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Journal of Gastroenterology and Hepatology (2015) 30 (Suppl. 3)

Inflammatory Bowel Disease it was hypothesized that there would be a reduction in penetrating disease with a concomitant rise in stricturing disease as the primary indication of surgery. Methods: From 1996 to 2013, sequential surgical procedures performed Colonic ultrasound in inflammatory bowel on patients with Crohn’s disease at two large West Australian metropolitan disease: an accurate marker of disease activity hospitals were recorded. The cohort was divided into pre- biological agent and mucosal healing [pre-BA] availability (1996–2006) and post-biological agent [post-BA] A ASTHANA, A FRIEDMAN, K BRITTO, N HEERASING, availability (2007–2013). The difference in the frequency of indications for M SPARROW, S JAKOBOVITS, P GIBSON surgical procedures and outcomes between the cohorts was determined statistically using chi-square tests. Department of Gastroenterology, Alfred Health and Results: 224 patients underwent 244 surgical procedures (pre-BA, Monash University, Melbourne, Australia n = 105; post-BA, n = 139). The mean age was 40.6 years with a larger χ2 Background: Endoscopic mucosal healing is an established end point percentage of females in pre-BA (66.7%) than post-BA (47.5%; = = for deep remission in IBD patients and there is growing interest in the role (1) 8.92, p 0.003). There was no change in the primary indication for χ2 of IUS as a surrogate non-invasive marker for endoscopic mucosal healing. surgery. Rates of emergency surgery decreased from 19% to 8.6% ( = = There is good level evidence to support its for small bowel IBD but less so (1) 5.69, p 0.017). Patients requiring a stoma decreased from 30.5% to χ2 = = for colonic disease. 15.8% ( (1) 7.45, p 0.008). There was a significant difference in the Aims: To assess the accuracy of colonic ultrasound in evaluating disease number and types of anastomoses between groups. activity and distribution compared to colonoscopy in IBD. Conclusions: There was no clear evidence that the introduction of bio- Method: A prospective database was established for CUS. Findings from logical agents changed the indications for surgery in this cohort. The study CUS were compared to the gold standard of endoscopy within 6 months of does demonstrate a reduction in emergency surgeries and stomas, leading the scan. Recruitment occurred via the IBD clinic at Alfred Health. Data to better overall patient outcomes. Further investigation of individual were collected between June 2013 and December 2014, including clinical patient response to biological agents is warranted. and biochemical indices. Data from all patients in whom disease activity (as determined by endoscopic findings and clinical indices) was unchanged between the CUS and colonoscopy were analysed and the performance of CUS compared with that of endoscopic findings. Disease activity on colo- Investigating the predictive value of biochemical noscopy was defined by either the presence or absence of disease (not markers in Crohn’s disease phenotypes based on severity). Concordance between the two investigations was based A AZZAM, S SAFA, L BRETT, C MCIVOR on corresponding disease activity (not including severity) and distribution. Department of Gastroenterology, Logan Hospital, Data was analysed as per the disease phenotype – Crohn’s colitis (CC) and Brisbane, Queensland, Australia ulcerative colitis (UC). Results: Of 171 patients undergoing CUS, 89 met inclusion criteria. Introduction: The Montreal classification has been suggested as a phe- Sixty-seven had CC and 22 (24%) UC. 68 (76%) patients had evidence of notypic classification for inflammatory bowel disease (IBD). It is based on active disease, of whom 22 (32%) had left-sided disease, 38 (55%) had 3 parameters in Crohn’s disease (CD) – age at diagnosis, disease location (1) right-sided disease and 8 (11%) patients had pancolitis. The median time and disease behaviour . Many studies have attempted