Explore 2023 Research

Identifying predictors for the development of severe statinrelated muscle disease and optimising its treatment through exploring the role of the anti-HMGCR antibody
Funded by: Australia Rheumatology Association Research Fund
Recipient: Dr Thomas Khoo
Intended Department Southern Adelaide Local Health Network
Project: Identifying predictors for the development of severe statinrelated muscle disease and optimising its treatment through exploring the role of the anti-HMGCR antibody

 

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 ReviewArthritis 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.

 

 

 

 

Antibody response to the Pfizer and AZ COVID vaccination in patients with immune mediated inflammatory disease - An extension study
Funded by: ARA Research Fund
Recipient: Dr Ai Tran
Intended Department: University of Western Australia, Rheumatology Department
Project: Antibody response to the Pfizer and AZ COVID vaccination in patients with immune mediated inflammatory disease – An extension study

 

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)
Stopping blood vessel remodeling in vasculitis
Funded by: ARA Research Fund
Recipient: Dr Angus Stock
Intended Department: Walter and Eliza Hall Institute of Medical Research (WEHI), Inflammation Division
Project: Stopping blood vessel remodeling in vasculitis

 

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