Explore 2023 Research

Lay & Scientific Report

Lay Report

Scientific Report

Staying strong, Improving health for Rheumatoid Arthritis using Blood Flow Restriction – Scientific Report

Staying strong, Improving health for Rheumatoid Arthritis using Blood Flow Restriction – Lay Report

Lay summary
Systemic sclerosis, or scleroderma, is an autoimmune disease that causes scarring of the skin and internal organs. This multi-organ system involvement has meant that measuring important changes in disease status in clinical trials of novel therapies has remained challenging. In this project, we have addressed how patients and physician perceive overall disease and how they assess the totality of systemic sclerosis and its effects on patients. These results are being used to develop new global assessment instruments to use in clinical trials to better measure patients’ response to treatment. We have demonstrated that physicians evaluate multiple components, including patient symptoms, examination findings and test results when making their global assessment. Interviews of physicians and patients have highlighted significant uncertainty about the overall assessment of systemic sclerosis despite the perceived importance of global assessment instruments as a tool to evaluate disease progression.

Scientific Summary
Recent randomised controlled trials (RCTs) have failed to reach their primary endpoint and demonstrate efficacy of much-needed novel therapies for systemic sclerosis (SSc). The lack of fully validated outcome measures to assess overall disease status has contributed to the failure of recent RCTs.1 Analysis of the use of the both the patient global assessment (PGA) and physician global assessment (PhyGA) shows there is inconsistent application of these commonly used outcome measures and high variability of constructs assessed by both instruments. In contrast to multi-question patient-reported outcomes measuring individual organ manifestations or health-related quality of life, global assessments are presented as a single question and ask respondents to rate global disease status, either via a visual analogue, numeric rating or Likert scale. Newer multi-system outcome measures for use in SSc RCTs such as the American College of Rheumatology (ACR) Composite Response Index for Systemic Sclerosis (CRISS) include both patient and physician global assessments as part of a composite measure of response to treatment.2
Despite the long-recognised importance of measuring a global assessments in clinical studies, there are no standardised, SSc-specific global assessment instruments. There has never been any patient or broad physician input into the development of either instrument. Therefore, as they are currently applied, both the PGA and PhyGA in SSc have uncertain face and content validity and unproven construct validity. The Scleroderma Clinical Trials Consortium Global Assessment Working Group was convened in 2022 to address this issue.

Overall Project Aim:
The overarching aim of this project is to develop a SSc-specific patient global assessment (PGA) and physician global assessment (PhyGA) for use in randomised controlled trials.
Progress towards aims specific to this funding opportunity
1.Completion of systematic literature review
Successful publication of a review of the psychometric properties of both the patient and physician global assessment instruments as they are current used in Arthritis Care & Research (appendix 1).

2.Establish a SCTC Global Assessment Working Group & project steering committee
We have established a working group to address the need to develop a SSc specific patient global assessment instrument. The working group comprises of members from North America, Europe, the UK and Australia.
In addition to the 10 rheumatology members of the working group, a qualitative researcher Ms Hana Sabanovic (University of Melbourne, Australia) and two patient research partners, Mr Martin Retscko (Australia) and Ms Amanda Feagans (US) have been recruited to the project steering committee. These 13 members comprise the project steering committee.

Upon establishment of the working group, the need for the development of a physician global assessment instrument, in addition to a patient global instrument was recognised. Therefore, the working group has accepted as its aims to develop in parallel, both:
1. A patient global assessment instrument
2. A physician global assessment instrument.
The working group elected to proceed with the development of the physician global assessment first in order to refine the methods of development of a disease specific global assessment prior to commencing the development of the patient global assessment instrument.

3.Retrospective evaluation of global assessments in the Australian Scleroderma Cohort Study
Two retrospective analyses of the data from the Australian Scleroderma Cohort Study have been performed evaluating the performance of the physician global instrument. I have examined the concordance three different physician global assessments that are simultaneously applied at each study visit in the Australian Scleroderma Cohort Study to examine the effect of the various wordings of global assessments on outcomes measured by each instrument. Additionally, again using Australian Scleroderma Cohort Study data, I have evaluated whether including a physician global assessment as part of a composite outcome measure improves the sensitivity and specificity of each measure to predict clinically important disease outcomes. These projects have resulted in two manuscripts.