to identify associa- interval between the CUS and colonoscopy was 40 days (range 90 days tions between biochemical markers and various aspects of IBD. CRP and prior to 120 days post colonoscopy). The overall sensitivity of CUS was faecal calprotectin has been found to correlate with endoscopic and clinical (2) 97%, specificity 88%, positive predictive value 96% and negative predic- disease activity . The ability to assess disease activity with simple non- tive value of 90%. There was 100% concordance of CUS to colonoscopy invasive tests would enhance the management of patients with Crohn’s for left and right-sided disease but 87.5% concordance for pancolitis and Disease. Our study is the first known to the authors that looks at IBD 85% for inactive disease. There were 4 discordant cases; three of these had phenotypes and the utility of CRP and ESR is assessing the activity of CC and had endoscopic evidence of inactive disease whilst the CUS disease. documented mild activity. The remaining one patient had endoscopic evi- Methods: A retrospective analysis was conducted for CD patients with dence of mild pancolitis and this was missed on IUS. There was no endoscopies performed between August 2005 and March 2015. 42 patients discordance between IUS and colonoscopy in UC patients. were included in the final analysis. Data was obtained from endoscopic Conclusion: CUS has a high accuracy, with regards to disease distribu- records, case notes and pathology reports. CRP and faecal calprotectin tion and presence or absence of disease activity, in patients with colitis were checked in all patients. ESR was measured in most of these. Disease > μ compared to the gold standard of colonoscopy. Concordance between IUS was determined to be active if faecal calprotectin was ( 100 g/g). Chi- and colonoscopy was 100% in UC patients. Further prospective studies are squared/Fisher’s exact tests were performed to look for association needed to further define the role of IUS as a surrogate marker for endo- between IBD phenotypes (disease location and behaviour) in patients with scopic healing in UC and CC. active disease and abnormalities in CRP/ESR levels. Results: The study cohort included 42 patients (16 males and 26 females) with elevated faecal calprotectin. The mean age was 44 years and the average age at diagnosis was 35 years. The majority of patients had The evolution of indications and outcomes of ileal disease (n = 21; 50%), followed by ileo-colonic (n = 14; 33.3%), surgery for patients with Crohn’s disease during colonic (n = 8; 19.%). Twenty one patients (50%) had non-stricturing/non- the biological agent era penetrating disease. Fifteen patients (38%) had penetrating disease. C ATTREE,1 J STATON,1 D ORMONDE,2 C PLATELL2 A significant association was found between CRP levels (>10 mg/L) and 1School of Medicine Fremantle, Notre Dame University disease behaviour in patients with active disease, as determined by a raised Australia, 2Saint John of God Hospital, Subiaco calprotectin level. 82% of patients with active, non-stricturing/non- penetrating disease had an elevated CRP (>10 mg/L) and this was statisti- Aims: To determine if the introduction of biological agents has changed cally significant (p < 0.05). Further analysis found no association between the indications and outcomes of surgery for patients with Crohn’s disease. disease location (regardless of phenotype) and CRP/ESR levels. Of note, In accordance with the theorized mechanism of action of biological agents, 83% of patients with active colonic disease had a normal ESR (<20 mm/

