Chronic systemic inflammatory disease

Using tear biomarker analysis versus medical imaging in patients with chronic rheumatic disorders.

Project reference number: HLSLTC002

Background

Rheumatic diseases are among the most common and disabling long-term conditions in Western society. Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disorder, characterised by systemic and chronic inflammation of synovial joints. In contrast, the most common rheumatic disorder, osteoarthritis (OA), is normally confined to one or a limited number of joints with low-grade inflammation of the synovium. In both OA and RA, medical imaging (most commonly MRI) is routinely utilised to assess joint damage and synovial inflammation (synovitis). In addition, serum biomarkers of inflammatory activity (e.g. TNF-α, IL-6, and overall erythrocyte sedimentation rate) are frequently measured to quantify inflammation. For research purposes, the difficulties associated with these techniques are the deficits in precision, sensitivity and specificity of imaging modalities in accurately identifying inflammation, and the ethical and practical implications of needing to pierce the skin barrier to collect blood samples from research participants. A validated non-invasive technique for measuring inflammatory and pro-inflamatory biomarkers, combined with optimised imaging, would provide a step-change in the assessment of inflammation in rheumatic disease.

In the field of personalised medicine, proteomic analysis of tissues samples is under investigation to better identify novel biological markers for diagnosis and monitoring of disease progression. Specifically, tear fluids are now being used to assess potential biomarkers of connective tissues diseases. For example, inflammatory mediator proteins such as EGF, IP-10, MCP-1, MIG and MMPs are significantly increased in the tears of Systemic Sclerosis patients. Moreover, in Vision Sciences, we have identified changes to tear fluid cytokines in those with dry eye, a common ocular surface inflammatory disease (Hagan and Tomlinson, 2013).

This project will investigate tear (and plasma) inflammatory biomarker levels, alongside medical imaging (e.g. MRI, CT or ultrasound) in two patient populations: Rheumatoid arthritis (systemic inflammation) and Osteoarthritis (local low-grade inflammation), versus healthy controls. The objective will be to establish if non-invasive tissue (tear) protein analysis can be used alongside imaging to better identify future disease risk. Moreover, it is anticipated that this will serve to facilitate personalised medicine in monitoring disease activity/progression, and response to therapy.

Tear proteomes will be assessed alongside imaging modalities (MRI, CT and/or ultrasound), ocular surface health, Quality of Life (QoL) and other clinical parameters (age, sex, duration, medications).

Example references

Aqrawi LA et al. Identification of potential saliva and tear biomarkers in primary Sjögren's syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Res Ther. 2017;19(1):14.

Aluru SV et al. Tear Fluid Protein Changes in Dry Eye Syndrome Associated with Rheumatoid Arthritis: A Proteomic Approach. Ocul Surf. 2017;15(1):112-129.

Dell'Isola A, Steultjens M. Classification of patients with knee osteoarthritis in clinical phenotypes: Data from the osteoarthritis initiative. PLoS One. 2018;13(1):e0191045.

Farquharson D, Butcher JP, Culshaw S. Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis. Mucosal Immunol. 2012;5(2):112-20.

Hagan S, Martin E, Enríquez-de-Salamanca A. Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine. EPMA J. 2016 Jul 13;7:15.

Hagan S, Tomlinson, A. Tear fluid biomarker profiling: a review of multiplex bead analysis. Ocul Surf. 2013;11(4):219-35.

Villani E et al. Inflammation in dry eye associated with rheumatoid arthritis: cytokine and in vivo confocal microscopy study. Innate Immun. 2013;19(4):420-7.

Aim

This PhD will focus, for the first time, on tear fluid protein profiles and MRI imaging in patients with RA and OA. It is anticipated this work will a) investigate if measures derived from medical imaging correlate with tear fluid inflammatory mediators, b) if QoL and tear proteins are linked and c) determine novel diagnostic biomarkers of RA, OA and of disease progression, which may ultimately be used as an early-screening tool.

Research supervisors

Candidates are encouraged to contact the following researchers for further details:

Modes of study

This project is available as a:

  • PhD: 3 years full-time
  • 1 + 3 route to PhD: Undertaking MRes (1 year full-time) + PhD as above.

Eligibility

Applicants will normally hold a UK honours degree 2:1 (or equivalent); or a Masters degree in a subject relevant to the research project. Equivalent professional qualifications and any appropriate research experience may be considered. A minimum English language level of IELTS score of 6.5 (or equivalent) with no element below 6.0 is required. Some research disciplines may require higher levels.

Specific requirements of the project

The successful applicant will either be a) a qualified optometrist (or ophthalmologist) with an interest in cell biology or b) have a relevant Life Sciences background with a particular interest in biomarkers of eye disease.