An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis

Background and Aims: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. Methods: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [nonMRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. Results: MRUC–control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10−9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10−19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10−6]. No SNPs reached significance in the non-MRUC–control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10−8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. Conclusions: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.Sally Mortlock, Anton Lord, Grant Montgomery, Martha Zakrzewski, Lisa A.Simms, Krupa Krishnaprasad, Katherine Hanigan, James D. Doecke, Alissa Walsh, Ian C. Lawrance, Peter A.Bampton, Jane M. Andrews, Gillian Mahy, Susan J. Connor, Miles P.Sparrow, Sally Bell, Timothy H. Florin, Jakob Begun, Richard B. Gearry, Graham L. Radford-Smit

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Rural IBD patients' access to care, rural surgeons' and IBD nurses' perspectives: Good practitioner knowledge, but significant barriers to optimal care

Introduction: The management of IBD in rural and remote settings of Australia is often led by rural surgeons, yet rural surgeon knowledge and comfort with managing IBD is uncertain. Many city based IBD services have IBD nurses who will have a proportion of rural patients who they see in conjunction with city based IBD centres. Both these groups of health practitioners would have possibly differing but important perspectives as to any barriers to care rural and remote patients with IBD might face. Methods: A questionnaire was sent to Rural Surgeons and metropolitan IBD nurses Australia-wide. It sought practitioner perspectives on knowledge of and exposure to and perceived barriers to care for rural patients with IBD. Results: To date 440 invitations have been distributed yielding 74 completed questionnaires (response rate 44%, 21/48 IBD metropolitan nurses,14% 53/392 rural surgeons). IBD exposure data: Rural surgeons have a variable exposure to IBD, although a significant number report having more than 10 current patients with IBD (25%, 13/51). Whilst most surgeons felt generally happy and comfortable managing IBD patients, the majority felt uncomfortable or extremely uncomfortable to initiate or use immunomodulators and biologic therapies (65% and 85% respectively)and a majority felt that an IBD action plan would be useful (37/48). IBD knowledge data: With the use of a previously validated screening tool,1IBD knowledge appeared to be good with correct answers in 85% of surgical replies and 95% of IBD nurse replies. Perceived barriers to care data: Rural surgeons and IBD nurses generally felt that rural patients did not have the same health outcomes compared with their urban counter-parts. 56% of rural surgeons and 74% IBD nurses felt that current access to specialist IBD care was not adequate, with 79% of rural surgeons and 84% IBD nurses believing that some adverse health outcomes could have been prevented if access was improved. The three most important barriers to optimal IBD care for rural patients included distance to specialist services(42/68 – 30 surgeons, 12 IBD nurses), lack of multi-disciplinary IBD teams(33/68 – 22 surgeons, 11 IBD nurses) and the financial costs of access specialist services (31/69 – 26 surgeons, 5 IBD nurses). A significant proportion (21/48) of surgeons did not feel that they had adequate knowledge/training in the care of IBD patients, with 14 feeling that this was a barrier to the optimal care of this cohort of patients. Of the suggested options aimed at enhancing access to specialist Gastroenterology care, those perceived to be most helpful were annual information sessions for patients and their family held in the local region by an IBD coordinator and specialist (45/64 – 30 surgeons, 15 IBD nurses), a teleconference between the primary care physician, patient and Gastroenterologist (38/64 – 25surgeons, 13 IBD nurses) and the availability of emailing an IBD nurse coordinator by patient (35/64 – 22 surgeons, 13 IBD nurses).Conclusion: This interim data demonstrates that a substantial majority of surveyed surgeons and IBD nurses thought that rural patients do not have the same health outcomes as their metropolitan counterparts. Reported or perceived barriers were predominantly distance, lack of access to MDTs and financial cost; however inadequate training was also identified. Although IBD knowledge appeared to be sufficient with the use of the multiple choice questions, a large proportion of participants still felt uncomfortable using more advanced IBD therapies. Despite this, there appears significant interest in improving care from the rural surgeon group, with a desire to achieve better integration with city based services. References 1. Tan M, Holloway RH, Lange K, Andrews JM. General Practitioners’ Knowledge of, and Attitudes to, Inflammatory Bowel Disease (Ibd).Intern Med J. 2012 Jul;42(7):801–7AL Bennett, M Wichmann, JM Andrews, PA Bampto