4. Development of a physician global assessment instrument using qualitative research methods
We have performed 13 semi-structured interviews of 20 physicians and 1 patient research partner to investigate the physician and patient perspective of the physician global assessment instrument and explore the construct that should be assessed by this instrument in systemic sclerosis RCTs. These interviews have provided 15 hours of interview transcript that has undergone content and discourse analysis. This study has resulted in one manuscript currently in preparation and these results will form the basis of the futures steps of this project.

5. Development of a project protocol using qualitative research methods to develop a patient global assessment instrument
A project protocol to develop a patient global assessment instrument has been developed, drawing upon the expertise of the working group and qualitative research experience of Ms Sabanovic. Development and finalisation of this protocol was delayed by the late recruitment of Ms Sabanovic to the project steering committee. Initial methodological input was provided by the qualitative research team at the University of Bristol. However, due to conflicting work schedules, the Bristol qualitative research team were unable to continue to provide methodological support to this project. There were delays in finding a suitably qualified qualitative researcher with capacity to take on this project and assist in the ongoing development and then implementation of the project. The final protocol for the development of a patient global instrument has been developed and submitted for Human Research Ethics approval.

Research outputs supported by this grant:
1.
Ross et al, Patient and Physician Global Assessments of Disease Status in Systemic Sclerosis Arthritis Care Res 2023 75(7) 1443-1451
2.
Ross et al, A Comparison of Three Physician Global Assessment Instruments in Systemic Sclerosis 2024 manuscript under review at Arthritis Care Res
3.
Ross et al, Does the physician global instrument improve the performance of existing systemic sclerosis composite outcome measures? Manuscript in preparation
4.
Sabanovic H, Pauling J & Ross L, A multinational qualitative research study exploring the physician global assessment in systemic sclerosis Manuscript in preparation

Lay Summary

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

We conducted a mixed-methods project comprising two key components, designed to provide complementary information on health literacy and financial distress, and the drivers of high-value and low-value arthritis care. The first component was a national survey of health literacy (measured via the Health Literacy Questionnaire (HLQ)) and financial distress (measured via the Comprehensive Score for Financial Toxicity patient-reported outcome measure (COST-PROM)) among people living with osteoarthritis or inflammatory arthritis. The second component was focus groups and nominal group techniques to identify and prioritise participants’ perspectives of what drives high- and low-value arthritis care.

For the national survey, data from 191 participants (across all Australian states) were available for analysis. This included people living with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and non-radiographic axial spondyloarthritis. Health literacy scores varied; participants scored highest on Domain 9 of the HLQ which relates to understanding health information well enough to know what to do with it, and scored lowest on Domain 7 which relates to navigating the healthcare system. The median financial distress score as measured by the COST-PROM was 19 (on a 0-44 scale where 0 = the highest level of financial distress).

For the focus groups and nominal group techniques, 21 survey respondents participated. The two highest-ranked drivers of high-value care were having a two-way relationship with clinicians (with respect to knowledge and communication), and having friends, family, and colleagues who understand arthritis (about the disease, how it manifests, and the impact it has on the person). The two highest-ranked drivers of low-value care were the financial burden of living with arthritis (including medications, supplements, GPs, gym memberships, etc.), and clinicians being dismissive of patient-centred care. These drivers were also categorised into themes and mapped to the Health Belief Model. The main themes focused on the balance between patient responsibilities, clinician’s responsibilities to their patient, and the role of social and government support services.

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

As the number of Australians living with arthritis continues to grow (anticipated to increase to 5.4 million people by the year 2040, representing 18% of the population), it is essential to identify and prioritise research that is relevant and translatable into meaningful outcomes for consumers. This mixed-methods project was consumer-led; where the chief investigator (Dr Danielle Berkovic) lives with psoriatic arthritis and has identified research topics that are important to consumers based on her prior research and her own lived experience.

This project was designed to address an important evidence gap. While a range of national and international guidelines for arthritis have been developed over the past decade to promote high-quality arthritis care, little attention has been given to the fact that in real-world settings, low-value care is frequently accessed at the expense of the patient. By better understanding why people access low-value arthritis care, we can develop strategies and educational directives to better direct patients’ financial resources towards evidence-based arthritis interventions. Further, while the relationship between poor health literacy and poorer patient outcomes is well-documented, little is known about the impact of poor health literacy on the uptake and use of low-value arthritis treatments and related financial distress. Considering this relationship may provide another avenue through which to provide tailored patient education. Finally, arthritis-associated financial distress has not been sufficiently quantified in an Australian context, and gathering this data provides important baseline data to tackle this issue.