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 117 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Hr). ESR values were similar in other groups of CD phenotypes regardless 83% & 71% (AUC 0.81 [95% CI 0.57, 1.0]), 83% & 57% (AUC 0.75 [0.41, of disease activity. 1.0]) and 83% & 100% (AUC 0.88 [0.66, 1.0] respectively. Conclusion: A significant association was found between disease behaviour and CRP in non-stricturing/non-penetrating CD. We found no significant association between CRP/ESR and distribution of disease in CD Variable OR [95% CI] p patients with active disease. A significant relationship between ESR/CRP or Medians value and disease location may not have been detected in this study due to small Primary Day 3 IFX level ≥501 0.08 [0.01,1.3] 0.10 sample size. We plan to examine this in a larger cohort of patients. endpoint CRP AUC Day 1 to 3 ≥401 0.03 [0.002, 0.7] 0.03 References: Calprotectin AUC Day 1 0.08 [0.01,1.3] 0.10 1. Satsangi, J., et al. “The Montreal classification of inflammatory bowel to 3 ≥10000 disease: controversies, consensus, and implications.” Gut 55.6 (2006): Single IFX dose only (vs 3.3 [1.3, 8.6] 0.02 749–753. two doses) 2. Schoepfer, Alain M., et al. “Fecal calprotectin more accurately reflects Day 3 partial Mayo score2 5.0 vs 7.0 0.03 endoscopic activity of ulcerative colitis than the Lichtiger Index, Day 3 calprotectin level2 798 vs 2666 0.03 C-reactive protein, platelets, hemoglobin, and blood leukocytes.” Day 3 IFX drug level2 33.0 vs 50.0 0.10 Inflammatory bowel diseases 19.2 (2013): 332–341. Secondary Day 3 IFX level ≥501 0.3 [0.08, 0.8] 0.02 endpoint UC duration >3 years1 30.0 [1.5, 612] 0.03 Day 3 IFX drug level2 27.0 vs 50.0 0.04 The predictive value of early serum infliximab, IFX dose: BMI ratio 2 17.4 vs 15.2 0.01 crp and faecal calprotectin levels post-first 1cutoff based on median of cohort. 2median of ‘endpoint achieved’ vs infliximab rescue dose for acute severe colitis: ‘not achieved’ groups respectively. Comparisons shown only where ‘day 1 to 3 is key’ p ≤ 0.10. L BESWICK,1,2 DR VAN LANGENBERG,2 O ROSELLA,1 B HEADON,1 B LE,2 MG WARD,1,2 GTC MOORE,3 MP SPARROW,1 PR GIBSON1 Conclusions: Post-first IFX dose in ASUC early higher CRP and FC levels predicted poorer week 6 outcomes. Yet unexpectedly, an early dec- 1Department of Gastroenterology, Alfred Health and 2 rement in IFX levels from day 1 through day 3 appeared to confer better Monash University, Melbourne, Australia, Department of outcomes; this might reflect appropriate IFX binding/utilisation in early Gastroenterology, Eastern Health and Monash University, responders compared to static levels in potential non-responders (e.g. 3 Melbourne, Australia, Centre for Inflammatory Diseases, where a non-TNF pathway predominates). Further prospective evaluation Southern Clinical School, Department of Medicine, of the predictive value of Day 1–3 biomarkers in ASUC is warranted given Monash University, Melbourne, Australia these findings. Background: Efficacy of infliximab (IFX) rescue therapy in acute severe ulcerative colitis (ASUC) depends on multiple factors including IFX phar- macokinetics, disease burden and timing of further doses. Hence, early, Adjunctive Allopurinol in Azathioprine/ serial assessment of both serum IFX and inflammatory biomarkers may aid mercaptopurine non-responders optimises clinical decisions and thus, patient outcomes. 6-thioguanine nucleotide production and Aim: To assess relationships between, and the predictive value of early improves clinical outcomes in inflammatory measurement of serum IFX levels and inflammatory biomarkers post IFX bowel disease: the multicentre, prospective, dose in relation to clinical outcomes in ASUC. Methods: This prospective multicentre pilot study consecutively double blind, dose-ranging AAA study 1 2 3 recruited inpatients with ASUC as per Truelove-Witts criteria refractory to AB FRIEDMAN, SJ BROWN, P BAMPTOM, 4 5 6 1 IV hydrocortisone, who then received either 1 or 2 IFX doses (5 mg/kg IV) M BARCLAY, A CHUNG, F MACRAE, J MCKENZIE, as rescue therapy. The timing and number of IFX doses were at the treating J REYNOLDS,7 PR GIBSON,1 SB HANAUER,8 clinician’s discretion. Serum IFX (QS-INFLIXI Matriks Biotek ELISA), MP SPARROW1 CRP, albumin and faecal calprotectin (FC) (Buhlmann ELISA) concentra- 1Gastroenterology Department, The Alfred Hospital and tions were measured daily during inpatient admission and at 7, 14 and 28 Monash