided within 24 hours. Mild to moderate pain is expected in some people with knee osteoarthritis while exercising, and provided it is short term and
returns to baseline relatively quickly, should not be perceived as damaging.

The next research direction should examine the optimal combination of high speed resistance and balance exercises and its effect on the actual number of falls in people with knee osteoarthritis.

Since receiving the Arthritis Australia Project Grant in 2017 we have undertaken a number of research activities. Firstly, we utilised the Western Australian Rheumatic Disease Epidemiological Registry (WARDER) to produce measures of hospitalisation rates, and mortality rates for patients with SLE over the last 35 and 20 years, respectively. These findings have been presented at national and international scientific meetings and the manuscripts for these projects are currently being written. Secondly, we made inroads to describe the clinical characteristics and disease course of SLE patients in WA in more detail. This was achieved through a collaboration between the Departments of Rheumatology, Immunology, Pathology and Renal Medicine at Sir Charles Gairdner Hospital, where we undertook a retrospective review of all patients undergoing a renal biopsy in Perth, Western Australia. This collaboration resulted in 4 abstracts, 4 poster presentations, 1 manuscript undergoing peer-review and 1 more to be finalised amongst the author group. These research outputs detail the differences in health outcomes across ethnic groups as well as looking at the differences in histopathology and clinical outcomes between Indigenous and non-Indigenous Australians. While the bulk of the research has been completed data collection will enable us to do an additional project that will look at the disease course of a sub-set of patients with multiple renal biopsies. Finally, we aimed to increase the number of participants in the Perth Lupus Registry and Biobank (PLRB). So far we were able to increase patient recruitment to over 100 patients, up 100% year-on-year, and the project is closing in on the target of 250 participants by the year end of 2018. Progress with the PLRB includes partnering with Infobite™ a mobile application system that securely stores data on Amazon Web Services servers to collect health-related quality of life information via a participant’s mobile or email. The partnership to collect data with Infobite™ aims to ease time pressures of clinicians to collect data during their consultation, and streamline data collection by reducing the need for paper questionnaires and face-to-face interviews. The PLRB has been running since 2015 and as a result we have up to 3 years of data collection for some participants. We are still on track to produce research outputs, including a manuscript, describing an inception cohort from July 2019. This grant was not about generating a single answer to one specific research question, but rather, it enabled us to establish or contribute to the development of a number of research databases, i.e. Lupus Nephritis Database, Perth Lupus Registry and Biobank and the Western Australian Rheumatic Disease Epidemiological Registry (WARDER). From these databases we have produced 8 abstracts, 6 poster presentations, 1 oral presentation, 1 manuscripts under review and 1 manuscript on lupus mortality rates in WA is currently being drafted for submission. While our research is descriptive and epidemiological in nature we were able to describe for the first time the way in which Western Australians with SLE experience lupus nephritis from both an ethnographic and histopathological perspective. Furthermore, we were able to detail the mortality rates and causes of death from 1980 to 2015, of which, a more refined analysis on the period from 1995 to 2015 was presented in Europe and will be published on later this year. This research is important to describe the Western Australian context for patients with SLE. SLE is relatively rare and the ‘noise’ created by cancer(s), cardiovascular disease, diabetes, etc. can often drown out the awareness in the community about other conditions. By producing this research we are actively raising awareness about the condition within the health and medical research community, teaching hospitals, consumer advocacy groups (LupusWA) and the Arthritis Foundation of Western Australia), patients and the wider community.

There are few consensus-based treatment guidelines for Systemic Lupus Erythematosus (SLE). The goal of our project is to develop an evidence-based treatment algorithm for SLE, taking into account patient and physician preferences, and which draws on understanding of factors that influence treatment decision in this disease. There are, broadly, three steps involved in completing this project – firstly, understanding current practice and the current evidence-base regarding SLE treatments; secondly, understanding the patient, physician and other factors that influence treatment decisions in SLE; and finally combining knowledge gained from fulfilling the first two steps into the development of a patient and physician-centered, evidence-based treatment algorithm for SLE. It is hoped that development of such an algorithm, applied to routine clinical practice, will lead to improved treatment outcomes for patients with SLE.

In order to gain a better understanding of current practice, and the current evidence-base regarding SLE treatments, we are currently performing systematic reviews of treatment for each different SLE organ system involvement. We anticipate that these will be completed by the end of 2018, and submitted for publication. We have performed a systematic review of recent phase 3 clinical trials for SLE, which has been published in Seminars in Arthritis and Rheumatism, and presented at the American College of Rheumatology Annual Scientific Meeting in 2017. This study showed that few of the novel treatments tested in phase 3 clinical trials for SLE were successful in meeting their primary trial endpoints, however there was often benefit seen in biologic parameters, and in secondary clinical endpoints, in particular, in decreasing the need for the use of steroids. This study also added to the available literature suggesting that a chosen outcome measure can influence study success. To this end, we have also undertaken a post hoc analysis of a novel lupus disease remission outcome measure, the Lupus Low Disease Activity State (LLDAS), which was pioneered by the Asia Pacific Lupus Collaboration, led by Australian rheumatologists, in the pivotal phase 3 clinical trials of belimumab, the only phase 3 trials to meet their primary endpoints. We have found that the LLDAS is able to differentiate those who responded to belimumab from those who did not, but that it is a more stringent outcome measure than that used in the original trial. More stringent endpoints could have a potential benefit of being able to differentiate novel drugs with more robust effects. On the subject of outcome measures in SLE, we are also engaged in collaborative work with lupus experts in the United States, to develop a better understanding of the influence of laboratory parameters on the Physician Global Assessment (PGA) score in SLE. We have submitted work on the LLDAS in belimumab studies, and laboratory measures influence on the PGA, to be presented at the upcoming American College of Rheumatology Annual Meeting later this year.