With this in mind, our research had four aims: (1) to quantify levels of financial distress using the Comprehensive Score for Financial Toxicity patient-reported outcome measure (COST-PROM) among people living with arthritis, (2)  to measure health literacy using the Health Literacy Questionnaire (HLQ) among people living with arthritis, (3) to explore the drivers of high-value care from the perspective of people living with arthritis and (4) to explore the drivers of low-value care from the perspective of people living with arthritis.

What did you discover during the course of the grant? 

In total, survey data were available for 191 participants. Respondents scored highest on domain 9 of the HLQ: understanding health information well enough to know what to do with it (mean 3.30). Respondents scored worst on domains 4: social support for health (mean 2.59) and 7: navigating the healthcare system (mean 2.52).

The median score for all COST-PROM respondents was 19. COST-PROM scores ranged from 0 (the highest level of financial distress scored on the COST-PROM) to 44 (the lowest level of financial distress scored on the COST-PROM). Participants indicated the highest levels of distress in response to statements 2 – 4 of the COST-PROM respectively: (2) My out-of-pocket medical expenses are more than I thought they would be, (3) I worry about the financial problems I will have in the future as a result of my illness or treatment, and (4) I feel I have no choice about the amount of money I spend on care. Participants indicated lower levels of distress in response to statements 7 – 9 of the COST-PROM: (7) I am able to meet my monthly expenses, (8) I feel financially stressed, and (9) I am concerned about keeping my job and income, including work at home.

In total, 21 participants contributed across five focus groups and nominal group techniques (NGTs). There were four participants in the first group, three participants in the second, six participants in the third group, four participants in the fourth group, and five participants in the fifth group. Across the groups, 56 unique high-value items and 52 unique low-value items were identified.

The two highest-ranked drivers of high-value care were having a two-way relationship with clinicians (with respect to knowledge and communication), and having friends, family, and colleagues who understand arthritis (about the disease, how it manifests, and the impact it has on the person). The two highest-ranked drivers of low-value care were the financial burden of living with arthritis (including medications, supplements, GPs, gym memberships, etc.), and clinicians being dismissive of patient-centred care. The drivers of high- and low-value care were also categorised into themes via a directed content analysis approach and mapped to the Health Belief Model. The main themes focused on the balance between patient responsibilities, clinician’s responsibilities to their patient, and the role of social and government support services.

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

This consumer-led research program brings together lived experience, quantitative and qualitative methods, and innovative techniques to examine issues relating to health literacy, financial distress, and the drivers of high- and low-value care relevant to people living with arthritis in Australia. The findings can be used to guide future consumer-focused initiatives.

Are you planning to continue the research? 

Yes. Based on financial distress findings we are planning to co-design a standard for informed financial consent, similar as to what exists in oncology, to communicate with patients about the financial impacts of their diagnosis (for example, treatment costs, the impact of reduced work capacity, etc.). It should be noted as well that there are over 100 types of inflammatory arthritis conditions, affecting each individual differently. Because of this heterogeneity, it is likely that if this study were replicated with another sample, the results may differ. Our future research will include underrepresented arthritis populations, such as those living in lower socioeconomic areas, First Nations people, and those living with rarer arthritis conditions in future research.

Scientific Summary

What were the main scientific objectives of the grant?

This research had four aims: (1) to quantify levels of financial distress using the Comprehensive Score for Financial Toxicity patient-reported outcome measure (COST-PROM) among people living with arthritis, (2)  to measure health literacy using the Health Literacy Questionnaire (HLQ) among people living with arthritis, (3) to explore the drivers of high-value care from the perspective of people living with arthritis and (4) to explore the drivers of low-value care from the perspective of people living with arthritis.

What were the main scientific achievements of the grant? 

In total, survey data were available for 191 participants.

Respondents scored highest on domain 9 of the HLQ: understanding health information well enough to know what to do with it (mean 3.30). In line with this result, respondents also scored well on domain 1: feeling understood and supported by healthcare providers (mean 3.24), domain 3: actively managing my health (mean 3.21), and domain 5: appraisal of health information (mean 3.09). Respondents scored worst on domains 4: social support for health (mean 2.59) and 7: navigating the healthcare system (mean 2.52).

