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Purpose: We report outcomes and evaluate patient factors and the impact of surgical evolution on outcomes in consecutive ulcerative colitis patients who had restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) at an Australian institution over 26 years.Methods: Data including clinical characteristics, preoperative medical therapy, and surgical outcomes were collected. We divided eligible patients into 3 period arms (period 1, 1990 to 1999; period 2, 2000 to 2009; period 3, 2010 to 2016). Outcomes of interest were IPAA leak and pouch failure.Results: A total of 212 patients were included. Median follow-up was 50 (interquartile range, 17 to 120) months. Rates of early and late complications were 34.9% and 52.0%, respectively. Early complications included wound infection (9.4%), pelvic sepsis (8.0%), and small bowel obstruction (6.6%) while late complications included small bowel obstruction (18.9%), anal stenosis (16.8%), and pouch fistula (13.3%). Overall, IPAA leak rate was 6.1% and pouch failure rate was 4.8%. Eighty-three patients (42.3%) experienced pouchitis. Over time, we observed an increase in patient exposure to thiopurine (P=0.0025), cyclosporin (P=0.0002), and anti-tumor necrosis factor (P

Ulcerative colitis (UC) is a major form of inflammatory bowel disease with increasing global incidence. There is significant phenotypic heterogeneity defined by a range of clinical variables including age of onset and disease extent. Clinical outcomes range from long-term remission on minimal therapy to surgical resection. Close to 70% of UC risk can be attributed to genetics and understanding the genetic mechanisms contributing to this risk and disease heterogeneity is vital for understanding disease pathogenesis and improving patient outcomes through targeted screening and therapies. This study aims to characterise the genetic heterogeneity of UC by identifying genomic risk variants specific to mild and/or severe forms of UC, exploring variations in the effect size of known risk variants and assessing the clinical value of a genetic risk score (GRS). We conducted genome-wide association (GWA) analyses in 287 patients with mild UC, 311 patients with severe UC and 583 age- and gender-matched controls. Odds ratios (OR) for mild vs control, severe vs control and combined mild and severe UC vs control were calculated. Using the combined UC data, two independent loci in the HLA region reached genome-wide significance. An additional genome-wide significant signal on chromosome 1 was identified in severe cases only. OR for known risk loci varied between mild and severe patients and were similar to previously published results. Effect estimates from the most recent UC GWA meta-analysis were used to calculate a GRS for each individual. A higher mean GRS was observed in both mild and severe UC cases compared to controls however, there was no difference between the mean GRS for mild and severe UC. Heterogeneity in effect sizes of UC associated variants between mild and severe disease burden suggests the presence of genetically distinct signatures. While large consortium data are needed to identify genome-wide significant variants, additional risk loci may be identified by targeted recruitment of individuals with a history of severe disease.Author SummaryUlcerative colitis (UC) is a chronic and often debilitating form of inflammatory bowel disease affecting approximately 0.3% of the population in industrialized economies. The disease displays significant clinical heterogeneity including age at presentation, disease severity, and the propensity to develop disease-related complications. Several previous studies have demonstrated the heritability of UC, identifying over 30 loci specific to the disease. The majority of these loci have small to modest effect sizes other than those within the Human Leucocyte Antigen (HLA) region on chromosome 6. Using stringent clinical criteria for defining mild and severe forms of UC in an extremes of phenotype approach, we undertook a genome wide association study in a dataset of 1222 participants to investigate genetic heterogeneity in this disease. We demonstrated substantial differences in genetic associations in severe UC as compared to mild UC. While over 2,000 SNPs achieved genome-wide significance in the severe UC analysis, none reached significance for mild UC. These results were reflected in significant differences in odds ratios. We identified Complement Factor B (CFB) as a potential susceptibility gene for severe UC in the Caucasian population with additional tissue gene expression demonstrating a positive correlation with disease severity.

Background Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications. Aim To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts. Results Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model. Conclusion A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD.

Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre-diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD. A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis. For patients with Crohn’s disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p

Background Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers. Methods Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD). Results Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 ± 13.8 years and mean BMI was 27.8 ± 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10-9; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10-4). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10-11), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10-6), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10-5) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10-5) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153). Conclusions It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone.

Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

Background: Many patients presenting with an acute severe ulcerative colitis to a regional hospital are transferred to a metropolitan hospital for specialised care.Aims: To evaluate the outcomes and characteristics of these patients.Method: A retrospective observational cohort study was conducted to examine the 30-day colectomy rate using prospectively collected data on 69 consecutive index cases of acute severe ulcerative colitis transferred from regional hospitals to our metropolitan hospital meeting Truelove and Witts criteria. Those that avoided colectomy were followed out to 1 year to examine outcomes.Results: The 30-day colectomy rate was 46.4% (32/69) in regional transfer patients. Rescue therapy was administered to 65% (45/69) of patients after transfer to our metropolitan hospital. Colectomy was avoided in 55% of these patients at 30 days. Colectomy free status was maintained in 78%(29/39) of these patients. Mortality was 0% at 30 days and 1 year.Conclusion: Over 50% of the patients failing therapy in a regional centre and requiring transfer avoided short term colectomy with co-ordinated referral for rescue therapy in a tertiary metropolitan inflammatory bowel disease unit. These patients would have ultimately required colectomy in their regional hospital without intervention.

Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort. Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire. A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38–19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6–6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4–10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9–16.0). Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.

Background: Patients on immunosuppression at the time of acute severe ulcerative colitis have been suggested to be at a higher risk of colectomy than those who are treatment-naïve. The aim of this study was to examine the effect of immunosuppressive therapy on the risk of colectomy. Method: We conducted a retrospective observational cohort study using prospective data examining the 30 day and 1 year colectomy rates of 200 consecutive patients with an index episode of acute severe ulcerative colitis as defined by the Truelove and Witts criteria. Results: Immunosuppression on admission was shown not to increase colectomy rate at 30 days post-admission (immunomodulator: p = 0.422, oral steroids: p = 0.555). A total of 24 patients underwent colectomy between 30 days and 1 year. A three-fold higher risk of colectomy at 1 year was seen in those requiring an immunomodulator prior to the index admission compared with those started de novo during the index admission [41% versus 14% odds ratio (OR): 2.93 (1.19–7.24 p = 0.016)]. Factors most predictive of colectomy at 30 days were abdominal radiographic colonic dilation ⩾5.5 cm, first presentation of ulcerative colitis, C-reactive protein ⩾ 45 mg/l on day 3 of therapy and bowel frequency ⩾8 on day 3. Conclusion: The need for an immunomodulator prior to admission with acute severe ulcerative colitis increases the medium-term colectomy rate by three-fold at 1 year. Prospective studies are needed to confirm these findings and develop strategies to reduce the high risk in this subgroup of patients.

Smoking increases CD risk. The aim was to determine if smoking cessation at, prior to, or following, CD diagnosis affects medication use, disease phenotypic progression and/or surgery.Data on CD patients with disease for ≥5 yrs were collected retrospectively including the Montreal classification, smoking history, CD-related abdominal surgeries, family history, medication use and disease behaviour at diagnosis and the time when the disease behaviour changed.1115 patients were included across six sites (mean follow-up-16.6 yrs). More non-smokers were male (p=0.047) with A1 (p0.0001), L4 (p=0.028) and perianal (p=0.03) disease. Non-smokers more frequently received anti-TNF agents (p=0.049). (p=0.017: OR 2.5 95%CI 1.18-5.16) and those who ceased smoking prior to diagnosis (p=0.045: OR 2.3 95%CI 1.02-5.21) progressed to complicated (B2/B3) disease as compared to those quitting at diagnosis. Patients with uncomplicated terminal ileal disease at diagnosis more frequently developed B2/B3 disease than isolated colonic CD (p0.0001). B2/B3 disease was more frequent with perianal disease (p0.0001) and if i.v. steroids (p=0.004) or immunosuppressants (p0.0001) were used. 49.3% (558/1115) of patients required at least one intestinal surgery. More smokers had a 2nd surgical resection than patients who quit at, or before, the 1st resection and non-smokers (p=0.044: HR=1.39 95%CI 1.01-1.91). Patients smoking3 cigarettes/day had an increased risk of developing B2/B3 disease (p=0.012: OR 3.8 95%CI 1.27-11.17).Progression to B2/B3 disease and surgery is reduced by smoking cessation. All CD patients regardless of when they were diagnosed, or how many surgeries, should be strongly encouraged to cease smoking.