With regard to understanding factors which influence treatment decisions in SLE, we are currently collaborating with Korean lupus experts to survey rheumatologists with expertise in treating lupus throughout the Asia-Pacific, on infrastructural influences on treatment, and also experts’ personal treatment preferences. We anticipate results from this research by the end of year, and to present the research at the upcoming 13^th International Congress on SLE in early 2019.

We plan to continue this research over the next 2-3 years, and have plans to survey patients throughout the Asia-Pacific region on their preferences regarding treatment, in early 2019, and to use data from the Asia–Pacific Lupus Collaboration on SLE database to gain an understanding of current treatment practices throughout the region. Thereafter, we plan to convene a patient-physician roundtable to formulate the treatment algorithm, and pilot-test it in lupus clinics at St Vincent’s Hospital and the Monash Medical Centre.

We would like to thank Arthritis Australia for providing this Fellowship, so that Dr Oon could carry out this research, which we hope will improve understanding and outcomes of SLE treatment.

Osteoarthritis (OA) is the most prevalent form of arthritis in Australia and worldwide. OA is a chronic and painful disease of the synovial joint, and a leading cause of disability. Knees, hips and hands are the most commonly affected joints. Pain is the most prominent symptom which drives patients to seek healthcare. Thus, OA represents an enormous health and economic burden on patients and societies. There were 100,000 knee and hip replacement procedures (mainly due to OA) performed in Australian hospitals during 2015, with a cost of $2 billion a year. Current pain control is unsatisfactory. There are no proven strategies to prevent, slow, halt or reverse the OA progression. Current OA management is mostly palliative and focuses on pain relief. ‘First-line’ agents, such as paracetamol and non-steroid anti-inflammatory drugs (NSAIDs), have only small to moderate efficacy, with >75% of patients reporting the need for additional symptomatic treatment. Furthermore, there are increasing safety concerns about their use. For example, NSAIDs have long been associated with gastrointestinal adverse events, both minor and life-threatening. A more in-depth understanding of the contribution of the central nervous system to chronic musculoskeletal pain offers additional appreciation for the exploration of centrally-acting medications in OA. Nonetheless, pain control remains a substantial unmet need in OA treatment. In addition to the need to develop drugs that can slow disease progression, there is a critical need to develop more effective pain relief agents for OA patients.

Current OA management and ongoing clinical trials tend to use a ‘one size fits all’ approach. This partly explains the overall lack of treatment efficacy and frequent negative findings from OA clinical trials. OA is a heterogeneous condition characterised by a complex and multifactorial nature. This leads to the large variation in clinical presentations (pain) and responses to OA treatment. Therefore, in order to optimise treatment effects in OA, the ‘one size fits all’ treatment approach needs to change to more tailored managements and strategies targeting specific subgroups/phenotypes. It is likely that different subgroups/phenotypes will differ in the underlying causes, mechanisms and health outcomes, and will consequently require different therapeutic approaches.

There are homogenous pain subgroups/phenotypes that exist within knee OA populations. Pain experience is a complex phenomenon which is affected by factors across multiple domains–peripheral, psychological, and neurological. This heterogeneity could explain poor responses to pain treatments. Although research studies have examined these factors on an individual basis, no study has examined all of these factors in the same population. Discoveries from my own research have demonstrated the existence of distinct OA subgroups. Moreover, my most recent work, recently received a revision in the Rheumatology journal (Top 3 journal in Rheumatology field), which is the first study to comprehensively classify pain phenotypes using a wide spectrum of factors such as neurological, psychological factors and structural damage on MRI, identified three distinct pain phenotypes. These three pain phenotypes that potentially represent subgroups may benefit from different treatment approaches in general practice, and have different health outcomes.

My research tackles the urgent unmet need for OA pain control by identifying clinical subgroups characterised by different phenotypes. The findings will facilitate the development of targeted therapies to this highly heterogeneous condition. My research, therefore, has great potential to improve quality of life and save substantial healthcare costs as a result of a reduction in joint replacements due to pain relief.

The aims of the grant are to identify OA phenotypes, understand the mechanisms underlying these phenotypes, develop targeted treatments for subsets of patients with different phenotypes and investigate the impact of pain on patients’ health outcomes.

Knee OA is a heterogeneous condition, which involves variations in pathophysiologic aetiologies, disease progression, and factors specific to patient’s pain complaint. There has been great interest in the OA field to identify homogenous subgroups or phenotypes that exist within knee OA populations. Some studies have considered disease or structural progression to identify knee OA phenotypes, while others have considered pain perception. The latter is more clinically relevant as the ultimate goal of identifying clinical phenotypes is to improve the effectiveness of clinical interventions for knee OA patients. The pain experience is a complex phenomenon which is affected by factors across multiple domains – peripheral, psychological, and neurological. This complexity has hindered the identification of pain phenotypes in prior work. Peripheral structural damage in the knee has historically been thought to be the key origin of pain in knee OA; however, there is a weak association between radiographic disease and knee pain. Magnetic resonance imaging (MRI) studies show there is moderate level of evidence for an association between MRI structural abnormalities and knee pain. A recent study showed that 20-35% of the variation in pain is explained by structural damage. Psychological and neurological factors are also important contributors to pain and worse clinical outcomes in knee OA. This heterogeneity could explain poor responses to pain treatments. Latent class analysis (LCA) is an effective approach for identifying underlying unobserved subgroups of individuals based on multiple observed individual characteristics within a heterogeneous population. It is based on a finite mixture model and hypothesises that a population is consisted of two or more underlying latent groups which may differ in the response to prevention or treatment. LCA is superior to traditional cluster analyses as it can provide a model-based clustering approach using probability and additional assessment for model fit such as maximum likelihood. Given the heterogeneity of pain in knee OA, successful identification of pain phenotypes using LCA while considering peripheral, psychological, and neurological domains has the potential to further our understanding of the pain experience and improve pain management in knee OA patients. There is, however, only one cross-sectional study identifying pain phenotypes related to knee OA across multiple pain-related domains. Furthermore, to our knowledge, no studies have validated whether identified pain phenotypes were accurate through examining the clinically relevant association with distal pain features. Therefore, the aims of this study were to identify and validate ‘knee pain phenotypes’ in an older population with an average follow-up time of 10.7 years (range 9.2-12.5 years) across different pain-related domains.