The median score for all COST-PROM respondents was 19. COST-PROM scores ranged from 0 (the highest level of financial distress scored on the COST-PROM) to 44 (the lowest level of financial distress scored on the COST-PROM). Participants indicated the highest levels of distress in response to statements 2 – 4 of the COST-PROM respectively: (2) My out-of-pocket medical expenses are more than I thought they would be, (3) I worry about the financial problems I will have in the future as a result of my illness or treatment, and (4) I feel I have no choice about the amount of money I spend on care. Participants indicated lower levels of distress in response to statements 7 – 9 of the COST-PROM: (7) I am able to meet my monthly expenses, (8) I feel financially stressed, and (9) I am concerned about keeping my job and income, including work at home.

In total, 21 participants contributed across five focus groups and nominal group techniques (NGTs). There were four participants in the first group, three participants in the second, six participants in the third group, four participants in the fourth group, and five participants in the fifth group. A total of 109 drivers of high-value care, and 80 drivers of low-value care, were identified across the five groups. After accounting for repeat mentions of 53 high-value items and 28 low-value items, 56 total high-value items and 52 low-value items were identified.

The two highest-ranked drivers of high-value care were having a two-way relationship with clinicians (with respect to knowledge and communication), and having friends, family, and colleagues who understand arthritis (about the disease, how it manifests, and the impact it has on the person). The two highest-ranked drivers of low-value care were the financial burden of living with arthritis (including medications, supplements, GPs, gym memberships, etc.), and clinicians being dismissive of patient-centred care. The drivers of high- and low-value care were also categorised into themes via a directed content analysis approach and mapped to the Health Belief Model. The main themes focused on the balance between patient responsibilities, clinician’s responsibilities to their patient, and the role of social and government support services.

The combined quantitative and qualitative findings reveal an important gap that needs to be filled to meet the clinical communication and social support needs of people living with arthritis. Communicating about the costs associated with arthritis (especially the unexpected costs of self-management strategies and community-based allied health to manage symptoms), as well as ensuring that people living with arthritis understand how the Australian healthcare system works, may give patients more confidence in managing their disease and advocating for themselves.

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

Recruitment was slow at times, but this is likely due to the high volume of arthritis research currently being conducted. We would have liked more survey participants especially. Having said that, each state was represented in our research, and participants were from metropolitan, regional, and rural Australia, providing adequate representation.

1. Have you disseminated, or plan to disseminate, the results of this research? 

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

The findings were presented at the Australia and New Zealand Musculoskeletal Clinical Trials Network Annual Scientific Meeting in September 2023 in Sydney, as an oral. We are yet to publish the final results in a scientific journal as we are completing the writing of the manuscripts. We anticipate publishing two manuscripts, one quantitative and on qualitative.

Scientific summary: ARA Ken Muirden Overseas Training Fellowship

Overview:

I am very grateful for the support of the Ken Muirden overseas training fellowship in completing a year with the Manchester Myositis Research Group, University of Manchester, and Salford Royal NHS Foundation Trust, in the United Kingdom.

This fellowship combined both research and clinical training with leading experts in the field of muscle diseases. The opportunity to immerse myself in this sub-specialty interest has allowed me to benefit from a wealth of knowledge, resources and collaborations, which I hope to apply to my ongoing PhD studies, as well as future clinical practice and research endeavours, in Australia.

From a research perspective, this fellowship year progressed from outlining the epidemiology of the idiopathic inflammatory myopathies (IIM), to identifying the areas of need in a unique subset of IIM, anti-HMGCR positive immune-mediated necrotising myopathy (IMNM), to establishing a multi-site clinical collaboration and submitting a proposal for an international genetic collaborative investigation.

Clinically, I joined the Rheumatology department at Salford Royal Hospital, a quaternary referral centre of excellence for muscle diseases. Participating in the weekly neuromuscular clinic, interacting with the multidisciplinary team, and assisting with quality improvement projects, I benefited from a broad exposure to complex muscle pathology spanning inflammatory, autoimmune, and genetic aetiologies.

Finally, the support of the Ken Muirden ARA Fellowship has been invaluable in enabling me to attend multiple international scientific meetings, connect with worldwide IIM experts for future collaborations, interact with patient-partners from different countries, and contribute to the forefront of myositis research as an investigator on various phase 2 and 3 clinical trials.

Research outputs/publications:

The following research publications and associated presentations have occurred during my Ken Muirden Fellowship year.