University, Melbourne, Australia, days post-discharge. Patient demographics were recorded at baseline and 2Gastroenterology Department, St Vincent’s Hospital, clinical remission was defined as a partial Mayo score of zero. The primary Melbourne, Australia, 3Gastroenterology Department, endpoint was met if CRP <3 mg/L AND clinical remission was achieved Flinders medical Centre, Adelaide, Australia, at/prior week 6. Secondary endpoint was met if clinical remission was 4 achieved at week 12. Gastroenterology Department, Christchurch Hospital, 5 Results: In this interim analysis of 13 patients recruited thus far the Christchurch, New Zealand, Eastern Health and Monash 6 median age was 34 years (range 18–72), 7 (54%) were female and 4 (31%) University, Melbourne, Australia, Department of had extensive colitis (E1). 10 (77%) received two IFX doses and 3 one dose, Colorectal Medicine and Genetics, Royal Melbourne 5 (38%) were on immunomodulators at baseline, 3 (23%) had subsequent Hospital, Melbourne, Australia, 7Department of colectomy (111, 130 and 233 days post first dose of IFX). All 7 (100%) Epidemiology and Preventative Medicine, Monash patients in clinical remission at 3 months did not then undergo colectomy, University, Melbourne, Australia, 8Digestive Health Center, yet 3/6 (50%) not in remission did (p = 0.07). Bivariate comparisons for Feinberg School of Medicine, Northwestern University, primary and secondary endpoints are tabulated below. Also, ROC analysis Chicago, USA showed that the area under curve (AUC) of consecutive day 1 to 3 levels for serum IFX (cutoff ≤158 μg/ml), CRP (≤33 mg/L) and FC (≤4910 μg/ml) Objectives: 15% of IBD patients who do not respond to azathioprine each predicted the primary endpoint (6w) with a sensitivity & specificity of (AZA) or mercaptopurine (MP) are “shunters”. They preferentially

118 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease metabolise MP to 6-methylmercaptopurine (6MMP) instead of the effica- Aim: To study gut microbial profiles in IA, healthy controls (HC) and cious 6-thioguanine nucleotides (6TGN). Allopurinol may reverse this IBD patients. shunting. This multicentre, prospective, double-blind, dose-ranging, Methods: Tissue samples were obtained from 79 patients (17 IA, 22 CD, randomised trial aimed to determine whether a regimen of low-dose allo- 18 UC, 22 HC). 16S rRNA amplicon based analysis (Custom phylogenetic purinol with thiopurine achieves steroid-free clinical remission and microarrays and 454-pyrosequencing) were employed to detect microbial minimises toxicity in patients with IBD who are shunters and have active diversity from mucosal samples obtained at the time of colonoscopy. disease; and to compare outcomes of allopurinol 50 vs 100 mg/d. Metagenomic studies were performed on a subset of patients (HiSeq 2000). Methods: Patients with clinically-active or steroid-dependent IBD, Differences in relative abundance of microbial populations between patient thiopurine shunting (6TGN < 260 pmol/8x108 RBCs and 6MMP: groups were verified using Principle Correspondance Analysis (PCA) and 6TGN ratio ≥20) and total leucocyte count ≥3.5 x109/L were randomised Between group analysis (BGA) from ‘R package’ with ade4 and made4 to a blinded dose of 50 or 100 mg/d allopurinol and 25% of their library. screening thiopurine dose. Thiopurine doses were then optimised, aiming Results: There were significant differences in the microbial profiles for 6TGN >260. The primary endpoint was steroid-free clinical remission (Figure 1) between the 4 groups (p = 0.001). IA were noted to have a higher after 24 weeks (SFR24) using the Harvey Bradshaw Index and the Simple abundance of Prevotella sp, lactic acid producing bacteria (e.g Lactoba- Clinical Colitis Activity Index. An intention-to-treat analysis was cillus) and Betaproteobacteria but a lower abundance of Bacteroides when performed. compared to HC and IBD patients. CD and UC groups had a high abun- Results: 73 patients were enrolled: 46 had Crohn’s disease and 27 ulcer- dance of