Musculoskeletal pain is a leading cause of disability in the elderly and has an adverse impact on other health outcomes such as poor physical function and reduced quality of life. Its prevalence is high, with an estimate of 74% in community-dwelling older adults. The causes of musculoskeletal pain encompass a spectrum of conditions where osteoarthritis (OA) is the most common cause of pain. Studies have shown that 20% of musculoskeletal pain is ascribed to OA and the proportion increases markedly with age, with 78% of knee pain attributed to radiographic knee OA (ROA).

OA in the knee is a disabling condition ranked as the 11^th highest contributor of the 291 conditions to global disability. Pain in the knee results in a significant impact on individuals’ physical and psychological outcomes. However, pain relief remains an unmet clinical need, with modest efficacy of currently used pain medication. Lack of in-depth understanding of pain mechanisms might partly explain the reduced effectiveness of current treatments.

Pain is generally considered to gradually get worse in parallel with structural changes over time. While worsening of pain is often noted at the group level, recent studies have found a high variation in the individual course of structural progression and pain with some patients remaining stable, experiencing improvement or worsening. This suggests that not all patients with pain have progressive symptoms. Within this highly heterogeneous population there may be homogenous subgroups of patients who follow distinct trajectories. In this context, there have been some attempts to identify knee OA pain trajectories and their risk factors over periods of 5-8 years. These studies identified at least three trajectories with the most common factors related to pain trajectories being higher BMI, lower education level, presence of psychological problems and comorbidities. Although peripheral structural factors have traditionally thought to be an important factor in the genesis of pain, results about the association between radiographic severity and knee pain trajectories have been mixed. No study has examined whether structural damage on magnetic resonance imaging (MRI) can predict pain trajectory, and whether it is independent of other pain dimensions.

Therefore, this study aimed to identify distinct knee pain trajectories over 10.7 years in an older population and those with ROA, and to examine predictors of identified pain trajectories including MRI-detected structural pathology, demographic, psychological, lifestyle and comorbidities.

Musculoskeletal pain is common in western countries with a prevalence estimated as high as 70% in the general population. It leads to restrictions in physical function and activity, reduced quality of life and disability. Musculoskeletal pain has become a major public health burden worldwide. A recent study of the global burden of the 328 diseases and injuries reported that low back pain, neck pain, other musculoskeletal disorders and osteoarthritis were ranked 1^st, 6^th, 7^th and 12^th, respectively, for years lived with disability (YLDs).

In pain research, the concept of ‘multi-site’ or ‘multiple site’ pain (MSP) has been proposed; defined as musculoskeletal pain occurring at more than one site, although, currently, an exact definition is still unclear. The prevalence of MSP is approximately 41-75% depending on study population and number of painful sites measured. It has been found to be associated with poorer physical and psychological health, worse health-related quality of life, and more severe depressive symptoms as compared to single-site musculoskeletal pain in both cross-sectional and longitudinal studies. In addition, several studies also reported the adverse effects of MSP on other health outcomes, including risk of falls, cognitive impairments and sleep quality. There is also evidence of a strong dose-response relationship between the extent of pain and these outcomes. Many of these outcomes may result from and lead to reduced physical activity (PA).

Low PA is the fourth leading cause of mortality worldwide. Lack of PA is associated with an increased risk for cardio-metabolic disorders such as diabetes and heart diseases; and common mental disorders, such as depression and anxiety. A recent meta-analysis of seven studies found that older people with musculoskeletal pain are less likely to engage in PA than those without musculoskeletal pain. All included studies have relied on a self-reported PA from which it is hard to quantify total PA across different domains. Self-reported activity levels are however poorly correlated with objective measures of PA participation, i.e. accelerometer, with self-reported PA estimates more likely to be higher than those measured by objectively measured PA. This highlights the need for accurate and reliable measurements of PA in assessing the relationship between PA and health outcomes. To our knowledge, there are no previous studies reporting on the relationship between pain at multiple sites and objectively measured physical work capacity (PWC) and PA. Therefore, the aim of this study was to describe the association between MSP and objectively measured levels of PWC and PA in a population-based sample from the UK biobank.