Khoo T, Lilleker JB, Thong BY, Leclair V, Lamb JA, Chinoy H. Epidemiology of the idiopathic inflammatory myopathies. Nat Rev Rheumatol. 2023 Oct 6. doi:10.1038/s41584-023-01033-0

Khoo T, Lilleker JB, Thong BY, Leclair V, Lamb JA, Chinoy H. Reply to: Current classification criteria underestimate the incidence of idiopathic inflammatory myopathies by ignoring subgroups. Nat Rev Rheumatol 2024.

• This review article, published in the leading Rheumatology journal, Nature Reviews Rheumatology, was a collaboration between international authors summarising the global epidemiology of IIM and areas that need representation in the future IIM research agenda. This article, and the figures that were designed specifically to accompany this publication, has generated significant interest since publication and been cited at international conference presentations on IIM.

Khoo T, Chinoy H. Anti-HMGCR immune-mediated necrotising myopathy: Addressing the remaining issues. Autoimm Rev. 2023, doi:10.1016/j.autrev.2023.103468

• Anti-HMGCR IMNM is a rare sub-type of IIM which can cause profound weakness and is often refractory to treatment. Research is limited for anti-HMGCR IMNM due to the rare incidence of this unique side effect of statin medications, lack of awareness, and difficulty accessing reliable testing for the anti-HMGCR antibody. However, given the close relationship with statin use, there are potentially key learnings to be derived from anti-HMGCR IMNM that can be generalised to our understanding of the genetic-environmental interactions culminating in IIM. This review article summarises the research that has been performed in this area so far and highlights the wide-reaching issues that still need to be investigated to inform how anti-HMGCR arises and how this unique myopathy can best be treated, or potentially even prevented.
• Presentation: “Anti-HMGCR: Past, Present and Future”, UK myositis network (MYONET) meeting (London, UK)

Khoo T, Lyu X, Lilleker J, Lamb J, Limaye V, Chinoy H. Anti-HMGCR Immune-mediated Necrotising Myopathy: Calculation of Incidence and Confirmation of Low Malignancy Risk in Two Independent Cohorts. A Retrospective Case Review. Arthritis Rheumatol. 2023; 75 (suppl 9).

• This research is an international collaboration (UK and Australia) involving three specialist myositis centres contributing detailed clinical data on patients with anti-HMGCR IMNM. Given the rarity of anti-HMGCR IMNM, the method of this research enabled the analysis of a unique cohort; multi-national data of this sample size has not been previously assembled.
• This research has been presented at national and international meetings, and is in the process of being reviewed for anticipated journal publication.
• Presentation: “Anti-HMGCR Immune-mediated Necrotising Myopathy: Calculation of Incidence and Confirmation of Low Malignancy Risk in Two Independent Cohorts. A Retrospective Case Review”, American College of Rheumatology (ACR) Annual Convergence (San Diego, USA)
• Presentation: “Anti-HMGCR myopathy – a retrospective multi-site case series”, South Australian branch of the Australian Rheumatology Association (SA ARA) Annual Meeting (Adelaide, Australia)

Ongoing research projects:

These projects commenced during the period of my overseas fellowship and are in various stages of completion.

Myositis Genetics Consortium (MYOGEN)/International Myositis Assessment and Clinical Studies Group (IMACS) project: Exploring the genetic architecture of patients with anti-HMGCR immune-mediated necrotising myopathy

• This project will involve the largest international analysis of genetic associations of anti-HMGCR with the aim of proposing a genetic risk score of HLA and non-HLA interactions that predispose to this rare side effect of statin exposure.

Editorial: Is there a role for complementary medicine in the management of fatigue in rheumatic diseases?

• The concept of this editorial came from the anecdote that many patients reviewed for rheumatological issues try, and sometimes derive benefit from, complementary and alternative medicine (CAM) options for symptoms that are difficult to treat, such as fatigue. This editorial aims to summarise the concepts behind CAM use, what role CAM may have in treating rheumatic conditions, and how we, as physicians, may need to adapt our everyday practice to deal with a world where social media is increasingly being used to promote CAM.

