Medicine (St Vincent's) - Theses
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ItemInvestigating the natural history, serologic and genetic associations with disease outcomes, disability and cost of care in inflammatory bowel disease( 2018)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.
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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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ItemChronic hepatitis B in an Australian tertiary hospital cohort: natural history of disease and the association of viral markers with histological and serological outcomes( 2015)Chronic Hepatitis B (CHB) is a major worldwide public health problem with an estimated 240 million people chronically infected and at risk of the complications of liver cirrhosis and hepatocellular carcinoma. There are recognized phases of disease in CHB which are usually defined using a combination of HBeAg status, HBV DNA level and ALT level. These can provide a useful framework to conceptualise a patient’s risk of fibrosis and need for treatment. Using the large CHB cohort at our tertiary hospital in Melbourne, we described our patient group in terms of their phase of disease in a cross-sectional analysis in chapter 3. This analysis highlighted some of the limitations of tests used, eg the insensitivity of older generation HBV DNA. Histological liver injury due to hepatitis B virus (HBV) was also able to be examined in a large proportion of our cohort with liver biopsies and in chapter 4 we evaluated the effect of HBV DNA on liver fibrosis. We found that increasing HBV DNA was associated with increasing prevalence of significant fibrosis in HBeAg negative patients, however in HBeAg positive patients, the reverse was true. This once again leads back to the concept of phase of disease in which HBeAg positive patients in the immune tolerant phase have normal ALT and minimal fibrosis despite very high HBV DNA levels. Longitudinal analysis of untreated HBeAg negative patients in chapter 5 brought to light some of the weaknesses of current classification systems for phase of disease, since we showed that low level fluxes in viral load in HBeAg negative patients were common and strict thresholds for HBV DNA to define the immune control phase were often crossed. The effects of HBV genotype and viral variants (precore and basal core promoter) on liver histology were examined in chapter 6. No significant associations were found although there was a trend towards higher prevalence of significant fibrosis in patients with HBV genotype C. Furthermore we explored the role of the novel markers of quantitative HBeAg and HBsAg (qHBeAg and qHBsAg) for classification of patients into phases in the natural history of CHB and found significant differences in qHBsAg levels in patients in different phases of disease in chapter 7. Finally we evaluated the role of qHBeAg and qHBsAg in the setting of Nucleos(t)ide analogue treatment by comparing 2 groups of HBeAg positive patients, one of which was known to lose HBeAg during the 18 months of followup and the other group which did not. Differences in both baseline and on treatment levels of qHBeAg were found between the 2 groups, however no significant differences in qHBsAg levels were noted. Management of CHB frequently involves monitoring patients to decide on the need and optimal time for therapy. A better understanding of the tools used in evaluating patients and the performance of these in different phases of disease and on therapy helps to enhance the clinical care of CHB patients.
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ItemEpidemiology, natural history and impact of inflammatory bowel disease in Australia( 2010)The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract. International studies have demonstrated a dramatic rise in the incidence of these conditions over the past several decades. There are no corresponding studies from Australia to determine the local incidence. CD has been shown to have a complicated disease course, with high requirements for surgery and progression to disability. Psychological morbidity is also common, with a negative impact on health related quality of life. International studies have also demonstrated high direct and indirect health economic costs associated with CD. Australian data in each of these areas is either limited or totally absent. The aim of this work was to address the deficiencies in each of these key areas. The first Australian population-based study of IBD incidence was conducted prospectively over a one-year period in the region of Barwon. This utilised an extensive capture-recapture methodology, with near complete case identification and rigorous verification of diagnosed cases. The IBD incidence rates observed are among the highest reported in the world literature. The natural history of CD was then assessed in a retrospective, inception cohort study over a five-year period from the time of diagnosis. There was the progressive development of a more complicated disease phenotype, with high requirements for surgery. The results from surgery were not durable, with 60 percent needing escalation of therapy within 5 years. 41 percent of the cohort met the definition of disabling disease, with the presence of perianal fistulae at diagnosis highlighted as a key risk factor. This was followed by two cross-sectional, questionnaire-based, cohort studies to assess psychological health and health related quality of life (HRQoL) in CD. The first study was conducted in patients from the Inflammatory Bowel Disease Clinic at St. Vincent’s Hospital, Melbourne. The second was in a cohort of patients from the same institution who had required the formation of an ileostomy for CD. Both studies revealed high rates of depression, anxiety and poor HRQoL. These negative factors were contributed to by increased disease activity, but the strongest predictive factor was found to be the use of a negative, maladaptive coping style. Some patients with a stoma have adapted well, but others found it to be a negative experience, with ongoing concerns regarding sexuality and body image. The health economic costs of CD were then established using prospective cost diaries. Both direct and indirect costs were high, in keeping with the complicated natural history of CD. These studies highlight that IBD is common in Australia, and that CD has a complicated natural history, with negative impacts on psychological health and HRQoL, and with high economic costs. There is a need for increased public awareness as well as ongoing research and funding to improve clinical care.