Biomarker Need in Paediatric Rheumatology: from Discovery to Clinical Translation

Abstract

Thesis Outline

Part I of this thesis focuses on the need for biomarkers for juvenile idiopathic arthritis (JIA) and existing and newly identified biomarkers are discussed. In Chapter 2, the management of JIA, including SJIA, is discussed in detail. Current treatment protocols and guidelines from around the world are summarised and concepts of management, such as the “window of opportunity” and treatment targets are also covered along with the role that biomarkers could and currently play in the diagnosis and management of JIA. In Chapter 3 an in-depth systematic literature review of biomarkers in SJIA is presented. Papers were evaluated for their identification of potential biomarkers pertaining to the diagnosis and management of SJIA. This paper highlighted the great lack of validation studies for SJIA biomarkers, but also more positively indicates the huge variety of potential biomarkers that are being explored by various research groups around the world in this field. Continuing to study such potential biomarkers could further our understanding of the different mechanisms at play in this systemic autoinflammatory disease.

Part II focuses on two projects aimed at discovering new biomarkers for the AIDs Familial Mediterranean Fever (FMF) and Systemic onset JIA (SJIA). Chapter 4 outlines the search to identify if sub-phenotypes of SJIA can be identified from a biomarker profile and to identify a potential biomarker panel to discriminate SJIA from patients presenting with infection. Secondary objectives were to evaluate the use of multiple platforms to identify biomarkers of various molecular sizes and to use proteomic techniques which have been so far under-used in SJIA for both discovery and validation studies. The focus of Chapter 5 was to identify patterns of S100A12 of IL-18 neutrophil secretion of patients with FMF, which was measured in the serum of patients and in vitro secreted from patient and healthy control neutrophils. Results were correlated with genotype and disease activity.

Part III changes tact by focusing on the translation of biomarkers into clinical practice. The most important aim of biomarker studies is the development of clinically relevant and applicable tests which will positively impact patient care and experience. A study of the biomarker S100A12 and response to therapy is included as well as two commentary papers which focus on the importance of innovation and the translational process of biomarker development. Chapter 6 investigated the association of S100A12 and treatment response in patients with JIA treated with methotrexate or anti-TNF biological therapy. Patients were categorised as treatment responders or non-responders based on various clinical evaluation parameters including ACRpedi50 score, JADAS-10 score and achievement of inactive disease and other risk factors including baseline and follow-up S100A12. Concluding Part III, the two commentaries are strongly influenced by personal experience in translational research settings (Chapter 7 and Chapter 8) and discuss the practical role of the clinical scientist in translational medicine and the directly related concept of interdisciplinarity as a way of driving innovation to reach the overriding goals as discussed above.