A Biomarker-Driven Approach to Identify Pathogenic Mechanisms and Novel Therapeutic Targets in Pyoderma Gangrenosum

Abstract

Pyoderma Gangrenosum (PG) is an inflammatory cutaneous disease with no standard highly effective treatment. Novel therapeutics with a predictable treatment response are desperately needed, although a major barrier for this is the incomplete understanding of the molecular mechanisms that underpin this disease. Traditionally, PG was thought to be driven by a local dysregulated neutrophilic response. Recent investigations however have identified elevated levels of interleukin (IL) -23 and IL-17 in the serum and tissue of PG patients, suggesting that the Th17 axis may play a role within this disease.

This thesis characterises the molecular mechanisms underlying PG and assesses whether the Th17 axis and related cytokines are major drivers of this disease. A systematic review was performed to collate biomarkers that have been associated with PG. Following this, an exploratory analysis of existing and other possible biomarkers of disease activity associated with active and resolving PG was conducted through an open label, single arm clinical trial. Participants diagnosed with active PG underwent lesional and non-lesional biopsies at baseline, with subsequent systemic administration of subcutaneous tildrakizumab (IL-23 antagonist) 200 mg, at dosing intervals of week 0, week 4, and week 8, with repeat lesional and non-lesional biopsies performed at week 12 (trial completion). Clinical markers of disease activity such as ulcer size, physicians’ global assessment, visual analogue scale scores, and quality of life scores were measured throughout the trial. An a priori analysis of biomarkers gathered from the systematic review conducted was performed on biopsied whole skin samples either through RNA sequencing by a nanostring multiple gene expression assay, or through immunohistochemistry, with comparisons made between healthy control (HC), baseline lesional, non-lesional and lesional tissue at week 12 of the trial.

Various biomarkers associated with PG including IL-23, IL-17A and IL-17F cytokines were elevated in baseline lesional tissue, and to a lesser extent non-lesional tissue, when compared to HC. These inflammatory mediators had a reduced expression within PG tissue in response to IL-23 antagonism. A statistically significant improvement in quality-of-life scores and VAS scores was identified in participants. A reduction in ulcer size was also noted in ulcerative PG but not peristomal PG.

The results of this thesis give valuable insights into the role of the Th17 axis in the development of ulcerative PG, and identifies the IL-23 antagonist tildrakizumab as an effective treatment for ulcerative PG.