Other presentations:

“Myositis – current treatments, clinical trials and future possibilities”, Myositis UK Patient Meet up (national webinar, UK)

“Diagnosis and management of myositis-related interstitial lung disease”, North-West Respiratory Meets Rheumatology Conference (Warrington, UK)

“The skin as a snapshot of systemic inflammation”, British Society of Rheumatology Case-Based Conference (Liverpool, UK) – awarded best oral presentation

“Tissue is the Issue”, North-West Rheumatology Club Winter Meeting (Warrington, UK) – awarded best case presentation

“A case of VEXAS: enough to tick the boxes?”, North-West Rheumatology Club Spring Meeting (Knutsford, UK) – awarded best case presentation

Salford Royal Hospital Peer-Review Education Meetings:

“Anti-SAE antibody positive myositis”

“Unifying diagnosis or overlap syndrome: paediatric autoinflammation?”

“Anti-GBM in a patient with diffuse systemic sclerosis”

“How to besiege a Castle: IL-6 antagonism in Castleman’s Disease”

“Hypervitaminosis – an emerging concern?”

Clinical skills:

In 2023, I also had the opportunity to join the clinical Rheumatology team at Salford Royal Foundation NHS Trust. These clinical activities allowed me to continue developing my skills as a clinician, lead a team of junior doctors, experience another country’s healthcare system with different merits and challenges to Australia, and participate in regular departmental educational events.

My clinical activities included:

• Conducting a weekly specialised Rheumatology neuromuscular clinic with a national referral base
• Participating in a weekly multidisciplinary neuromuscular meeting
• Participating as an investigator on multiple Phase 2 and 3 clinical trials in myositis
• Contributing to the on-call roster and holding the consultant-connect Rheumatology referral phone
• Supervising junior doctors on the Rheumatology unit
• Fortnightly teaching sessions with medical students from the University of Manchester
• Coordination of a weekly journal club/clinical case discussion

Summary:

The past year has been full of incredible opportunities. The research and clinical exposures, international collaborations and conference presentations have been invaluable. I am confident that this plethora of varied experiences has improved my skills as a clinician and researcher. I am very thankful to Arthritis Australia and the Ken Muirden ARA Fellowship for enabling me to participate in an overseas fellowship of such high calibre, and I am enthusiastic to translate my new skills and experiences to ongoing clinical work and research endeavours back home in Australia.

Lay summary: ARA Ken Muirden Overseas Training Fellowship

I am very grateful for the support of Arthritis Australia and the Ken Muirden ARA Fellowship in completing a year overseas with the Manchester Myositis Research Group and Salford Royal NHS Foundation Trust.

My clinical and research work overseas has mainly focused on myositis, a condition which causes muscle weakness, and can also affect the skin, lungs, heart and gut. Although rare, myositis can be debilitating and, in some cases, life-threatening. I have had the opportunity to work with leading experts on myositis and have published research in highly acclaimed journals during my time overseas. In particular, I have formed an international collaboration researching a particular type of myositis called anti-HMGCR myopathy, which can happen as a side effect of statin medications. Statins are the most common medication prescribed globally, used to lower cholesterol, but can rarely result in myositis.

There is still a great deal to learn about how statins cause myositis, why the muscles are affected in some people but not others, and how we can best treat people who develop this side effect.

My year overseas has been invaluable in producing a research output of international significance, and planning ongoing collaborations which aim to significantly progress our understanding of myositis.

Additionally, I have had the opportunity to experience clinical work in a myositis centre of excellence. This level of clinical exposure has allowed me to gain knowledge, experience and familiarity with the approach to diagnosing and treating myositis, especially in situations of unusual, complex and challenging symptoms. I have also had the chance to interact with patients, their families and advocacy organisations, helping me to develop a deeper appreciation of the patient perspective on healthcare journeys with muscle problems.

The support of Arthritis Australia and the Ken Muirden ARA Fellowship has equipped me with a broad spectrum of research and clinical experiences which I look forward to bringing home, to benefit Australians with rheumatic conditions.

Overview

This research focused on how well two COVID-19 vaccines, AstraZeneca and Pfizer, work in people who have autoimmune diseases such as rheumatoid arthritis. These people were taking different types of drugs that change the way their immune system works. The study was extensive and involved 240 patients from different centres. They looked at how the body’s defense system (the immune system) responded after these people got vaccinated. We measured the SARS-CoV-2 IgG titre, which is a way of seeing how many protective substances (antibodies) the body makes after getting the vaccine.