Metabolic syndrome (MetS) has been suggested as having a role in osteoarthritis (OA) pathogenesis. No study has assessed whether MetS and its components are associated with pain severity and number of painful sites (NPS) and their courses over time. We aimed to examine the association of MetS and its components with trajectories of pain severity and NPS in people with radiographic knee OA (ROA) over 10.7 years. 1,099 participants (mean age 63 years) from a population-based older adult cohort study were recruited at baseline. 875, 768 and 563 participants attended years 2.6, 5.1 and 10.7 follow-up, respectively. Data were collected on demographic, psychological, lifestyle and comorbidities, blood pressure, glucose, triglycerides, and high-density lipoprotein (HDL) cholesterol. MetS was defined based on National Cholesterol Education Program-Adult Treatment Panel III criteria. ROA was assessed by X-ray. Knee pain was measured by Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire at each time-point. Presence/absence of pain at the neck, back, hands, shoulders, hips, knees and feet was collected by questionnaire at each time-point. Group-based trajectory modelling was applied to identify pain trajectories. Multi-nominal logistic regression was used for the analyses. 60% of participants had ROA and 32% had MetS at baseline. Three pain severity trajectories were identified: ‘Marginal pain’ (50%), ‘Mild pain’ (35%) and ‘Moderate pain’ (15%). Three NPS trajectories were identified: ‘Low NPS’ (10%), ‘Medium NPS’ (38%), and ‘High NPS’ (52%). In univariate analyses, MetS was associated with increased risk of both ‘Mild pain’ (relative risk: 1.47, 95%CI: 1.10−1.96) and ‘Moderate pain’ (2.22, 1.54−3.20) relative to ‘Marginal pain’. It was also associated with increased risk of both ‘Medium NPS’ (2.25, 1.11−4.54) and ‘High NPS’ (3.36, 1.70−6.63) compared to ‘Low NPS’. In multivariable analyses, abdominal obesity was associated with increased risk of both ‘Mild pain’ (1.70, 1.17−2.49) and ‘Moderate pain’ (2.75, 1.63−4.64), and MetS and low HDL were associated with ‘Moderate pain’. Abdominal obesity was the only component associated with increased risk of both ‘Medium NPS’ (2.82, 1.39−5.70) and ‘High NPS’ (3.60, 1.79−7.24), and MetS was only associated with increased risk of ‘High NPS’. However, these associations became non-significant after further adjustment for body mass index, but hypertension became protective with ‘Mild pain’. MetS is predominantly associated with trajectories of pain severity and number of painful sites through abdominal obesity, suggesting that weight management is the most important way of controlling OA pain.

Pain is common in older adults typically involving multiple sites. Pain at multiple sites has been shown to be associated with a number of adverse health outcomes; however, whether pain at multiple sites is associated with fractures, and whether this association is dependent of falls risk and bone mineral density (BMD) are unknown. This study aimed to examine the associations of number of painful sites with prevalence and incidence of fractures, and to explore whether pain at multiple sites is an independent marker for fractures. Data from a longitudinal population-based study of older adults (mean age 63 years, 51% female) were utilized with measurements at baseline (n=1086), and after 2.6 (n=875) and 5.1 years (n=768). Presence/absence of pain at the neck, back, hands, shoulders, hips, knees and feet was assessed by questionnaire at baseline. Fractures were collected by questionnaire at each time-point. BMD was measured by Dual-energy X-ray absorptiometry (DXA). Baseline demographic, lifestyle and fall risks data were also obtained. A total of 385 fractures were reported at three time-points and 86 incident fractures were observed over 5.1 years. Greater number of painful sites was associated with higher prevalence of fractures at any sites, fractures occurring at vertebral, non-vertebral and major sites (including the femur, radius, ulnar, vertebrae, rib and humerus) within 5.1 years in univariable and multivariable analyses with adjustment for age, sex, body mass index, smoking history, physical activity, pain medication, BMD and falls risk. There was a dose-response relationship between number of painful sites and prevalence of fractures at these sites (all P for trend <0.05). In addition, risks of incident fractures occurring at any sites and major sites over 5.1 years increased with greater number of painful sites in a dose-response manner before and after adjustment for confounders (all P for trend ≤0.15). No significant association between number of painful sites and prevalent and incident hip fractures was observed. Pain at multiple sites is associated with a higher risk of prevalent and incident fractures, which is independent of falls risk and BMD, suggesting that widespread pain may be a useful marker for screening older population at high risk of fractures. Counting number of painful sites and managing MSP are particular of importance in clinical practice to prevent fractures and reduce health burden.

I am not a real statistician, so took me long time to learn the sophisticated statistics (latent class analysis and group based trajectory model which were used for identifying distinct pain phenotypes and trajectories). In particular, traditional methods for dealing with missing data cannot be used for trajectory models, it’s very complicated to address the influence of missing data on the results while using the trajectory models.

I was very grateful for this award and used the grant towards funding an overseas research fellowship in Salford, UK. I planned to pursue my existing interest in autoimmune muscle disease, also termed “myositis” or “idiopathic inflammatory myopathies”, as, although rare, I had witnessed these conditions cause significant suffering for patients and felt that much needed to be done to improve their care and outcomes. Because of the rarity of the conditions, only a few centres around the world see more than a handful of patients regularly and I wanted to maximise my exposure to learn as much as possible. I also wanted to use the fellowship to improve my research skills as I planned to start my own research program on return to Australia. Salford is both a world-renowned centre for neuromuscular disease and myositis in particular but is also affiliated with a world-class academic rheumatology department at the University of Manchester.

During my twelve months in Salford I spent two days per week at the hospital attending the weekly neuromuscular clinics, the neuromuscular pathology meetings and the myositis clinic where I learnt a huge amount about the assessment and treatment of these conditions. I also learnt to perform minimally invasive muscle biopsies, something which is not currently offered by any rheumatologists to my knowledge in Australia. This can help avoid the need for large incisions and/or general anaesthetics in patients who require a biopsy. I was involved in a variety of clinical trials being run in the Department.

I spent my remaining time undertaking my own research based predominantly at the University of Manchester as a Clinical Research Fellow. Over the course of the year I authored and published two book chapters, two review articles, two case reports and one original research article. Two further original research projects have been written up and are awaiting publication and I presented the results of these at four international scientific meetings. The work covered a wide range of subjects including the epidemiology (who gets the disease) of myositis, the performance of new classification criteria, the use of new tests in diagnosis and a review of the current best evidence for treatments. I also published reports on a number of cases that were important learning experiences for me and hopefully, therefore, for others looking after similar patients in the future.

Another great benefit of this fellowship was in fostering an international network of research colleagues that I will continue to work with now back in Australia. I met and worked with researchers from Europe, the USA and Asia and am now in a position to collaborate directly with them which should hopefully in time directly improve the care of Australian patients with myositis. The work from last year will form a substantive part of a PhD which I am due to enrol on in the coming months at the University of Sydney. I am currently busy setting up a myositis clinical service, modelled on the Salford service which I witnessed worked so effectively, and in building a network of Australian clinicians and researchers to help improve the care for patients with these conditions in Australia.

