Improving the clinical pathway for Crohn’s perianal fistulas - novel approaches to aetiopathogenesis, treatment and outcome measurement

Abstract

Crohn’s perianal fistulas are often complex and represent a challenging and disabling disease phenotype with unknown optimal treatment strategy. There are paucities in understanding of disease aetiopathogenesis, paucity in real word data on long-term outcomes in the biologic era, and the best medical / surgical treatment strategies remain unknown. There is limited ability to measure robust and comparative outcomes due to heterogeneity in outcome measurement with uncertain relevance to patients.

Metabonomics (metabolic profiling/metabolomics) is a rapidly advancing field in systems biology that generates disease-relevant micro-molecular information downstream of the genome and proteome. Metabolic profiling studies utilising nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) have demonstrated early promise in inflammatory bowel disease research. In this thesis, I have implemented a metabolic profiling strategy using mass spectrometry for evaluation of fresh frozen fistula tissue from idiopathic and Crohn’s fistula patients and in so doing have distinguished these two groups of fistula patients by their fistula metabolic phenotype, developing corroborative hypotheses on factors involved in pathogenesis.

Using real world data from a single institution I have catalogued the disease course for a cohort of patients with Crohn’s perianal fistula on anti-TNF therapy over an 11 year period, representing one of the longest follow-up durations / largest cohorts investigated. I have also investigated and chronicled the disease course and natural history for a cohort of patients refractory to anti-TNF, who inevitably have limited options in management. I have also characterised the disease burden in this group, using novel disease states to model transition probabilities between these over time. In order to attempt to streamline patients into avoiding futile treatments and stemming the burden of futile treatment and potential side effects in refractory patients, I have investigated the potential of tissue levels as a biomarker of treatment response. I demonstrate the absence of tissue anti-TNF (infliximab and adalimumab) in a small cohort of Crohn’s fistula patients on maintenance anti-TNF therapy for Crohn’s perianal fistula. Further work is required to corroborate this interesting finding and relate it to clinical outcome as well as develop the search for such a biomarker to facilitate personalised treatment pathways for these patients.

I have explored novel minimally invasive surgical treatment options for perianal fistulas, describing early success with FiLaC, VAAFT and OTSC for idiopathic fistulas but with even more limited evidence in Crohn’s fistulas. This thesis introduces the concept of symptom amelioration for symptom refractory Crohn’s perianal fistulas, demonstrating patient reported benefit in amelioration of symptoms of pain and discharge. However, this was limited by the absence of a control arm and the lack of a validated patient reported outcome measure.

To address the latter issue I have developed a new patient reported outcome measure, the Crohn’s Anal Fistula Quality of Life (CAF-QoL) questionnaire, using a qualitative exploration into the lives of patients with Crohn’s perianal fistulas as well as a multidisciplinary nationwide consensus exercise to inform a process of item generation and psychometric testing, and investigating stability, reliability, construct and content validity and sensitivity to change.