Exploratory analysis to investigate the diseases of polymyalgia rheumatica, giant cell arteritis and rheumatoid arthritis

Manning, Julia Elizabeth (2023). Exploratory analysis to investigate the diseases of polymyalgia rheumatica, giant cell arteritis and rheumatoid arthritis. University of Birmingham. Ph.D.

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Abstract

This thesis uses exploratory forms of analysis to investigate three inflammatory, autoimmune rheumatic diseases; polymyalgia rheumatica (PMR), giant cell arteritis (GCA) and rheumatoid arthritis (RA).

PMR and GCA are closely related diseases. Whilst glucocorticoids (GCs) effectively manage the inflammation and some related symptoms (i.e., pain and stiffness) in these diseases, they also cause adverse effects and subsets of patients still suffer from fatigue. In this thesis, we performed metabolomics on serum from patients with PMR and GCA to assess the effect of disease. In PMR, we went on to evaluate associations with GC treatment and patient symptoms. Compared to controls, this identified several metabolite alterations (e.g., glycerol and lactate) in PMR and GCA patients. Correspondingly, metabolite changes also correlated with inflammation, pain and stiffness (e.g., ketone bodies). Furthermore, PMR patients reporting high and low fatigue had different metabolomic signatures, both before and after treatment. Notably, low glutamine associated with high fatigue at both time points.

In RA, we investigated the role of stromal cells in disease. Firstly, we examined the changing role of the endothelium, investigating a curated list of functionally important molecules. From publicly available bulk RNA-sequencing, we observed a heterogeneous expression pattern, which varied depending on pathotype. Whilst multiplex imaging revealed the majority of these molecules increased with disease duration. We then used transcriptomic analysis to explore the role of fibroblasts (from non-inflamed, resolving arthritis, very early RA and late-stage RA) on healthy endothelial cells and macrophages. Whilst we observed Few transcriptomic changes in endothelial cells according to the diagnosis of fibroblast in coculture, there were many transcriptomic changes in macrophages. These included alterations in IFN and TNF-α signalling. Notably, co-culture with either cell type induced transcriptional changes in the fibroblasts. Indeed, co-culture with macrophages revealed different differentially expressed genes in the fibroblasts, with changes in TGF-β signalling and genes associated with migratory phenotype.

Thus, within this thesis we have identified a number differentially regulated molecules in GCA, PMR and RA. However, due to the exploratory nature in all of these analyses, and limitations in samples sizes, validation of these findings is required.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):