As a result, I feel like I have had a very broad further education which I do not believe I would have been able to gain solely in Australia or without the assistance of the award. I consider myself very privileged to have been supported in such a fantastic opportunity.

Osteoarthritis (OA) is the most common cause of pain and disability in Australia, affecting 1 in 4 Australians. OA is estimated to cost our health care system >$4 billion annually. Currently, a total knee or total hip replacement is the only solution for OA patients. These solutions are expensive and the artificial implants have a limited lifespan of 5-8 years after which a revision surgery is required. Obesity is a well-established risk factor for OA. It has been estimated that up to 80% of OA cases are attributed to obesity.  Studies indicate that OA could be avoided each year if body mass index (BMI) was kept below 25 throughout adulthood. There is currently an obesity epidemic in the Australia, and it is crucially important to find ways to lessen the impact of obesity on OA progression. This fellowship proposal is focused on understanding the biological links between obesity and OA and finding treatments that will reduce or eliminate the contributions of obesity to the development and progression of OA. These studies will improve the clinical outcome for overweight or obese people including postmenopausal patients who tend to acquire weight due to hormonal imbalance leading to reduction in incidence and disability from this disease.

Osteoarthritis (OA) incidence in Australia has been steadily increasing at alarming levels over the past several decades. The reasons for this are not completely clear, but an increased prevalence of known predisposing factors may be promoting this trend. Several major risk-factors for OA have been identified. Among these, obesity is notable because its incidence has risen dramatically during this same period of time. OA is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of OA is probably the most promising approach to reduce OA incidence, however, the field has so far failed to deliver such an effective preventative program.

OVERALL AIM: The aim of the fellowship project is to investigate the impact of obesity on OA and evaluate anti-obesity or anti-inflammatory treatments for the prevention and/or treatment of OA.

Specifically:

AIM1: To determine if obesity-induced modulation of macrophage activation/polarization affects the development and progression of OA pathology.

AIM2: To determine if anti-obesity treatments, including caloric restriction with/without volunteer exercise and as well as common weight loss drugs, break the cycle of obesity, inflammation, and OA.

AIM3: To determine if fats such as lauric acid (a type of saturated fat) and plant derived phytochemicals inhibit metabolic syndrome and whether this nutritional intervention reverses obesity initiated inflammation and OA.

Over the duration of the fellowship my research is focused on researching the cellular, structural, and molecular changes that happen in joint tissues in obese animals and patient samples. From this research we made four important observations:

(1) Obesity, diabetes, hypertension, hypocholesteremia separately and together cause osteoarthritis (OA).

(2) Activation of inflammatory cascade mediated by pro-inflammatory macrophages in synovium precedes cartilage degradation in obesity models.

(3) Certain saturated fat diets (Palmitic acid and stearic acid) cause OA and certain saturated diets supress OA (Lauric acid).

(4) Obesity promotes cartilage degeneration through three pathways: activation of autophagy machinery, membrane-lipid remodelling and mitochondria induced oxidative stress.

These findings provide valuable novel insights into the development of obesity-associated OA and open up new possibilities for its control. Furthermore, I have showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that metabolic factors precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.

Currently our team is working with collaborators in industry and healthcare in a multi-faceted approach to prevent OA, diagnose it early and treat it successfully. With industry partners, our team aims to develop nutraceutical products, containing bioactive components that can reduce obesity and keep joints in a healthy state.

During the AQ fellowship tenure I have identified novel targets that are impacted in metabolic OA. The overall aim of my future research is to build on this research to identify the factors involved in OA development and progression, in order to develop effective prevention and treatments for metabolic OA. The detailed aims include identifying possible common molecular pathways for OA and metabolic syndrome (MetS) by focusing on common factors such as hypertension, obesity, dyslipidemia and hyperglycemia, and to study the role of mitochondrial dysfunction and tissue inflammation in the onset of MetS OA.

The 2017 Arthritis Australia and State/Territory Affiliate Translational Grant, kindly funded by Arthritis South Australia, allowed us to run a productive research program into giant cell arteritis (GCA). GCA is an inflammatory condition of blood vessels which can cause sudden onset blindness, joint stiffness, headache, fevers and jaw pain in older people. The current best test to make the diagnosis is a temporal artery biopsy. This involves surgery to remove a small piece of the artery on the side of the head. Our key objective was to test a new type of positron emission tomography (PET) scan in patients suspected of having this condition to see if it was better at diagnosing the condition than the biopsy. The new scanner allowed us to see active disease in arteries in regions of the head and neck that could not be seen on older PET scanners.

We enrolled a total of 64 patients in the study. All patients were initially suspected by their doctors as having GCA and had been treated for less than three days. This made them a perfect group to test the accuracy of the new scan. Patients undertook a survey, clinical examination, blood tests, PET scan and temporal artery biopsy. They were then followed up at three monthly intervals. Some patients had a second PET scan at 6 months.

We have published two articles in peer reviewed medical journals describing our findings and presented results at the Australian Rheumatology Association and American College of Rheumatology conferences in 2017. We are currently in the process of finalising the PET results for our full group of 64 patients. Once complete, we will know if the scan can be used to accurately diagnose GCA and whether it can predict how aggressively the disease will behave in the first two years.

The main question we sought to answer was whether our new PET scan technique was accurate in diagnosing GCA. A fast and accurate diagnosis is critical for this condition, as early treatment prevents both sudden onset vision loss and the characteristic debilitating symptoms of headache, joint stiffness and fevers. It also minimises the risk of treating the wrong condition in those who have a different illness. The current ‘best’ diagnostic test is a temporal artery biopsy which is problematic in that it is negative in a significant number of patients who have the disease. It also requires the patient to undergo surgery.