Gammaproteobacteria such as E. coli and Enterobacteriaceae ative colitis. Mean daily doses of AZA reduced from 164 mg at screening when compared to HC who had higher abundance of Bacteroidetes and to 67 mg at week 24 and MP from 88 mg to 45 mg (both p < 0.001). Bifidobacteria. In IA and HC, microbial function was associated with Significantly greater thiopurine dose reductions were seen in the 100 mg increased carbohydrate metabolism whereas in CD patients it was associ- allopurinol arm than the 50 mg arm (63–65% vs 35–53% reduction, ated with increased protein metabolism, likely reflecting the inflammatory p = 0.006 and 0.008). 39 patients [53% (95% CI 42–65)] achieved SFR24 state. IA microbiota were also enriched with enzymes that are involved in with no difference in rates of SFR24 between 50 and 100 mg arms propionate production. (p = 0.913). Mean 6TGN levels increased from 177 ± 14 to 402 ± 16 Conclusion: IA have an abundance of Prevotella sp and LAB which is (p < 0.001), 6MMP levels decreased from 9949 ± 485 to 1235 ± 547 likely due to their traditional lifestyle. This may account for the lower (p < 0.001) and 6MMP:6TGN ratio fell from 64 to 4 (p < 0.001). There incidence of IBD seen in this population. IBD patients have a higher was no significant difference in 6TGN between allopurinol arms, but mean abundance of E.coli, Enterobacteriaceae and Fusobacterium sp. There are 6MMP was significantly higher in the 50 mg arm (1987 vs 483, p = 0.023). differences in microbial function between the groups with a higher abun- Hepatitis decreased with ALT improving from 52 ± 6 U/L to 27 ± 6 U/L dance of enzymes involved in carbohydrate metabolism and proprionate (p < 0.001) across both arms. 26 of 32 patients (81%) were able to cease production in IA. steroids (p = 0.011). Total leucocyte count decreased from a mean of 7.1x109/L to 5.9 x 109/L (p < 0.001). Only two transient episodes of mild leucopenia occurred in 1 patient, resolving with a reduced thiopurine dose. Faecal calprotectin reduced in steroid-dependent CD patients from a mean of 864 to 122 μg/g (p = 0.043), and CRP reduced in UC patients from a mean of 6.1 to 3.6 mg/L (p = 0.019). 15 serious adverse events occurred; however, only two (one dental abscess and one perianal abscess) were possibly related to the drug combination. Conclusions: This prospective study has validated that low dose allopurinol-thiopurine combination safely and effectively optimises 6TGN and concurrently reduces 6MMP. Optimisation of thiopurine metabolites with allopurinol and dose-reduced thiopurines improves disease outcomes without additional toxicity. No clinically significant differences were seen between allopurinol doses

Indigenous Australians have a distinctive gut microbial profile compared to patients with inflammatory bowel disease and non Indigenous controls Figure 1. Microbial profiles (top left and bottom) between the 4 groups are different. Microbiota of IA have enzymes associated with carbohy- G IYNGKARAN,1,3 S KANG,2 C MCSWEENEY,2 drate metabolism. S SIVANESAN,1,3 M MORRISON,2 F MACRAE1 1Colorectal Medicine and Genetics, Royal Melbourne Hospital, 2Livestock Industries, CSIRO, Brisbane, QLD, Five years of faecal calprotectin: can it deliver Australia, 3Department of Medicine, Royal Darwin on convenience, cost reduction and clinical Hospital, Darwin, NT, Australia decision making in IBD? Background: Inflammatory bowel disease (IBD) is more common in S MOTAGANAHALLI, L BESWICK,D R VAN developed nations and urbanised communities. The incidence of IBD is LANGENBERG high in urban Australia but rare in Indigenous Australians (IA). The aeti- Monash University Department of Gastroenterology, ology of IBD is unknown but is thought to be due to a dysregulated Eastern Health, Box Hill, Victoria, Australia immune response to an environmental trigger in a genetically susceptible host. Urbanisation may alter the exposure to environmental microorgan- Introduction: Faecal calprotectin (FC) is a sensitive biomarker of isms and lead to dysbiosis, a potential trigger of IBD. disease activity in inflammatory bowel disease (IBD), yet the implications

