Medicine (St Vincent's)

Crohn’s disease is a chronic, disabling inflammatory condition that affects the gastrointestinal tract that is associated with significant morbidity. Up to 80 percent of patients require surgery at some point in their lives. A third of patients require surgery within five year of diagnosis even in the era of biologic therapy. Ant- Tumour Necrosis Factor alpha (Anti-TNF) therapies form the backbone of drug therapy in patients with moderate to severe Crohn’s disease and remain the most effective biologic drugs available. There are currently three classes of biological drugs available on the Pharmaceutical Benefits Scheme (PBS) for Australians with many more under development. Up to thirty percent of patients fail to have an adequate response to anti-TNF therapy and loss of response occurs at a rate of ten percent per year. There are at present no highly sensitive biomarkers of response to anti-TNF therapies. Without biomarkers to assist with selecting the most effective biologic for a particular patient, there is a risk of exposing patients to ineffective drug therapies with unnecessary side-effects and costs. This thesis comprises a range of clinical and scientific studies that seek to identify predictors of loss of response to anti-TNF therapies in Crohn’s disease. Two types of loss of response have been identified: Primary nonresponse (PNR), is defined as a lack of response to the initial drug therapy as determined at 12 weeks post induction, and Secondary Loss of Response (SLOR) is defined as the loss of response after the patient has had an initial response to the drug. Based on the clinical observation that patients with altered body composition and those with strictures have a variable to response to anti-TNF therapy, we sought to identify whether there were specific clinical, endoscopic, histologic and biochemical parameters that correlated with response to anti-TNF therapy amongst patients from whom longitudinal body composition and endoscopic data had been collected. A prospective cohort study of patients who had been newly started on anti-TNF therapies was also undertaken. In this cohort samples of urine, blood and faeces were taken prior to anti-TNF therapy delivery (baseline) and then at 3 monthly intervals thereafter. A combination of bioinformatic analyses and novel techniques evaluating the metabolome were applied to the cohort, in order to find clinical factors and biomarkers that might correlate with therapeutic response to anti-TNF therapy. This series of studies presented in this thesis on clinical and metabolic predictors of outcomes in patients receiving anti-TNF therapy for Crohn’s disease reveals new insights into the pathophysiology of Crohn’s disease and has identified biomarkers for the prediction of therapeutic response – thereby helping to come a step closer towards the ultimate goal of precision medicine.

Inflammatory bowel disease (IBD) is an emerging global health condition. In the second half of the 20th century, the incidence of Crohn’s disease (CD) and ulcerative colitis (UC) increased dramatically in the Western world. In the last two decades a corresponding rise has been observed in South East Asia(1) and Australia has one of the highest incidences of IBD in the world.(2) At this point in time there is no cure for IBD, and individuals with the condition usually receive lifelong treatment and a significant proportion will need intestinal surgery.(3) Early aggressive treatment with immunomodulator (IM) and biologic therapy can improve steroid free remission rates, reduce the need for surgery and hospitalisation, and reduce the rate of progression to a complex disease phenotype. (4-9) Medicare-subsidised biologic therapy for CD was first made available in Australia in late 2007, while infliximab was not available for use in UC in Australia until 2014. Although the rate of biologic prescription is steadily rising, the impact of increasing biologic use on the natural history and cost of care in the real-world is not clear. Furthermore, it is difficult to identify patients who would benefit from early biologic therapy, and it is uncertain if advancements in treatment are translating into improved patient function and reduced disability. Previous Australian researchers established a prospective community-based IBD inception registry in Barwon, Victoria in 2007 and collected cases to June 2013.(2, 10, 11) The initial aim of the registry was to establish the incidence and prevalence of IBD in Australia, to identify environmental exposures associated with disease aetiology, and to assess the course of disease and healthcare costs in the first 12 months from diagnosis. The aims of the work presented in this thesis were to use the community-based cohort from Barwon, in addition to a newly constructed tertiary IBD center hospital-cohort to determine the natural history of IBD in the first five years of disease, to identify clinical, serologic and genetic associations with disease course and outcomes in IBD, to determine the health care cost of IBD within the first four years of diagnosis from a health care system perspective and identify early clinical predictors of high cost of care, and to describe the burden of disability and identify determinants of disability in IBD. Incident cases diagnosed from July 2013 to April 2016 were identified through a multifaceted approach from Barwon and St Vincent’s Hospital Melbourne to ensure complete capture. Cases were enrolled into the IBD registry that was used as a basis to collect outcome data on disease course, healthcare costs, and disability. Serological analysis was performed for anti-Saccharomyces cerevisiae (ASCA) IgG and IgA antibodies in CD patients, as well as perinuclear anti-Neutrophil Cytoplasmic antibodies (p-ANCA) in CD and UC patients. DNA analysis was performed using 26 single nucleotide polymorphisms (SNPs) that were identified from the literature as potentially having a prognostic role. A total of 408 patients [243(59.6%) CD and 165(40.4%) UC] were included in the analysis of natural history, as well as the cost analysis. 56% of CD and 62% of UC patients were from the Community cohort. 20.8% of CD patients needed intestinal surgery at 5 years which is lower than older population-based studies from the pre-biologic era. 28.1% of CD patients progressed to complex disease phenotype and 8.9% of UC patients underwent colectomy by 5 years which is similar to population-based studies from the pre-biologic era. There was no significant difference in disease outcomes in CD or UC between the hospital and community cohorts. 38% of CD patients and 15% of UC patients were exposed to biologic therapy. Anti-Saccharomyces cerevisiae positivity was associated with progression to complex disease and surgery in CD. Anti-Neutrophil Cytoplasmic Antibody positivity was associated with the need for biologic therapy in UC. There were no significant genetic associations with disease outcomes in CD or UC. In both CD and UC, medication costs accounted for over 50% of total cost, of which biologics accounted for the majority of medication cost. In CD, the mean medication cost per patient per year increased by $3,144 between years 1 to 4 (<0.01), which was offset by a fall in medical and surgical hospitalisation costs of $1,547 (p <0.01) and $3,321 (p <0.01) respectively leading to a reduction in total cost of care over 4 years. There were no significant changes in cost over time in UC. In both CD and UC, surgery, biologic use, and hospitalisation use were associated with higher cost of care. Disability was measured using the newly developed and validated IBD Disability Index (IBD-DI). 334 patients completed the IBD-DI. 56% of all patients had no or only mild disability while 32% of patients in remission had moderate to severe disability. Patients who had previous surgery or current biologic therapy but were currently in remission were more likely to be disabled. Factors associated with greater disability on multivariate regression analysis were active disease, female gender, socioeconomic disadvantage, and biologic use. In summary, this thesis has shown a numerically lower rate of intestinal surgery in CD compared with studies from the true pre-biologic era. Colectomy rates in UC were stable compared with historical controls however biologic exposure rates in UC were modest. We have demonstrated for the first time the nature of changes in IBD-associated healthcare costs over 4 years. After the first year of diagnosis, the use of IM and biologics rose significantly in CD, while surgery and hospitalisation rates declined. Over this time, healthcare cost profiles shifted in a similar fashion, in that as biologic usage rates increased, so did the cost of medications. As hospitalisation and surgical rates fell, so too did their corresponding costs. Disability in IBD is prevalent, and although active disease is an important contributor to disability, a significant proportion of patients were disabled despite being in remission. This novel finding indicates that other factors such as mental health issues may be contributing to disability in IBD.

Medicine (St Vincent's) - Theses

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