Medicine (RMH) - Theses
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ItemRegulation of a cytokine pathway in inflammation and arthritis( 2015)Rheumatoid arthritis (RA) is an idiopathic autoimmune/inflammatory joint disease. The involvement of granulocyte macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of RA is being indicated in clinical trials, but the underlying mechanism of action is still unclear. GM-CSF exhibits macrophage (MΦ)-polarising properties, where it can generate a more pro-inflammatory MΦ population. This thesis illustrates, for the first time, an important signalling cascade involving GM-CSF that is important for the development of murine inflammatory arthritis models.
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ItemRetinal vascular calibre in rheumatoid arthritis: an evaluation of the relationship between systemic inflammation, immunosuppression and retinal vascular calibre( 2013)Background Retinal vascular calibre (RVC) measurement is currently a non-invasive research tool for assessing the human microcirculation for early vascular changes associated with systemic diseases. Widened retinal venular calibre is associated with systemic inflammation, increased cardiovascular (CV) risk and rheumatic diseases, particularly rheumatoid arthritis (RA) and high disease activity. To date there have been no longitudinal studies evaluating the impact of suppressing systemic inflammation on RVC in RA. Aims The primary aim of this thesis was to investigate the effects of suppressing systemic inflammation on serial RVC measurements in patients with RA with moderate to high disease activity. A secondary aim was to examine the stability of RVC measurements in patients with RA with well controlled, low disease activity receiving stable maintenance immunosuppression, to serve as a comparison for our primary analysis. Methods Two groups of patients with RA were recruited and studied concurrently. Group A included patients with moderate-to-high disease activity (DAS28-CRP>3.2) who required treatment escalation as standard of care. Group B had stable, low disease activity (DAS28-CRP≤3.2), did not require alteration of medical therapy and were the control for Group A. Patients in Group A underwent retinal photography at baseline, week six and week twenty-four to assess the respective early and late changes in RVC associated with escalation of systemic immunosuppression. Patients in Group B underwent retinal photography at baseline and at week twelve. Images were analysed by purpose designed software and a trained assessor masked to subject identity and timing of retinal photography. Linear regression and paired t-tests were used to compare serial RVC measurements in Groups A and B respectively, with a p value <0.05 considered significant. Results Group A included 26 patients (69% female) with a mean (SD) age of 50.7 (3.5) years and a mean (SD) disease duration of 7.1 (8.0) years. Disease activity significantly improved between baseline and follow-up at week six (mean reduction in DAS28-CRP score of -1.8 units; 95% CI -2.3 to -1.3 units, p<0.001) and week twenty-four (mean reduction in DAS28-CRP of -2.4 units; 95% CI -3.0 to -1.8 units, p<0.001). This improvement was accompanied by a significant reduction in retinal venular calibre (mean difference (MD) -10.6µm (95% CI -16.4 to -4.8µm, p=0.001) at week six, and MD -8.1μm (95% CI -14.1 to -2.1μm, p=0.009) at week twenty-four), which persisted after adjusting for companion retinal arteriolar calibre. Retinal arteriolar calibre significantly decreased at week six (MD -3.8μm; 95% CI -7.7 to -0.01μm, p=0.05) but not week twenty-four (MD -1.8μm; 95% CI -5.8 to 2.1μm, p=0.36). No significant change in retinal arteriolar calibre was found after adjusting for companion retinal venular calibre. Group B included 27 patients (81% female) with a mean (SD) age of 54.6 (1.8) years and a mean (SD) disease duration of 14.5 (10.9) years. As expected, disease activity and therapy remained unchanged between baseline and week twelve (DAS28-CRP MD -0.1, 95% CI -0.36 to 0.15, p=0.40). There was no significant change in retinal venular calibre (MD 1.37µm; 95% CI -2.83 to 5.58µm, p=0.51) or retinal arteriolar calibre (MD 0.39µm; 95% CI -3.05 to 3.83µm, p=0.82) in Group B during this period. Conclusion This is the first study to demonstrate that suppressing inflammatory disease activity in RA reduces retinal venular widening. This change was evident as early as six-weeks after treatment escalation and was maintained during twenty-four weeks follow-up. In contrast, retinal venular calibre measurements were unchanged in patients with RA with stable, low-level systemic inflammation during short-term follow-up. Taken together, these findings suggest that RVC measurement may be a biomarker of CV risk, and possibly endothelial dysfunction, in patients with RA and supports the concept that immunosuppressive treatment may have vascular benefits in RA.