We also wanted to determine if the PET scan could help predict which patients would develop vision loss, widened arteries or flares of disease when treatment was reduced. This knowledge could help doctors tailor treatment plans to individual patients. We made significant research discoveries with the assistance of the grant. The first was to show that key arteries in the scalp and neck, namely the temporal, occipital and vertebral arteries, can reliably be visualised on our new PET scan and are often inflamed. These arteries are known to be involved in GCA but had been poorly seen on older scanners. Importantly, 6 of our first 41 patients had PET abnormalities limited to these three arteries. Their diagnosis may have been missed using older scanners.

The second discovery was to identify the location of the maxillary artery, an artery near the jaw that supplies the chewing muscles, on PET scan and show that it also has signs of inflammation in a proportion of patients with GCA. Active inflammation may be the cause of jaw pain in GCA patients because the chewing muscles are starved of blood.

We are currently analysing the scans, biopsy and six-month diagnoses of all 64 patients to determine if scans are reliably positive in the correct patients. In 2019 we will have long-term follow-up on all our patients to determine how well PET scans predict artery blockages, widening and disease flares.

We have disseminated our research findings through the publication of two peer reviewed journal articles and five conference presentations. Further publications are planned for the coming year.

Once results are finalised in late 2018, we will know if the new PET scan is accurate in diagnosing GCA. If it is shown to be accurate, future patients may be able to forgo a surgical procedure (temporal artery biopsy) and be at a reduced risk of blindness and symptoms of joint stiffness, headache and jaw pain because of delayed treatment.

The research program facilitated by this Arthritis Australia Grant will be continued into the foreseeable future. The grant has allowed us to establish a large group of suspected GCA patients who all have had PET scans, multiple clinical assessments and blood tests. Future work beyond that specified above includes:

– Assessing a range of new blood tests for GCA

– Fine-tuning PET scan settings and reporting techniques

– Assessing how well PET predicts long-term disease outcomes

My research has focused on vasculitis, namely anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), and its management. AAV is an umbrella term that encompasses three conditions which share clinical characteristics, and an association with ANCA: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). These are rare autoimmune conditions resulting in inflammation of small blood vessels. Untreated, AAV can have devastating, severe organ and life-threatening consequences. This can involve any organ system, but most commonly affects the kidneys, lungs, nose and sinuses, eyes, skin and joints.

The treatment of AAV includes an induction phase for control of disease activity with the aim of achieving disease remission, and maintenance phase for prevention of relapse. Significant advances have been made in the induction of remission of AAV, allowing for better control of the disease. As these advances to induction treatment have been made, an important priority in the long-term management of people with AAV has become the prevention of relapse, which occurs in half of all patients. With each relapse, further disease activity can lead to more organ damage and worse overall outcomes. How to optimally prevent these relapses remains uncertain. Adverse effects of effective agents for treatment of AAV are another major issue, with a difficult balance between the pros and cons of using these treatments. Most importantly, as well as gauging assessments made by health professionals in the treatment of AAV and the adverse outcomes that we see from treatment, the effect of certain characteristics and treatments on quality of life for patients with AAV has been less clear. We have sought to address some of these areas through different studies, with a focus on rituximab, a medication used for the treatment of AAV. To date, there have been trials evaluating the use of rituximab for the maintenance of remission in AAV, and the frequency with which to give rituximab. However, a number of questions remain unanswered.

We have worked on developing consensus statements with experts in the field in the United Kingdom to address these gaps and provide guidance on these issues. We plan to evaluate quality of life, specifically in patients with a relapse of AAV, and those with severe kidney or lung involvement from AAV. We hope to learn more about what influences the changes in quality of life and learn more about whether there are specific interventions that will result in better quality of life in patients with AAV. Lastly, we have looked at a group of people with autoimmune disease who have been treated with rituximab at Addenbrooke’s Hospital in Cambridge and have been found to have lower levels of protective antibodies. We have looked at longer term outcomes in these patients, and their infection rates. Further work on why this occurs in some but not all patients who receive rituximab is ongoing.

With each of these research projects, we hope to better tailor the treatments that are provided to people with AAV. These projects have been made possible by joining the Vasculitis and Lupus service led by Professor Jayne, the international collaborative network that has been established between vasculitis clinicians and researchers, and the patients who have participated in these studies. With other projects, this work will contribute to a PhD on optimising the management of AAV.

Rheumatoid Arthritis (RA) is an inflammatory, destructive and debilitating autoimmune disease, where by the immune system infiltrates and attacks self-tissues. In RA patients these tissues are the synovial membrane, a specialised connective tissue encasing the fluid lubricant in joints. Although significant progress has been made in treating RA, current therapies are ineffective in over 50% of patients and long term disease remission is rare. In these patients with ongoing active disease, societal impact in terms of disability, quality of life and impact on work-capacity are profound. Strong evidence suggests that the immune cell types that invade the synovial membrane heavily influence disease prognosis as well as treatment success. However, the mechanisms regulating such responses remain poorly understood. In part because of this, current treatment approaches are mostly empirical, with very variable responses.

Current therapeutic intervention in RA costs the Australian health system approximately $500M/year, and better allocation of treatments presents a significant opportunity to improve patient outcomes while reducing the economic burden to the Australian taxpayer. Importantly, the research proposed in this application, and now well under way, will result in greater prediction of treatment responses, eliminating ineffective therapy and potentially reduce the time taken to achieve disease remission. This is particularly important as it is now known that effective early treatment of RA is critical to preventing irreversible bone loss and life-long disability. Moreover, approximately 50% of patients with RA are no longer in full-time work 4 years after diagnosis of disease; indeed, good treatment response translates to less deformity and disability and our previous work has shown that those who respond well to treatment stay in the work force longer.

