Discovery of circulating DMARD response biomarkers in rheumatoid arthritis

Abstract

Current clinical methods for determining disease activity and treatment response in rheumatoid arthritis (RA) are inadequate. The aim of this thesis was to discover accessible circulating biomarkers of disease activity and thus treatment response in RA. This has the potential to aid clinical decision making at an earlier time point and improve long-term patient outcome.
This study has established that the ratio between relative numbers of CD169+ monocytes and CD43+ Tregs, two key cells in inflammation, are positively associated with disease activity in RA patients. Furthermore, RA patients who have not responded to cDMARD treatment exhibited circulating Tregs with a lower activation state compared to those who have responded. Subsequent cell culture experiments used sialic acid (Sia) as a surrogate of CD169, because it binds to CD169 before ligation. Sia was found to suppress Treg activity, reducing intracellular activation markers FoxP3 and NFκB, and secretion of inflammatory cytokines. Thus, changes in levels of circulating CD169+ monocytes may be the cause of defective Treg activity in RA non-responders, potentially via the CD43 Treg cell surface marker.
A range of circulating plasma proteins were identified to be associated with RA disease activity as well as treatment response. With further validation, a biomarker panel of specific plasma proteins could prove to be a reliable method of determining treatment response earlier than currently possible. Such a panel may also improve knowledge of RA pathogenesis.
In summary, this thesis provides compelling evidence of the potential of how treatment response can be determined by analysing key cells and proteins in peripheral blood. It is postulated that with further validation, these markers could enable RA treatment response to be determined earlier than the current timeline of 3-6 months, which would be advantageous to both the clinician and the patient.

Date of Award	Apr 2018
Original language	English
Sponsors	DEL
Supervisor	David Gibson (Supervisor) & Tony Bjourson (Supervisor)