Acute severe ulcerative colitis: clinical and translational studies

Abstract

Acute Severe Ulcerative Colitis (ASUC) is a life-threatening condition that affects 20% of people with ulcerative colitis at some point in their life. Intravenous corticosteroids are first line therapy; however, approximately one-third do not respond, prompting the need for medical salvage treatment such as infliximab. Despite this, 20-30% of patients require life changing surgery to remove the large bowel with stoma formation within three months of presentation. Infliximab has been used as medical salvage therapy for over 15 years; however, the ideal dosing strategy is unknown.

This thesis aims to identify the optimal infliximab induction strategy in ASUC; to improve clinical response rates to infliximab and reduce colectomy rates, and; to explore clinical and experimental predictors and mechanisms of treatment response. A systematic review and meta-analysis was undertaken to examine the efficacies of different infliximab induction strategies. A retrospective study was performed to assess biomarkers of response to infliximab.

This thesis is built upon a clinical study which aims to determine the optimal infliximab induction strategy in ASUC by comparing high dose strategies to standard dose induction, in order to improve clinical outcomes in ASUC. Nested within this clinical trial are exploratory studies assessing biomarkers of steroid response. This study is also aligned with research examining the immunological processes driving ASUC in order to identify new mechanisms of disease and biomarkers of treatment response.

In summary, this thesis describes the implementation of the largest randomised controlled trial currently being undertaken globally to identify the optimal use of infliximab salvage therapy in ASUC. Comprehensive and longitudinal data collection will allow for the investigation of novel clinical, biochemical and immunological predictors of response to therapy.