The research proposed in the original study is set out with the aim to characterise cellular subsets and tissue phenotypes in early RA synovial tissue (ST) before and after treatments, in order to investigate different disease outcomes in response to traditional or biologic therapies. We gratefully acknowledge the Bruce Miller-ARA Post-Doctoral Fellowship for 2018, which enabled us to significantly advance our research by employing a research associate and establishment of novel techniques of analysis of synovial tissue (e.g. the Vectra microscopy) which would not have been possible without the support of this grant. The research methodologies we proposed to employ in this project can be separated in to 4 broad techniques: flow cytometry (perfect for assessing new cellular subsets), microscopy (ideal for assessing tissue phenotype), transcriptomic analysis (to assess the complete set of RNA transcripts that are produced by genes of inflammatory cells) and serum cytokine analysis (immune system messenger and inflammatory molecules), which together can be used for the identification of new biomarkers that predict effective responses in different patients. The 2018 Bruce Miller-ARA call for funding was submitted as a 2-year project, where our first step was to perform optimisation and analysis of flow cytometry to identify lymphocyte infiltrates in the ST and to perform routine Immunohistochemistry (IHC) for these early RA ST samples (see below). As the project progresses into the second year, upon which we will have recruited both pre- and post-treatment samples from the joints of RA patients (as well as matching blood samples from these patients) we plan to correlate clinical disease activity, with the presence or absence of the types of cells identified via flow cytometry and IHC, but also with the serum cytokine analysis (ELISA) and transcriptomic analysis (real-time PCR) biomarkers that might confer response or relapse to treatment.

In 2018, we have made significant progress towards achieving the aims of this grant. These achievement progress milestones include:

1. Establishment and implementation of multi-colour flow cytometry to investigate the cellular infiltrates in the tissue from early RA joints; during 2018, we expanded our panel to include novel T cell subsets;
2. We developed- for the first time in synovial tissue- a multi-colourmicroscopy method with automated computational assessment of tissue phenotype. This is a major milestone for several reasons including:
   1. RA ST is a finite resource and extracting the most amount of data from each sample is important;
   2. Preservation of structural information and identifying cells that express more than one marker is difficult with traditional IHC, but possible with multi-colour microscopy, and;
   3. The automation of sample analysis will remove human analysis bias and reliability issues.

In this application, we aimed to fully characterise the cellular composition of the synovial tissue (ST)infiltrates as well as clinical responses to routinely prescribed treatments in order to develop biomarkers that can predict the most effective treatment for each individual patient. Furthermore, in collaboration with a leading pharmaceutical partner we aim to identify new targets for potential therapies for the personalised treatment of RA. This is important as current therapies are ineffective in over 50% of patients and long-term disease remission is rare and it is known that effective early treatment can prevent lifelong bone loss and disability in RA. As detailed above, there are several research methodologies required to complete this 2-year project, and we have been successful in implementing and improving some of these methods in order to extract the most amount of data out of the limited samples. Furthermore, new patient recruitment is still ongoing.

Our main discovery since starting this project in 2018, is that early RA ST samples contain a novel immunecell subset called T peripheral helper cells. This is the first time anyone has characterised these cells in early RA and their identification is of critical importance to the pathophysiology of the disease as they have been proposed to be involved in the mechanisms perpetuating inflammation (but until now had not been identified in early RA). Furthermore, we identify more of these type of cells in patients that have more severe disease. We need to collect more data to confirm this second observation, however, it indicates to us that our original hypothesis, that the type of cells in the ST can influence patient prognosis, is indeed true. Additionally, we have recently used transcriptomic profiling by RNAseq on a subset of the early RA patients to identify unique immune cell signatures that are associated with disease and response to treatment. In particular we have identified alterations in gene expression of gene involved in both T cell and plasma cell differentiation after standard therapy in RA. Importantly, as per the aims of this project, we are now in the process of extending this transcriptional profiling to the remaining patients treated with standard therapies, but also those patients in the study that have been treated with biologic therapies. Finally, by the end of 2018, we mostly established a multi-colour microscopy technique for the histopathological assessment of ST. We now have the ability to use computational analysis to count the number of different cell subsets in the ST, and to distinguish between samples with different phenotypes. This is a step change in the way that histopathological analysis is performed, and development of this technique will translate into high impact data for this project as well as all future projects in all  rheumatology laboratories.

The research proposed in this project has the potential to provide stratified treatment options for patient with RA. The promise of personalised medicine for RA has resulted in a recent surge of interest in ST biology with the aim of translating a comprehensive understanding of the biological processes that governlymphocyte infiltration and maintenance in ST into better disease prognosis and treatment responses. The methods employed in this project, along with the unique cohort of patient samples from ST and blood, will allow for identification of cellular and molecular biomarkers that will help to provide personalised medicine for RA. Furthermore, the ST bio-bank at the Flinders Medical Centre is exclusive in Australia and the collection of treatment naive ST samples with matching post-treatment (either DMARD or biologic therapy) is a unique resource, unparalleled worldwide. This bio-bank provides the unique opportunity to identify ST and peripheral biomarkers that will allow for the application of personalised medicine in RA. The proposed project will facilitate a more comprehensive understanding of ST “pathotypes” to elucidate mechanisms of non-response. Critically, the data generated from this proposal will provide preliminary data for larger research grants enabling the joint development and testing of new-targeted therapies for RA. The long-term benefit of this work will be that this application will be greater prediction of treatment response, eliminating ineffective therapy to potentially reduce time to achieve disease remission and minimise exposure to treatments with potentially serious side effects.