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 119 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease of incorporating this test into routine clinical practice in Australia remain obtained could be more reliably extrapolated to a national level, and will uncertain. provide a basis for health care strategies for IBD in Australia. Aim/s: To evaluate the influence of FC testing on clinical decision- Aim: The aim of this study was to determine the incidence and preva- making in a specialist IBD centre and assess whether utilising FC routinely lence of IBD in the island state of Tasmania, Australia. results in a reduction in healthcare costs. Methods: A population-based incidence and prevalence study was con- Methods: Of 2041 FC tests done over 5 years to 31/12/2014, 358 were ducted between 1ST June 2013 and 31ST May 2014. Tasmania being an performed on 244 confirmed IBD patients attending Eastern Health IBD island with 513,100 people (3) provided a stable and clearly defined study clinics. Retrospective data were collected from hospital medical records population. Gastroenterologists, surgeons and paediatricians from across including CRP, colonoscopy and surgical/admission data post FC. All FC the state identified cases of IBD to a single investigator. Comprehensive tests were performed via Buhlmann Rapid test. Cut-offs were deemed searches were undertaken across all pathology and radiology services. ‘negative/normal’ if FC < 100 μg/ml, ‘positive’ if FC ≥ 100 μg/ml, Incident cases were confirmed using the Copenhagen diagnostic criteria (4) ‘definitely/ highly positive’ if FC ≥ 250 μg/ml. from patient history, investigations, endoscopy and histology and con- Results: Within this cohort, 55% were females, 75% had Crohn’s disease firmed by second gastroenterologist. Prevalent cases were included in the (CD – Montreal E1 29%/E2 47%/E3 24%), 25% had ulcerative colitis (UC study after being confirmed by treating clinicians. Age-standardised inci- – E1 3%/ E2 36%/ E3 50%), median IBD duration was 10 y (range 1, 47), dence and prevalence rates and associated 95% confidence intervals (CI) median follow-up post FC was 2 y (range 0, 5). 25% of patients were on are reported. World Health Organisation (WHO) 2000–2025 population anti-TNF and 57% on immunomodulator therapies at time of FC testing. was used as the standard (5). FC was negative in 38%, positive in 62%, highly positive in 42%. FC Results: A total of 149 newly diagnosed IBD cases (84 males) were testing resulted in treatment (de-/) escalation in 42% at next clinic visit. captured during the study period, of which 63 had UC, 74 CD and 12 Post FC, only 16% of patients proceeded to colonoscopy within 3 months. IBDU. Crude annual incidence rate per 100,000 for overall IBD, UC, CD 61% had avoided colonoscopy and only 5% had cross-sectional imaging and IBDU was 29.0, 12.3, 14.4 and 2.3 respectively. Age standardised rate post FC by end of follow-up. An independent clinician assessment deemed (ASR) for overall IBD incidence per 100,000 was 29.5 (95% CI: 24.5– that, in absence of FC, 67% of cases would have warranted colonoscopy at 34.5). When examined by type of disease, the ASR were 12.4 (9.2–15.6) time of FC testing above. Thus FC testing potentially enabled a cost for UC; 15.4 (11.7–19.1) for CD and 1.7 (0.7–2.8) for IBDU. reduction of 71% from total $322416 (colonoscopy only) to $94683 (FC A total of 1719 IBD cases (792 males) were identified as prevalent during +/- colonoscopy). the study period, of which 803 had UC, 874 CD and 42 IBDU. Crude Regarding colonoscopy post-FC, those with FC ≥ 250 were scoped earlier prevalence per 100,000 of overall IBD, UC, CD and IBDU was 335.0, than those with FC < 100 μg/ml (median 0.49 vs 1.0 years, p = 0.03). 