We read with interest the article by Castano-Rodriguez et al ,1 describing the role of Helicobacter pylori and Campylobacter spp in inflammatory bowel disease (IBD). While H. pylori infection has been shown to be protective against IBD, there is some ambiguity about the biological underpinnings of this effect. There is a spectrum of H pylori exposure across Caucasian populations with lower rates identified in Australian and USA studies.2 Importantly, Australia and other ‘new world’ regions such as the USA currently have some of the highest published incidence and prevalence rates for IBD.3–5 Multiple strains of H. pylori are observed, most notably, those with an active cytotoxin-associated gene A ( cagA ) and those without. The prevalence of the cagA gene in H. pylori is reported to be between 60% and 100% in western and eastern populations, respectively,6 potentially confounding any analysis on the …

Background and aim: The Montreal classification of disease behaviour in Crohn's disease describes progression of disease towards a stricturing and penetrating phenotype. In the present paper, we propose an alternative representation of the long-term course of Crohn's disease complications, the rolling phenotype. As is commonly observed in clinical practice, this definition allows progression to a more severe phenotype (stricturing, penetrating) but also, regression to a less severe behaviour (inflammatory, or remission) over time. Methods: All patients diagnosed with Crohn's Disease between 01/01/1994 and 01/03/2008, managed at a single centre and observed for a minimum of 5 years, had development and resolution of all complications recorded. A rolling phenotype was defined at each time point based on all observed complications in the three years prior to the time point. Phenotype was defined as B1, B2, B3, or B23 (penetrating and stenotic). The progression over time of the rolling phenotype was compared to that of the cumulative Montreal phenotype. Results: 305 patients were observed a median of 10.0 (Intraquartile range 7.3-13.7) years. Longitudinal progression of rolling phenotype demonstrated a consistent proportion of patients with B1 (70%), B2 (20%), B3 (5%) and B23 (5%) phenotypes. These proportions were observed regardless of initial phenotype. In contrast, the cumulative Montreal phenotype progressed towards a more severe phenotype with time (B1 (39%), B2 (26%), B3(35%) at 10 years). Conclusion: A rolling phenotype provides an alternative view of the longitudinal burden of intra-abdominal complications in Crohn's disease. From this viewpoint, 70% of patients have durable freedom from complication over time (>3 years).

BACKGROUND: The Montreal classification for patients with Crohn's disease describes disease phenotype in a hierarchy: B1 (Inflammatory), B2 (Stricturing), B3 (Internal Penetrating). It does not make allowance for description of resolution, or of repeated development, of internal penetrating or stricturing complications (IPSC). It therefore always observes increasing severity of disease phenotype over time, and does not accurately represent the burden of IPSC later in the disease course. AIM: To describe a novel classification of longitudinal disease phenotype in Crohn's disease, which allows description of both resolution and repeated development of IPSC. METHODS: Patients diagnosed at a tertiary referral centre (Brisbane, Australia) with Crohn's disease between 1st Jan 1994 and 1st March 2008, with more than five years of clinical follow-up, had all objective clinical data recorded in a longitudinal database. Temporal evidence of presence of IPSC was obtained from the following: computed tomographic enterography (CTE), magnetic resonance enterography (MRE), ileocolonoscopy, gastroscopy, findings at abdominal surgery and examination of macroscopic surgical specimens. Disease phenotype at each time point was classified as the presence or absence of IPSC over the previous three years of disease course. Longitudinal disease phenotype was compared to progressive Montreal phenotype. Subgroup analysis was performed for patients with B1, B2 or B3 Montreal phenotype within one year of diagnosis. RESULTS: 316 patients with a median follow-up of 10.0 years (interquartile range (IQR) 6.81 13.67) were analyzed. Mean age at diagnosis was 27.4 years and 55% were female. Montreal location classification at diagnosis was L1 (131 patients), L2 (58) and L3 (117). Progressive Montreal phenotype was comparable to published cohorts.1 In comparison longitudinal phenotype classification demonstrated a predominance of stricturing complications. Stricturing complications predominated regardless of Montreal phenotype within the first year (graphs not shown). The steep slope in all lines at 3 years represents patients with an isolated IPSC at presentation regressing to a less severe classification. CONCLUSION: B2 (Stricturing) complications make up the bulk of recurring or non-resolving IPSC in patients with Crohn's disease, regardless of Montreal phenotype within one year of diagnosis. This is not evident when disease classification is observed using the Montreal classification system alone. 1: Tarrant KM, Barclay ML, Frampton CMA, Gearry RB. Perianal disease predicts changes in Crohn's disease phenotype-results of a population-based study of inflammatory bowel disease phenotype. Am J Gastroenterol. 2008 Dec;103(12):3082-93.

