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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ItemImmunological and microbiological studies in post-operative Crohn's disease( 2017)Crohn’s disease is a chronic, inflammatory condition of the bowel. The aetiology of Crohn’s has not been fully elucidated, but is believed to arise from the interaction between the gut microbiota, the host immune system and environmental factors. A majority of Crohn’s disease patients will require a bowel resection as a result of disease, which causes significant morbidity and impacts on quality of life. While surgery can ameliorate clinical symptoms, the disease often initially recurs at the site of the resection. This may be sub-clinical initially, and can be identified endoscopically. This thesis investigates the immunological and microbiological characteristics of post-operative Crohn’s disease recurrence in, addressing serologic markers, the faecal microbiome and the possible contribution of Proteus species to gastrointestinal disease. Serologic markers, while disappointing for prediction of disease recurrence, did have some utility for identifying patients at the highest risk of disease recurrence. I also demonstrated lower rates of antibody positivity in Crohn’s patients who smoke for the first time, indicating that these results should be interpreted with caution in current and past smokers. I have further evaluated the faecal microbiome in the setting of post-operative disease using metagenomic techniques. This work showed that after resection for Crohn's disease, enrichment of the bacterial family Lachnospiraceae is associated with maintenance of disease remission, while patients enriched for the Enterobacteriaceae are more likely to recur. Recurrence may result from a higher abundance of enteric pathobionts such as Proteus, Klebsiella, Serratia, and Escherichia. The Lachnospiraceae are an important family of butyrate producing bacteria in the gut, and depletion of this bacterial family may perpetuate the expansion of Enterobacteriaceae via environmental perturbation and ecologic shifts. These findings indicate possible protective and pathogenic bacteria in post-operative recurrence. Finally, I addressed the potential contribution of Proteus species (from the Enterobacteriaceae family) to gastrointestinal diseases including to inflammatory bowel disease. Proteus spp. are low-abundance commensals of the human gut that harbour significant pathogenic potential. Preliminary evidence of a pathogenic role in the gut should stimulate further investigation. I have elucidated some aspects of the microbiome and host immune factors involved, in the pathophysiology of post-operative Crohn’s disease recurrence. This work should encourage further work on a unifying hypothesis for the aetiology of disease recurrence after resectional surgery for Crohn’s disease.
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ItemClinical and scientific features of post-operative Crohn's disease recurrence( 2016)Crohn’s disease is a chronic relapsing inflammatory condition, primarily affecting the gut. It is associated with a significant reduction in health-related quality of life and significant healthcare costs. Up to 80% of patients will require surgery at some point in their life, but this is not curative, with Crohn’s disease recurring in most patients. The pathophysiology of Crohn’s disease relates to the mucosal immune response to antigenic stimulation of the gut microbiota, on a background in some patients of genetic susceptibility. “Dysbiosis” of the gastrointestinal microbiota has been implicated in the cause of Crohn’s disease but how the microbiota behaves in the post-operative state has not been examined in detail. This thesis involves a range of clinical and scientific studies that are part of the Post-operative Crohn’s Endoscopic Recurrence (POCER) platform of studies. These studies aimed to characterise the optimal management for patients after intestinal resection, with a view to preventing disease recurrence. My work has involved scientific studies aimed at identifying key microbial elements that may play a central role in recurrent disease, and further studies addressing optimised clinical management. I have studied gut tissue from patients taken longitudinally from the time of surgery till 18 months post-operatively, and from surgical and healthy controls. Using molecular microbial sequencing techniques I have defined a microbial profile associated with endoscopic recurrence of Crohn’s disease, identifying a novel association between the Proteus genus and recurrence. I have also confirmed that the presence of Faecalibacterium pruausnitzii is associated with a lesser rate of recurrence. Lastly I have shown that smoking, known to increase the rate of recurrence, is associated with a specific bacterial profile. The role of therapeutic monitoring of anti-tumour necrosis factor (TNF) drugs in the post-operative setting has been defined. Blood levels of anti-TNF drugs do not explain why the disease sometimes recurs on these medications. I have evaluated how the faecal biomarkers calprotectin, lactoferrin and S100A12 can be used to diagnose the presence and severity of post-operative Crohn’s disease recurrence. I have shown that calprotectin is a reliable marker of disease recurrence, and can be used as a substitute for colonoscopy. The effects of surgery, immunosuppression, routine early colonoscopy and disease activity on health-related quality of life and healthcare costs in the post-operative period have also been explored in this large and well-characterised post-operative cohort. This series of studies on post-operative Crohn’s disease treatment, monitoring and pathophysiology hold the prospect of changing the paradigm of post-operative care. They may also provide insights in the cause of disease recurrence.
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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.
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ItemInflammatory bowel disease in the East and West: clinical, serological and microbiological studies( 2013)The incidence of inflammatory bowel disease (IBD) in Australia is equal to the highest in the world, in contrast to the incidence in Asia which is low but rapidly increasing. The pathophysiology of IBD relates to the mucosal immune response to antigenicstimulation from the gut microbiota, on a background of genetic susceptibility. Immigrants from low to high incidence areas, have a high incidence of IBD, suggesting that exposure to new environmental factors is a key factor in the development of IBD. “Westernization” of lifestyle and industrialization in Asia likely also plays a role. Our gut microbiota is affected by our genes, our immune system, and environmental factors. Patients with IBD have altered gut microbiota. Little is known about the gut microbiota of IBD patients in the Asia, and in particular whether it is changing to Western patterns, especially after migration. Initially the clinical characteristics and management of IBD patients in Australia and Asia were compared. Then gut microbiota was assessed and compared, using state-of-the-art metagenomic techniques, within and between China and Australia (countries with different IBD incidence) both in the healthy, and IBD populations in subjects of Caucasian and Asian (Chinese) ethnicity. Serological antibodies to microbial antigens, and environmental factors were also assessed. Studying clinical characteristics of disease, the gut microbiota and serological antibodies to microbial antigens in populations with changing incidence offers great hope of identifying potentially important aetiological factors in IBD.