156.5, 170.3 and 8.2 respectively. The highest prevalence rate of 514.7 per Moreover post-FC, the time to documented IBD flare/ surgery was shorter 100,000 was seen among 55 to 59 year-olds. Age-standardised (ASR) for in those with FC ≥ 250 compared to FC < 100 μg/ml (log rank test, overall IBD prevalence was 303.9 (95% CI: 288.6–319.2). When examined p < 0.01). Finally, of 69 patients with ≥2 FC tests serially performed, those by type of disease the ASR were 131.4 (121.7- 141.1) for UC; 165.5 with FC normalisation (compared to those with no change or worse FC) (154.0–177.1) for CD and 6.9 (4.7- 9.2) for IBDU. had more likely been escalated to anti-TNF and/or immunomodulator Conclusion: This is the first whole-of-state, population-based Australian therapy yet less likely on steroids (ANOVA, p < 0.05), with no other IBD incidence and prevalence study demonstrating that IBD rates in Tas- significant differences in IBD characteristics. mania are high and comparable to those previously reported in Victoria. Conclusions: Within 5 years, FC has changed practice, with significant These significant findings will inform local and national health care plan- management decisions made directly due to FC results in this centre in ning and resource allocation. almost half of tests. Furthermore, routine FC testing minimises need for, References and appears to result in substantive reductions in, colonoscopy and possi- 1) Wilson J, Hair C, Knight R, Catto-Smith A, Bell S, Kamm M, Desmond bly other imaging tests, and therefore, healthcare costs. FC was used P. High incidence of inflammatory bowel disease in Australia: A pro- successfully in this real world scenario for prediction of flare, triaging spective population-based Australian incidence study. Inflamm Bowel colonoscopy and monitoring response to therapy, translating research into Dis. 2010; 16: 1550–56. IBD practice. 2) Studd C, Desmond P, Connell W, McNeil J, Knight R, Cameron G et al. High incidence and prevalence of inflammatory bowel disease in Victoria; a prospective, observational, population-based Australian epi- Inflammatory bowel disease: a statewide demiology study. Journal of Gastroenterology and Hepatology. 2012; incidence and prevalence study in Tasmania, 27(sup 4): 118–19. Australia 3) Australian Bureau of Statistics 2013, Australian Demographic Statis- R BHATIA,1,2 C STUDD,1 J WILSON,1 K VAZ,1 S BELL,3 tics 2013, cat. no. 3101.0, ABS, Canberra. P OTAHAL,2 A VENN2 4) Burisch J, Cukovic-Cavka S, Kaimakliotis I, Shonova O, Al E. Con- 1Royal Hobart Hospital, Tasmania, Australia, 2Menzies struction and validation of web-based epidemiological database for Institute for Medical Research, Tasmania, Australia, 3St. inflammatory bowel disease in Europe. Journal of Crohn’s and Colitis. Vincent’s Hospital, Melbourne, Australia 2011; 5: 342–49. 5) WHO 2000–2025 standard, link http://seer.cancer.gov/stdpopulations/ Introduction: Inflammatory Bowel Disease (IBD) is a chronic, incurable world.who.html, date accessed April 2015. disease that affects all age groups. It adversely affects the quality of life of these individuals, causing significant impairment to growth, education, work, family and social life. IBD is generally described to be of three types: ulcerative colitis (UC), Crohn’s disease (CD) and inflammatory bowel disease unclassified (IBDU). The only population- based Australian data show a crude incidence rate of 29.3 (1) and 24.2 (2) per 100,000 in the greater Geelong area of Victoria and crude prevalence of 344.6 per 100,000 (2). To date however, there are no state-wide incidence and prevalence data available from Australia. Epidemiologically robust whole-of- state data