W1136 Fear and Fertility in Inflammatory Bowel Disease - A Mismatch of Perception and Reality Affects Patient Behaviour

Introduction: Overall fertility in male and female Inflammatory Bowel Disease (IBD) patients is similar to the general population, with the exception of reduced fertility in males on sulphasalzaine. Adverse pregnancy outcomes are slightly increased in women with IBD. Apart from methotrexate, IBD medications are safe in pregnancy. Voluntary childlessness has been described in IBD, thus we wanted to understand the extent to which fear of infertility and poor pregnancy outcomes affected behaviour in IBD patients. Method : 365 patients (146 male [M]; 219 female [F]; 18-50 yrs) from a hospital-based, IBD database were surveyed. Data were obtained by questionnaire on diagnosis, demographics, relationships, body image, sexual function, as well as fertility and pregnancy data. Descriptive data are presented, statistical comparisons made using a chi square test. A p value < 0.05 was considered significant. Results : 183 invitees participated; 109 CD, 69 UC (36 % M, 65% F , mean age 36.3 years; response rate 50% overall). 76% were in a current relationship, 6% had never been partnered. 58.7% of patients with CD and 14.5% with UC reported previous IBD surgery. Overall, 17.9% of patients reported consulting a doctor for fertility problems (22% of CD patients vs 11.6% UC patients,) p=0.078. 48% of CD patients feared a lack of fertility related to IBD vs 26% of UC patients, p=0.004. Respondents had fewer children than desired or planned in 25% of Crohn's and 23% of UC cases (p=0.84). Reasons volunteered for this centred around fear of adverse fertility and pregnancy outcomes. Termination of pregnancy was reported in females with IBD or female partners of male IBD patients in 17.4% of CD respondents, vs 14.4% in UC (p=0.61) The decision to terminate pregnancy was directly attributed to IBD in 20.7% of these patients. Conclusions: Despite no overall fertility reduction and only modest increase in adverse pregnancy outcomes amongst most IBD subgroups, Crohn's patients in particular report sufficient fear of such outcomes to influence their family planning.Reme E. Mountifield, Ruth Prosser, Peter A. Bampton, Jane M. Andrew

The effect of allopurinol on thiopurine metabolite concentrations in patients with inflammatory bowel disease

Poster abstract #P234T.L. Asser, N..AA.. KKeennnneeddyy, P.A. Bampton, J.M. Andrews, D. Elliott, M.P. Doogu

Colonoscopic bowel cancer screening is associated with more depression and anxiety in previously healthy people than those with inflammatory bowel disease