The patients were grouped based on the three type of medication they were taking which were conventional synthetic drugs (csDMARD), biological drugs (bDMARD), or a third group called targeted synthetic drugs (tsDMARD). The study compared the immune response in patients who kept taking their medication after getting vaccinated with those who temporarily stopped taking it, and also with a control group of people who did not have these immune diseases.

After the first dose of the vaccine, people with these immune diseases who continued taking their csDMARD and tsDMARD had lower rates of developing a protective immune response at 40.9 and 19.2% respectively. However, if they stopped these drugs right after getting the vaccine, their antibody response was better improving to 76.2 and 64.3% for csDMARD and tsDMARD respectively. Following the second vaccine dose the antibody response improved even further especially in the groups that paused therapy with the seroconversion rate being restored to 100% for all DMARD groups.  Specifically, stopping a drug called methotrexate which is a common drug used to treat rheumatoid arthritis for one to two weeks after getting vaccinated seemed to help, especially for people older than 60.

Six months after getting vaccinated, most people in the study still had protective antibodies. However, those who received the Pfizer vaccine tended to retain these antibodies for a longer time compared to the AstraZeneca vaccine. When people in the study got a third booster shot, their immune response was strong across all groups. However, those who continued with the tsDMARDs had slightly lower antibody levels compared to other groups.

In conclusion, this study suggests that for people with these immune diseases, temporarily stopping some of their medications right after getting the COVID-19 vaccine can help their bodies develop a better protective response. The Pfizer vaccine seemed to offer longer-lasting protection than the AstraZeneca vaccine.

In the extension phase, the study continued to look at how long people with immune diseases, who were on various immunosuppressive medications, kept their immunity after getting the AstraZeneca and Pfizer COVID-19 vaccines. We wanted to see how the immune response changed six months after getting the vaccines and after getting an additional mRNA booster shot.

The study included the same participants from the initial study and we checked to see how many of them still had protective antibodies six months after the first vaccinations. In the group that received the AstraZeneca vaccine, over 85% of people still had protective antibodies, regardless of whether they stopped or continued their medication, or if they were in the control group without an immune disease. The people who were administered the Pfizer vaccine had a slightly better response, with more than 91% of them still having protective antibodies.

After getting a booster shot, everyone in all groups developed a strong immune response, with 100% of them showing a good level of protective antibodies. However, we noticed was that people who were on a specific type of medication (tsDMARD) and continued it had lower levels of antibodies compared to the control group.

We also looked at how long the protective antibodies lasted. We found that this varied depending on which vaccine people received and what type of medication they were on. In general, the Pfizer vaccine gave longer-lasting protection than the AstraZeneca vaccine.

This part of the study shows that the type of medication people with immune diseases are taking can affect how long the vaccine protection lasts. However, a third booster shot was effective in restoring the protective antibody levels in all groups.

In summary we highlight that the effectiveness of the AstraZeneca and Pfizer vaccines improves when certain medications for immune diseases are paused shortly after vaccination. This is especially true for older people and for two types of these medications (csDMARDs and tsDMARDs). Six months after getting vaccinated, most people had a level of protection similar to those without immune diseases, except for those on tsDMARDs. The Pfizer vaccine provided longer-lasting immunity due to higher initial antibody levels after the second dose. Booster shots were effective for everyone, indicating they are a good way to maintain immunity in people with immune diseases on these medications and that getting a booster dose every year might be a good way to keep these patients protected. However, stopping the medication should be carefully considered to avoid worsening of the immune disease. More research is needed, especially about the long-term effects of repeated booster shots in these patients.

Research Accomplishments

Publications:

1. Tran, A.P., D. Tassone, J. Nossent, et al., Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease (RESCUE). RMD Open, 2022. 8(1).
2. Tran, A.P., D.F. Tassone, N.S. Ding, et al., Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease: an extension study (RESCUE 2). RMD Open, 2023. 9(1).

Abstract/Poster

1. European Crohn’s and Colitis Organisation 2022. Antibody response to the COVID-19 ChAdOx1nCov-19 and BMT162b2 vaccines in the immunosuppressed (RESCUE)
2. Australian Rheumatology Association Annual Meeting 2023. Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b2 vaccines after temporary suspension of DMARD therapy in immune mediated inflammatory disease – an extension study (RESCUE 2)

Study Overview 

Vasculitis refers to a group of diseases characterized by their ability to cause inflammation to develop in and around blood vessels. While there are many forms of vasculitis (such as Kawasaki Disease, Takayasu’s arteritis or Giant Cell arteritis), all share the potential to cause adverse remodelling of the inflamed blood vessels. In severe cases, this remodelling can lead to narrowing of the lumen, restricting blood flow to the downstream tissue. This process can lead to tissue-ischemia, which is the leading cause of morbidity and mortality for vasculitis patients. The aim of this study was to investigate the pathophysiology of adverse blood vessel remodelling and identify new treatment strategies to prevent this life-threatening pathology developing in vasculitis patients.