With the gratefully acknowledged support of the Bruce Miller-ARA Post-Doctoral Fellowship for 2019, we aim to continue this work. This additional funding, we believe, will be critical for the successful completion of this project. In 2019, we are confident we will make additional progress by facilitating a more comprehensive understanding of ST “pathotypes” to elucidate mechanisms of non-response; by building on the data generated from this proposal will provide preliminary data for larger research grants, accelerate research outputs, increase our international standing further and competitiveness for obtaining future funding. Given that it appears probable that ST biology has the potential to dictate treatment efficacy and that comprehensive analysis of ST infiltrates will yield new cellular targets for therapy, in 2019, we propose to continue this work by

1. Characterising novel and established lymphoid cell subsets in early RA ST tissue;
2. Investigating disease outcomes in a large cohort of early RA patients in the context of therapeutic intervention and cellular ST “pathotypes”; and
3. Identifying peripheral cellular and molecular biomarkers of treatment efficacy.

Vasculitis is a disease characterised by inflammation of the blood vessels. Without treatment, this inflammation can cause the vessel to block or burst, which can be life threatening. We believe that understanding how inflammation develops during vasculitis will allow the development of new therapeutic targets aimed at limiting the progression of vasculitis and treating established disease.

In this grant, we have studied the inflammatory processes that drive two common vascular conditions – Kawasaki Disease (KD) and Giant Cell Arteritis (GCA). KD is caused by inflammation of blood vessels in the heart (coronary arteries). It affects young children (0-5 years) and can result in life threatening coronary aneurysms within the heart. GCA affects the elderly (50 years plus) and can result in blindness due to inflammation of the temporal arteries. Here, we performed multiple assays to measure a wide panel of immune factors present in the blood of KD patients and the temporal arteries of patients with GCA. Our hypothesis was that through identifying the major immune factors that emerge in these disease (KD and GCA), we could design therapies that limit their pathogenic activity, which would in turn limit vascular inflammation. We successfully identified the unique immune signatures of KD and GCA. Specifically, we have found a family of mediators in KD patients; these include the cytokines CCL17 and CCL2, which are responsible for recruiting immune cells. Notably, these do not appear in GCA or in unrelated diseases such as pneumonia. Intriguingly, our earlier studies identified the pathway by which CCL17 and CCL2 are expressed and we have developed a therapeutic approach to block this process. Hence, our study supports the application of this therapy in KD. In contrast, for GCA we found that a different family of immune factors (notably IFN-gamma and CXCL9-10) were expressed in the inflamed temporal artery. This demonstrates that distinct types of immune responses drive pathology in these two diseases.

Our findings provide information on how these common inflammatory diseases develop and identify new biomarkers for diagnosis and potential therapeutic targets. Specifically, our findings demonstrate that for KD, therapies that target a pathway involving CCL2/17 (as well as GM-CSF, another immune mediator actively researched in our laboratory) may be effective, while therapies aimed at treating the IFNg-CXCL9-10 axis will be effective for GCA. These results were presented at a leading international conference on inflammation (Cold Spring Harbour in Asia, Suzhou, China, 2017) and will form the basis of future publications. Furthermore, we plan to assess the efficacy of targeting the above pathways in future pre-clinical trials. Funding by the Australian Rheumatology Association and Arthritis Australia was instrumental in achieving these goals and we gratefully acknowledge their support.

Arthritis is a systemic inflammation that affects millions of people, causing joint pain and deformity. Pathological bone destruction by osteoclasts, cells that take away bone is a characteristic feature of rheumatoid arthritis. Drugs that inhibit bone destruction are critically needed for the prevention and treatment of bone loss by osteoclasts. Although there has been some success in conventional pharmacological treatment of arthritis, with the use of analgesics, steroids, non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs), there is a growing trend of arthritis patients using complementary and alternative medicine. Accumulating evidence indicates the great potential of natural compounds for the treatment of arthritis conditions. The popularity of using natural compounds in arthritis treatment is ever increasing, thus it is important to study natural compounds to provide professional advice to the public. However, evidence of the effectiveness and mechanisms of actions of these therapies in the treatment of arthritis remains lacking. Importantly, we have pursued laboratory investigations of naturally occurring compounds that demonstrate in vitro activity. Over the past several years, we have developed assays and protocols that enable efficient and high through put in-vitro screening of natural compounds for the inhibition of bone resorbing osteoclasts, a key therapeutic target for the treatment of osteolytic bone diseases. Previous work has shown that natural compounds, including parthenolide, mangiferin, and honeybee propolis inhibit osteoclast formation, bone resorption and RANKL-induced NF-kB activity. This work has been undertaken in anticipation of potential clinical development and application. The use of complementary medicines for bone and joint health requires very high levels of safety and efficacy, as well as evidence-based practice.

Pathological bone destruction by the osteoclast is a characteristic of many bone diseases such as rheumatoid arthritis, osteomyelitis, septic arthritis and periodontitis-related bone loss. Arthritis is a major cause of disability and chronic pain in Australia, with rheumatoid arthritis affecting around 400,000 Australians. Excessive osteoclastic bone resorption is a hallmark of RA. The economic cost of this condition extends beyond the cost of healthcare, with only 31% of affected individuals able to participate in full time employment compared to 53% of the general population. Drugs that inhibit osteolysis are critically needed for the prevention and treatment of bone loss by osteoclasts. Development of strategies to control the formation or activities of osteoclasts has been a major focus of research into the suppression of osteolysis. The proposed research explores the potential use of natural compound Carnosol for the suppression of osteoclastogenesis, and their potential as treatments for inflammation and infection related bone loss diseases. The outcomes of this work has therefore helped us to: 1) Understand the mechanisms of action of Carnosol, as a prototype compound inhibitor for osteoclast inhibition and bone resorption. 2) Provide essential pre-clinical information on Carnosol for the treatment of RA and pathological osteolysis.

We intend to apply for NHMRC and other commercial funding agents to further carry out this study for human study.