Background: Surveillance for colorectal cancer in Inflammatory Bowel Disease (IBD) is generally recommended, although more recent data suggest the risk of colorectal cancer in this population is less than previously supposed. Given this, it is important to determine if any psychological harm is occurring to patients on a surveillance program. Aims: To compare the psychological effect of colonoscopy in an IBD surveillance program with colonoscopy performed in response to a positive faecal immunohistochemical test in previously well individuals. Methods: 60 subjects aged over 40 yrs who underwent colonoscopy after a positive fecal immunohistochemical test in the National Bowel Cancer Screening Program (NBCSP) and without known previous bowel disease were mailed a questionnaire, along with IBD database patients meeting the criteria for 2 yearly colonoscopic screening for colonic dysplasia and cancer. Respondents would be age and gender matched across groups. The questionnaire incorporated the Speilberger State-Trait Personality Inventory for Anxiety, Depression, Anger and Curiosity, as well as demographic questions. Speilberger comparisons between groups were made using the independent sample t test, whilst demographic data were compared using the Chi-square test. Results : 42/60 NBCSP subjects returned a completed questionnaire (70%), whilst 139/286 (49%) IBD subjects responded, allowing 42 patients to be age and gender matched in each group. Mean age was 57.71 years (NBCSP) vs 57.73 years (IBD) p=0.89, 53% being male. The groups were demographically comparable apart from a higher rate of car ownership amongst IBD subjects (42 vs 38 (p=0.04). NBCSP subjects had higher Overall Anxiety (Speilberger Score 28.5 vs 24.9, p=0.00) and Overall Depression scores (27.4 vs 22.7, p=0.00) than their IBD counterparts. (Table 1) NBCSP patients had higher State Anxiety (20.54 vs 17.97, p=0.00) and Depression (22.23 vs 16.73, p=0.00) scores than people with IBD, whilst IBD patients had higher State Curiosity scores than previously healthy people (26.00 vs 22.92, p=0.03). Interestingly, Trait Anxiety scores were higher amongst NBCSP patients (15.92 vs 13.76, p=0.00), whilst Trait Depression scores were increased in people with IBD (11.92 vs 10.28, p=0.02). Conclusion: Patients who are previously healthy and undergo colonoscopy for a positive faecal immunohistochem- ical test suffer more anxiety and depression symptoms after colonoscopy than those who are previously aware of their increased risk of cancer due to Inflammatory Bowel Disease. This should be considered in planning Bowel Cancer Screening Programs in previously healthy populations.Reme E.Mountifield, Amanda Moseley, Ruth Prosser, Antonina A. Mikocka-Walus, Graeme P. Young, Jane M. Andrews, Peter A. Bampto

Tu1330 Thiopurine Metabolite Testing to Guide Management in Inflammatory Bowel Disease (IBD) Yields Clinical Benefit At 12 Months: A Retrospective Observational Study

Background: Azathioprine & 6-mercaptopurine (AZA/MP) metabolites, 6-thioguanine nucleotides (6TGN) & 6-methyl-mercaptopurine (6MMP), are commonly measured. Cross- sectional observational data have led to a proposed "therapeutic range". Short-term studies support the use of therapeutic drug monitoring (TDM) to guide AZA/MP dosing and to identify "shunters" (preferential 6MMP producers). However, few data have evaluated TDM- led management in the longer-term. We therefore evaluated patient outcomes ≥12 months after AZA/MP TDM-led management in a large adult IBD cohort. Methods: A multi-centre cross-sectional retrospective study was performed in 3 Australian IBD Services. Data were collected from clinical records of IBD adults, on AZA/MP for >4 weeks at index TDM. Patient demographics, disease characteristics, physician global assessment, IBD therapy at index TDM, and again ≥12 months after TDM-led management were collected. Indications for TDM were categorized. Therapeutic 6TGN was defined as 235-450pmol/8x108RBC. Shunters were defined as a 6MMP:6TGN ratio ≥11. Statistical analyses were performed using SAS 9.3. Results: 343 patients were included for analysis. 247 (72%) had Crohn's disease (CD), 177 (52%) male, mean age 41 years, 218 (64%) had active disease at baseline. TDM was most commonly performed for proactive dose assessment (48%), flare (23%), ongoing active disease (21%) & adverse drug reactions (7%). Prior to TDM, 52% of patients would have had blind dose escalation, cessation of AZA/MP or escalation to another therapy. Overall, TDM led to continuation of AZA/MP (±dose adjustment ±allopurinol) in 290 (85%). At 12 months, 248/343 (72%) were in clinical remission, 19 (6%) improved disease activity, 67 (19%) active disease and 9 (3%) unknown activity status. Of the 267 with 12-month clinical remission/improvement, 157 (60%) achieved this with AZA/MP alone (±allopurinol). In comparison, this was achieved with anti-TNFa therapy, another medical agent, surgery (±medical therapy) in 61 (23%), 13 (4%) and 25 (9%) respectively. Univariate logistic regression analysis found only baseline remission to be a predictor of 12-month clinical remission/improvement on thiopurine therapy (OR 2.87, CI 1.20-6.89, p=0.02). CONCLU- SION AZA/MP TDM-led management allows many patients apparently "failing" therapy to continue the agent and also identifies "shunters". TDM facilitates appropriate adjustment of therapy. TDM also promptly identifies those who require escalation to another agent or surgery, leading to an overall remission rate of 72% compared to 36% at baseline. AZA/ MP±allopurinol alone achieved clinical remission in 60% of patients. This is the largest study to pragmatically evaluate longer-term outcomes of AZA/MP TDM and supports its clinical value.Soong-Yuan J. Ooi, Michael Gounder, Rachel Grafton, Peta Leach, Peter A. Bampton, Alexandra Sechi, Wa Sang Watson Ng, Susan J. Connor, Jane M. Andrew

