Crohn’s disease is a chronic immune-mediated disease which can cause inflammation in the
gastrointestinal tract anywhere between mouth and anus. It is now understood to be the
result of a complex interplay between genetic, microbial and environmental factors. The
detail of these interactions remains an important focus of research. Clinicians and patients
are faced with an increasing range of therapeutic options for Crohn’s. Key decision points
include first presentation to gastrointestinal services, assessment of risk of disease
progression, escalation to biologic therapy, and withdrawal of immunomodulator or
biologic therapies. Biomarkers are needed that help stratify patients at these times to
facilitate shared decision-making. In this thesis, I have brought together seven of the first-author papers published from the work conducted during my period of study.
I first investigated the associations between NOD2, the strongest genetic association for
Crohn’s disease, and the faecal microbiome. NOD2 encodes a bacterial pattern recognition
receptor, and so disease-associated genetic variants might be expected to lead to an
alteration in the microbiota. Although I demonstrated clear associations between the
presence of inactive Crohn’s and changes in the faecal microbial composition, I was unable
to show an impact of NOD2 genotype in either patients with Crohn’s or in volunteers
without gastrointestinal disease.
Calprotectin is the dominant protein in the cytosol of neutrophils. Its measurement in
faecal samples has become well-established as a tool for non-invasive assessment of
intestinal inflammation. I have investigated its use here for both diagnosis and prognosis in
Crohn’s disease. In the diagnosis paper, I have assessed the diagnostic accuracy in of faecal
calprotectin in a large cohort of patients referred to secondary care with lower gastrointestinal symptoms. I demonstrated a high negative predictive value, with very few
false negatives even after three years of follow-up. In patients with established Crohn’s
disease, I have then gone onto show that higher concentrations of faecal calprotectin,
independent of symptoms, are associated with a greater risk of progressing to stricturing or
penetrating disease, hospitalisation or resectional surgery.
All of the therapies used in Crohn’s disease carry long-term risks including an elevated risk
of infection and certain cancers. For this reason, among others, clinicians and patients must
regularly assess the risk-benefit of continued therapy versus withdrawal of medication. I
conducted two national, multicentre studies to better understand the outcomes of
treatment withdrawal; one for thiopurines, and the other for anti-tumour necrosis factor
alpha (anti-TNF), two of the most widely used classes of maintenance medication for
Crohn’s disease. I demonstrated a relapse rate of 39% at two years following withdrawal of
thiopurines for Crohn’s disease, and for 56% two years following anti-TNF withdrawal. I
identified factors predictive of an increased risk of relapse, and for anti-TNF performed a
systematic review and meta-analysis of all of the available published data.
Anti-TNF therapies were the first targeted biologic therapy licensed for Crohn’s disease and
they remain an important tool for the induction and maintenance of remission. Their
introduction has been transformative for many patients, but secondary loss of response is
common. In the final paper included in this thesis, I present the results from PANTS, a 120-
site study of infliximab and adalimumab in 1,610 patients with Crohn’s disease. I have
demonstrated the importance of good early drug concentrations for outcome, and explored
the relationship between patient factors, drug and anti-drug antibody concentrations and
longer term outcomes. As part of the PANTS study, we have collected longitudinal biological samples, and building
on the clinical data presented in this thesis, I have described some of the early downstream
analyses of genetic associations with anti-drug antibody formation, as well as plans for
analyses of DNA methylation, transcription, serum protein concentrations, immunoglobulin
G glycosylation and variation in the microbiome.
This thesis brings together work spanning a breadth of translational and clinical research
into Crohn’s disease. I have contributed to better understanding of pathogenesis, and to
prediction of outcome at key decision points within the clinical disease course. These
projects, particularly the PANTS study, provide a strong foundation for further research to
better understand this important disease
