Clark, Kristina Elizabeth Neergaard; (2022) The molecular basis for the clinical diversity in systemic sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin and organ-based complications. Understanding molecular differences between patients, which reflect clinical outcomes in a meaningful way, have the potential to benefit clinical practice and research and give insight into pathogenesis of disease. The BIOPSY (BIOlogical Phenotyping in SYstemic sclerosis) dataset provided a platform for the integrated analysis of skin and blood samples, along with detailed clinical phenotyping. Through this I was able to explore key molecular differences in early dcSSc, in the context of the full scleroderma spectrum of patients (established dcSSc and lcSSc). The work presented in this thesis demonstrates that there were molecular differences between autoantibody state in the early dcSSc cohort, in skin and blood in serum protein analytes, histological analysis and skin gene expression. These differences are not appreciated when analysed by skin trajectory over a 12-month period. This could explain the clinical heterogeneity seen in SSc, and emphasized the importance of incorporating known autoantibody states in any clinical trial analysis. This work helps move SSc therapeutic strategies towards a more personalized medicine approach, as autoantibody differences may also explain differing response to therapeutics. The BIOPSY dataset also provided an opportunity to utilise blister fluid as an anchor for identifying plasma proteins that reflect skin severity. Blister fluid provides a unique insight int the local environment of the skin. Integrating skin biopsy transcriptomics and blister fluid allowed for the development of a surrogate skin score, using these modalities to identify key analytes in the plasma, and ensuring the plasma analytes reflected skin severity in a multisystem disease. The findings from this thesis are relevant to understanding disease behaviour and potentially impact future clinical trial design and interpretation.

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