Serious infective complications associated with anti-TNF alpha therapy in inflammatory bowel disease

Background: Anti-TNFαmedications are effective in the management of patients with difficult Crohn’s disease (CD) and ulcerative colitis/IBDU(UC/IBDU). They are, however, associated with an increased risk of tuberculosis (TB) reactivation, initial TB infection, and potentially other bacterial, viral or fungal infections. Aims: To examine the Australasian experience of TB and serious infective complications in IBD patients treated with an anti-TNFα. Methods: Data was collected from eight sites across Australia and New Zealand specialising in IBD management. Overall IBD patient numbers managed, patient numbers ever treated with an anti-TNFα, and patients suffering TB, or a serious infection while receiving anti-TNFαtherapy were analysed. A serious infection was defined as ‘an infection requiring hospital admission’. Patient demographics, concurrent IBD medications, the anti-TNFαmedication used, time on the anti-TNFα, infection type and infection outcome was also collected. Results: A total of 5613 IBD patients (2904 CD, 2709 UC/IBDU) were managed across the centers. Anti-TNFαtherapy was used in 16.9% of CD(491; 442-infliximab, 94-adalimumab, 45-both) and 3.7% of UC/IBDU patients (100 UC/IBDU; 94-infliximab, 14-adalimumab, 8-both). There were no cases of reactivation of latent TB and no new cases reported. There were nine serious infections (4M/5F, 1 UC/IBDU/8 CD, average 36.1 years, range 14–57 years). Infections occurred in three patients receiving 24 months of an anti-TNFα. All these patients were receiving additional immunosuppressive (IS) medication: 2-pred, 1-pred/AZA, 2-AZA, 1-methotrexate (MTX), 1-pred/MTX, 1-pred/AZA/MTX and 1-pred/MTX/mycophenolate mofetil. Seven of the infections occurred while on an anti-TNFαand two within 3 months of the last treatment. There were two primary varicella zoster, one Pneumocysits carnii peunmonia, one UTI with enterobacteraerogenes, and five infections where no organ-ism was identified (1 pneumonia, one diverticular abscess, one conjunc-tivitis and two unidentified source). All infections resolved. Conclusion: TB does not appear to be a problem with anti-TNFα therapy in Australasia. Infections, resulting in a hospital admission, are low occur-ring in only 1.8% of patients receiving anti-TNFαtherapy, but all those patients were also on other IS medications. All the infections were successfully treated.IC Lawrance, Pabampton, M Sparrow, RB Gearry, RW Leong, JM Andrews, THJ Florin, A Croft, And GL Radford-Smit

A nurse-led model at public academic hospitals maintains high adherence to colorectal cancer surveillance guidelines

