Medicine (St Vincent's) - Theses
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ItemPredicting response to anti-TNF therapy in Crohn's disease: clinical and metabolic studies( 2018)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.
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ItemThe natural history of inflammatory bowel disease in an Australian community cohort: investigating the aetiology, clinical course, predictors of severe disease and health cost( 2015)Inflammatory Bowel Disease (IBD), including Crohn’s Disease (CD), Ulcerative colitis (UC) and IBD undifferentiated (IBDU), are chronic disorders of the gastrointestinal tract that exert a major impact on an individual’s quality of life and result in very high usage of health care resources. The aetiology of IBD remains unknown. Clinical course can vary from mild to severe and debilitating, and it remains unclear at diagnosis what disease progression will be. Identifying early clinical prognostic factors that predict a severe course is important, thereby enabling early medical therapy to minimize complications of disease. In recent years there has been greater emphasis on intensive therapy and disease monitoring. The greatest impact has been the introduction of biological therapy. However, it remains unclear if these advances are translating into better disease outcomes in the community and at what cost. A population based inception cohort study of patients with IBD was set up in Barwon, Victoria. The aims of the study were to validate the previously reported high incidence, to identify environmental exposures that are associated with disease aetiology, to assess the early course of disease as measured by objective markers such as surgery and hospitalization rates, to identify early clinical prognostic factors associated with severe disease and to determine the health care cost early in the course of IBD. Incident cases from 2007/2008 and 2010-2013 in a well-defined geographical area were prospectively identified through a multifaceted approach to ensure complete capture. Cases were subsequently enrolled into the IBD registry that was used as a basis to collect outcome data on the disease progression, environmental exposures and health care cost. A number of environmental exposures were found to be associated with increased risk of CD included smoking, frequent fast food intake and childhood events such as tonsillectomy and chicken pox infection. In UC, the risk factors included smoking, childhood chicken pox infection as well as frequent fast food. In UC, high caffeine intake was protective (a novel finding), while frequent fruit intake and pets as a child reduced the risk of UC. Objective clinical outcomes were measured for a median of 18 months from diagnosis (range 12-60 months) for 252 patients comprising 146 CD, 96 with Ulcerative colitis UC and 10 IBDU. Immunomodulators (IM) were prescribed in 57% of CD patients, and 19% with UC; biological therapy in 13% of CD patients. A third of all CD patients were hospitalised, the majority (77%) in the first 12 months. Risk factors for hospitalisation included penetrating, perianal and ileocolonic disease. A quarter of UC patients were hospitalized, most within the first 12 months. Resective surgery rates were 13% at 1 year in CD, and 26% at 5 years. Risk factors at diagnosis included penetrating, stricturing and ileal disease. Colectomy rates in UC were 2% and 13% at 1 and 5 years. High CRP at diagnosis was associated with colectomy. Health cost analysis in the first year of disease showed that per patient cost was higher in CD than UC; and that there has been a shift from inpatient to outpatient resources driving the majority of health cost in IBD compared to older studies. This was primarily due to the expense from medications. This first Australian population based study of an inception cohort confirms a high incidence of IBD in Barwon, Victoria that has remained stable over 6 years. A number of environmental risk factors associated with an increased risk of IBD were identified, as well as protective factors, of which high caffeine intake is a novel finding. Disease progress in this cohort was optimistic, compared to historical cohorts, with low rates of intestinal surgery. This was associated with high rates of IM and biological therapy. Early clinical predictors of severe disease were identified that can be used in clinical practice to tailor therapy. Health cost analysis in the first year shows a shift from inpatient to outpatient resources, with medications and investigations contributing the most.