Monitoring disease activity in large vessel vasculitis
Item statusRestricted Access
Embargo end date07/02/2024
Large vessel vasculitis (LVV), including giant cell arteritis (GCA) and Takayasu arteritis (TAK), is the most common form of primary vasculitis and is characterised by chronic inflammation of medium and large arteries. Accurately determining disease activity in LVV is challenging, particularly once treatment has started. This often leads to a mismatch between disease activity and treatment intensity leaving patients at risk of the consequences of over-treatment, including adverse effects of toxic therapies, or under-treatment, leading to unchecked vascular inflammation and arterial damage. The aim of this thesis was to develop novel methods of assessing disease activity in order to better guide treatment for patients with LVV. The results presented here demonstrate that hybrid positron emission tomography with magnetic resonance imaging (PET/MR) is able to accurately distinguish active from inactive LVV and can track disease activity longitudinally. MR metrics provide complementary information to that provided by PET metrics for determination of disease activity status. A novel, PET/MR-specific disease activity assessment score – the VAMP score – appears more effective at distinguishing active from inactive LVV than established PET-only scoring systems. The imaging data provided by PET/MR have the potential to positively influence ‘real-world’ clinical decision making. Considering that PET/MR utilises a significantly lower radiation dose compared with PET/CT, these results support the use of PET/MR for longitudinal disease monitoring in LVV. This thesis has also demonstrated the efficacy of a series of new and emerging serological biomarkers of disease activity in LVV. Plasma concentrations of leucine-rich alpha-2- glycoprotein-1 (LRG1), angiopoietin-2 (Ang-2), soluble fms-like tyrosine kinase-1 (sFlt-1), osteopontin, and calprotectin are elevated in LVV compared with health. Additionally, LRG1, Ang-2 and osteopontin can distinguish active LVV from inactive LVV, with all biomarkers outperforming C-reactive protein (CRP) for this indication. Correlations were observed between several of the evaluated biomarkers and previously defined measures of disease activity. Finally, I have demonstrated the ability of microcirculatory changes to inform LVV disease activity based on examination of retinal microstructures using optical coherence tomography (OCT). Patients with LVV exhibit chorioretinal thinning which is reversible with treatment. Correlations were also observed between OCT metrics and both PET/MR-based and serological measures of disease activity. These results suggest that microcirculatory dysfunction plays a role in the development and maintenance of inflammation in LVV and may be amenable to therapeutic targeting. Additionally, consideration should be given to the eye as a window through which to define and track disease activity in LVV. In summary, this thesis has identified several ways in which monitoring of disease activity in LVV might be improved. These findings have the potential to enhance LVV patient care by facilitating more accurate matching of treatment intensity with disease activity. Larger, multi- centre studies are now required to confirm and expand on these findings.