OBJECTIVE:To examine the compliance of colorectal cancer surveillance decisions for individuals at greater risk with current evidence-based guidelines and to determine whether compliance differs between surveillance models. DESIGN:Prospective auditing of compliance of surveillance decisions with evidence-based guidelines (NHMRC) in two decision-making models: nurse coordinator-led decision making in public academic hospitals and physician-led decision making in private non-academic hospitals. SETTING:Selected South Australian hospitals participating in the Southern Co-operative Program for the Prevention of Colorectal Cancer (SCOOP). MAIN OUTCOME MEASURES:Proportions of recall recommendations that matched NHMRC guideline recommendations (March-May 2015); numbers of surveillance colonoscopies undertaken more than 6 months ahead of schedule (January-December 2015); proportions of significant neoplasia findings during the 15 years of SCOOP operation (2000-2015). RESULTS:For the nurse-led/public academic hospital model, the recall interval recommendation following 398 of 410 colonoscopies (97%) with findings covered by NHMRC guidelines corresponded to the guideline recommendations; for the physician-led/private non-academic hospital model, this applied to 257 of 310 colonoscopies (83%) (P < 0.001). During 2015, 27% of colonoscopies in public academic hospitals (mean, 27 months; SD, 13 months) and 20% of those in private non-academic hospitals (mean, 23 months; SD, 12 months) were performed more than 6 months earlier than scheduled, in most cases because of patient-related factors (symptoms, faecal occult blood test results). The ratio of the numbers of high risk adenomas to cancers increased from 6.6:1 during 2001-2005 to 16:1 during 2011-2015. CONCLUSION:The nurse-led/public academic hospital model for decisions about colorectal cancer surveillance intervals achieves a high degree of compliance with guideline recommendations, which should relieve burdening of colonoscopy resources.Erin L Symonds, Kalindra Simpson, Michelle Coats, Angela Chaplin, Karen Saxty ... Peter A Bampton ... et al

Smoking cessation following the diagnosis of Crohn's Disease still reduces the rates of surgery and complicated disease

Abstract #Su1204Introduction; Smoking affects CD and is associated with more complicated disease, failure of medical therapy and surgical intervention. It is unclear, however, if patients who stop smoking following diagnosis remain more likely develop complicated disease or if they revert to the nonsmoker risk profile. Aims & Methods: The aim was to determine if smoking cessation prior to, or within 1-2yrs or 3yrs following diagnosis alters the long- term development of complicated disease, need for surgery and medication use. All patients had been followed for a minimum of 5 years from diagnosis. Demographic data including the Montreal classification, detailed smoking history, number and dates of CD abdominal surgeries, family history and medication use were analyzed. Results: 1103 patients were included (589 had ever smoked and 572 were female). The mean follow up was 14.2yrs (range 5-66yrs). No differences were detected in the family history of IBD, use of immunosup- pressants or need for colectomy between any group. Comparing lifelong non-smokers (NS) to patients who had ever smoked, significantly more NS were male (p=0.01), were A1 (p<0.0001), with less having B2 disease at diagnosis (p=0.02), but more prevalent perianal disease (p=0.02). Bowel resection during follow-up was more common in smokers (p=0.03), as was the need for a 2nd (p=0.0001) or 3rd intestinal resection (p=0.0001). NS were more likely to have received anti-TNF-alpha therapy (p=0.0001). Comparing NS and ex-smokers at diagnosis with current smokers (CS), NS and ex-smokers had less L1 (both p<0.005) and B2 disease (both p<0.05), less with B1 disease at diagnosis developed complicated disease by 5 years (both p<0.001), and bowel resection was less common (both p<0.0001) as were 2nd (both p<0.01) and 3rd intestinal resections (both p<0.0001). Although numbers were smaller, comparing smokers who gave up within 1-2yrs, and 3yrs, following diagnosis with CS, the findings were similar with less abdominal surgery (p=0.04 and 0.002), less repeated abdominal surgery (both p<0.0001), less progression to complicated disease by 5 years (p=0.004 and p<0.0001), less need for oral steroids (p=0.08 and 0.02), but more use of anti-TNF-alpha therapy (p=0.03 and <0.001). No differences in surgery rates, development of complicated disease or medication use was observed in the ex-smokers at diagnosis or those who gave up within 1-2yrs and 3yrs after diagnosis compared to NS. Conclusion: As previously identified, current smoking affects the long-term rates of surgery and the development of complicated CD. Cessation of smoking prior to or within 3yrs after diagnosis reduces the rate of developing complicated disease and the need for abdominal CD surgery. These patients had the same risk of these outcomes as NS. This further supports the need for CD patients to be strongly encouraged to cease smoking.Ian C. Lawrance, Birol Batman, Richard B. Gearry, Rachel Grafton, Krupa Krishnaprasad, Jane M. Andrews, Ruth Prosser, Peter A. Bampton, Sharon E. Cooke, Gillian Mahy, Graham Radford-Smith, Anthony Croft, Katherine Haniga