Study Methodology

Adverse remodelling is caused by the excessive accumulation of fibroblasts within the intimal layer of inflamed vessels. In this study, we investigated how such intimal fibroblasts develop during Kawasaki Disease (KD), a paediatric vasculitis typically involving the coronary arteries. To follow the origin of intimal fibroblasts, we performed lineage tracing studies in a murine model of KD, induced by the injection of Candida albicans water soluble complex (CAWS). We also used conditional genetic deletion strategies to identify intrinsic regulators of intimal fibroblast formation and analysed patient samples to study this population in human disease.

Major Project Findings 

A summary of the major findings is given below. For a full description of these results, refer to the attached manuscript or https://www.biorxiv.org/content/10.1101/2023.12.15.571811v1 where  the paper has  been uploaded onto Biorxiv.

1. By using an array of lineage tracing systems in the CAWS mouse model of Kawasaki Disease, we have shown that the intimal thickening that emerges during vasculitis is caused by the migration and proliferation of smooth muscle cells (SMCs) into and within the intimal of inflamed vessels.
2. By using immunofluorescent microscopy, we have shown that migration of SMCs into the inflamed intima coincides with their activation of the mechanistic target of rapamycin (mTOR) signalling pathway.
3. By use Cre-LoxP genetic systems to selectively delete the mTORC1 subunit RAPTOR in SMCs, we have shown that genetically deleting mTOR signalling in SMCs completely abrogated their ability to migrate into the intima during vasculitis.
4. By using both genetic and pharmacological (i.e. rapamycin) strategies to inhibit mTOR, we have shown that stopping mTOR signalling reduces SMC proliferation and the severity of adverse blood vessel remodelling during vasculitis.
5. By analysing arterial sections (obtained during autopsy or biopsy) from patients with active Kawasaki Disease, Takayasu’s arteritis or Giant Cell arteritis, we have shown that the mTOR signalling pathway is activated by the intimal fibroblasts that drive intimal hyperplasia in human disease.
6. Pending – We are in the midst of completing RNA-sequencing of SMCs to describe the molecular basis for SMCs activation and how mTOR signalling controls this event (this analysis is underway).

Summary of the study findings and their clinical significance 

In total, our findings from this study reveal that the mTOR signalling pathway is an intrinsic, essential and druggable pathway which is activated in the intimal vascular fibroblasts that drive adverse blood vessel remodelling in vasculitis. We believe that these findings provide compelling rationale for using mTOR inhibitors as a novel therapeutic strategy in systemic vasculitis. Indeed, this study has prompted at Clinicians at the Royal Melbourne Hospital (RMH) to treat one Takayasu’s arteritis patient with mTOR inhibitors to control their progressive stenotic disease (Ian Wicks, Personal Communication). This illustrates the clinical potential for this approach. We hope that these results will lead to the further clinical application and/or clinical trials of mTOR inhibitors to treat vasculitis patients in the near future.

Project Publications 

The major findings from this study have formed the basis for the below manuscript, which is currently under External Peer Review at EMBO Reports. This manuscript is available on Bioxriv (see below link) and has been provided as an attachment with this report.

• mTOR signaling controls the formation of smooth muscle cell-derived intimal fibroblasts during vasculitis. T. Stock*, Sarah Parsons, Jacinta. A. Hansen, Damian. B. D’Silva, Graham Starkey, Aly Fayed, Xin Yi Lim, Rohit D’Costa, Claire. L. Gordon & Ian. P. Wicks*. Under Peer Review at EMBO Reports.
• The above manuscript is available online at: https://www.biorxiv.org/content/10.1101/2023.12.15.571811v1.

Presentations 

• I have given an Oral presentation of this study at the 2023 ARA Victorian/Tasmanian ASM. NB – I was awarded the best Basic Science Presentation.

I have been invited to give an Oral Presentation of this study at the 2024 International Kawasaki Disease Symposium (iKDS) in Montreal Canada