Acquired mutations as the link between rheumatoid arthritis and cardiovascular disease
Team: Dr. Annabelle Small, A/Prof. Mihir Wechalekar, A/Prof. Devendra Hiwase, A/Prof. Chung Hoow Kok, Prof. Arduino Mangoni, Dr. Athena Chin
Report
Rheumatoid arthritis (RA) is a chronic and highly diverse disease that leads to pain, swelling and irreversible joint deformity. Its complications are not confined to the joints, and can include early mortality, a significant (~50%) increase in cardiovascular-related complications, and an increased risk of blood disorders including lymphoma and myelodysplasia. In this project, we sought to understand the prevalence and influence of acquired genetic changes in patients with RA on disease outcomes and cardiovascular risk.
In the first part of the project, we extracted genetic material from blood samples from patients enrolled in the local trial, “Methotrexate (MTX), blood pressure, and arterial function in rheumatoid arthritis” study (trial number NCT03254589). Once isolated, we worked with collaborators from the South Australian Health and Medical Research Institute to develop a genetic test which we then used to examine the presence of changes in DNA sequences (mutations). Bioinformatic analysis of this part of the project remains ongoing at the time of submission of this report.
Meanwhile, in another patient group, we related mutation status and type with measures of RA disease activity, and found that patients with RA over the age of 60 were more likely to have detectable mutations. These were present in 20.5% of patients, significantly higher than the reported frequency in a control population of 5.6%. We found that patients with detected genetic changes and high disease activity at diagnosis were less likely to respond to therapy at their six-month follow up, and we further found that patients with these genetic mutations had higher rates of cancer, and were more likely to experience a cardiovascular event after their RA diagnosis.
Our findings offer new insights of mechanisms that are involved with driving disease severity in RA. Therapeutic agents targeting several of the genetic changes we identified already exist, and our project provides preliminary rationale for repurposing these agents. For people living with musculoskeletal conditions, this work brings us closer to more effective, personalised treatments that can reduce joint damage and improve quality of life.
Outputs from this work
Project outcomes were shared widely within the medical research Community. On May 4th, 2025, Dr. Athena Chin presented the study’s preliminary data at the Australian Rheumatology Association Annual Meeting in Adelaide. Further findings were shared at the 2025 American Congress of Rheumatology in Chicago as a poster, where it was selected and highlighted in the ‘Clinical Year in Preview’ session as an ‘abstract that will shape research in the near future’
Acknowledgements
This work was funded by the ARA Trust. We thank Arthritis Australia for their support, as well as all study participants and consumer advisors.