in the use of systemic steroids. Conclusions: At the moment of diagnosis of CD, smoking, abdominal pain, diarrhea, lower hemoglobin values and higher CPR, ESR or platelet values, as well as ileocolonic location of the disease, penetrating or stricturing disease, and perianal involvement are associated with a subsequent surgical outcome. The early recognition of these features in newly diagnosed patients should be seriously taken into account when deciding for more aggressive medical treatments, such as immunosuppressors or biological agents, in order to defer the more invasive surgical procedures.

BACKGROUND: The Montreal classification for patients with Crohn's disease describes disease phenotype in a hierarchy: B1 (Inflammatory), B2 (Stricturing), B3 (Internal Penetrating). It does not make allowance for description of resolution, or of repeated development, of internal penetrating or stricturing complications (IPSC). It therefore always observes increasing severity of disease phenotype over time, and does not accurately represent the burden of IPSC later in the disease course. AIM: To describe a novel classification of longitudinal disease phenotype in Crohn's disease, which allows description of both resolution and repeated development of IPSC. METHODS: Patients diagnosed at a tertiary referral centre (Brisbane, Australia) with Crohn's disease between 1st Jan 1994 and 1st March 2008, with more than five years of clinical follow-up, had all objective clinical data recorded in a longitudinal database. Temporal evidence of presence of IPSC was obtained from the following: computed tomographic enterography (CTE), magnetic resonance enterography (MRE), ileocolonoscopy, gastroscopy, findings at abdominal surgery and examination of macroscopic surgical specimens. Disease phenotype at each time point was classified as the presence or absence of IPSC over the previous three years of disease course. Longitudinal disease phenotype was compared to progressive Montreal phenotype. Subgroup analysis was performed for patients with B1, B2 or B3 Montreal phenotype within one year of diagnosis. RESULTS: 316 patients with a median follow-up of 10.0 years (interquartile range (IQR) 6.81 13.67) were analyzed. Mean age at diagnosis was 27.4 years and 55% were female. Montreal location classification at diagnosis was L1 (131 patients), L2 (58) and L3 (117). Progressive Montreal phenotype was comparable to published cohorts.1 In comparison longitudinal phenotype classification demonstrated a predominance of stricturing complications. Stricturing complications predominated regardless of Montreal phenotype within the first year (graphs not shown). The steep slope in all lines at 3 years represents patients with an isolated IPSC at presentation regressing to a less severe classification. CONCLUSION: B2 (Stricturing) complications make up the bulk of recurring or non-resolving IPSC in patients with Crohn's disease, regardless of Montreal phenotype within one year of diagnosis. This is not evident when disease classification is observed using the Montreal classification system alone. 1: Tarrant KM, Barclay ML, Frampton CMA, Gearry RB. Perianal disease predicts changes in Crohn's disease phenotype-results of a population-based study of inflammatory bowel disease phenotype. Am J Gastroenterol. 2008 Dec;103(12):3082-93.