120 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Early and persistent disturbance of the bile acid-microbial axis in a piglet short bowel syndrome model PRUE M PEREIRA-FANTINI,1 SUSAN LAPTHORNE,1 SUSAN A JOYCE,2 FIONA FOUHY,3,4 MICHELLE SCURR,1 PAUL D COTTER,2,4 CORMAC G. GAHAN,2,3 JULIE E BINES1,4,5 1Intestinal Failure and Clinical Nutrition group, Murdoch Childrens Research Institute, Parkville, Australia, 2APC Microbiome Institute, University College Cork (UCC), Ireland, 3Department of Microbiology, UCC, Ireland, 4Teagasc Food Research Centre, Moorepark, Fermoy, County Cork, Ireland, 5Dept. Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, Australia, 6Dept. Paediatrics, University of Melbourne, Parkville, Australia Introduction: Numerous lines of evidence suggest disruption of the bile acid-microbial relationship may contribute to the pathogenesis of SBS. Recently, we have observed primary bile acid (BA) dominance (Pereira- Fantini et al., 2014) and reduced bacterial diversity (Lapthorne et al., 2013) accompanied by failure to thrive, fat malabsorption, dysregulation of farnesoid X receptor (FXR) signaling processes and liver disease in a piglet model of SBS. The study of the interaction between BAs and colonic bacteria in the context of SBS is essential as it may hold the key to understanding the aetiopathogenesis of the disease. The primary aim of the current study was to detail temporal SBR-associated changes in bile acid Results: BA results are summarised in Figure 1. SBS-associated altera- composition at key enterohepatic sites in response to small bowel resection. tions in the biliary BA profile at 2 weeks included increased levels of Given the strong interplay between bile acids and intestinal bacteria, our GHCA and THCA (primary BAs) and reduced levels of LCA, GUDCA, secondary aim was to elucidate if SBS-associated alterations in bile acid THDCA and TUDCA (secondary BAs) Similarly, in SBS animals the composition were reflective of changes in colonic bacterial composition. 6-week bile biliary profile was dominated by primary bile acids (CDCA, Methods: 4-week old piglets underwent 75% small bowel resection GHCA and THCA) at the expense of secondary bile acids (GDCA, (SBS) or sham operation (SHAM), whilst an age-matched group acted as GLCA, GUDCA, TDCA, THDCA and TUDCA). A temporally associ- non-surgery controls. Piglets were fed a polymeric infant formula diet ated change in BA levels was observed in portal samples, with an early throughout and sacrificed at either two or six weeks (N = 5–6 piglets/ increase at two weeks post-SBR in TCDCA and THCA levels and group). UPLC-MS was used to determine bile acid composition in end- decreased HDCA, GHDCA, GUDCA, TDCA and THDCA levels. Whilst point bile, portal serum and colonic content samples. High throughput at 6 weeks post-SBR, portal levels of HCA, GCDCA, THCA and sequencing of colonic content was performed to identify changes in bac- TUDCA were increased and LCA, HDCA and GUDCA decreased. The teria with bile salt hydrolysing activity or 7α-dehydroxylation ability. bile acid profile of stool samples obtained at 2 weeks post-op was similar to that of bile and portal serum samples with increased levels of CDCA and HCA concurrent with decreased levels of the secondary BAs; DCA, HDCA and GHDCA. At six weeks post-SBR however, the stool BA profile differed from that of either bile or portal serum. Whilst levels of the primary, unconjugated bile acids CA, CDCA and HCA were increased, levels of the conjugated primary bile acids GHCA, TCA, TCDCA and THCA were decreased significantly when compared against either NOC or SHAM control groups. Similar to other sampling sites, we also observed significant decreases in the level of H DCA, GDCA, GUDCA, TDCA, TLCA, THDCA and TUDCA within SBS stool samples. Amongst the microbial changes observed in the present study was the long-term reduction in abundance of bacteria from the order Clostridiales including Subdoligranulum, Anaerotruncus, uncultured Ruminococcus, Peptostreptococcus incertae sedis and Clostridium. Conclusion: The present study is the first to comprehensively map time- dependent alterations in the BA profile of the piglet SBS model throughout the enterohepatic system. We report a shift to a primary BA dominant profile following small bowel resection (SBR). This shift was detected as early as two weeks post-SBR in samples of bile and portal serum, and persisted at six-weeks post-SBR. In parallel high throughput studies, we have described an early and persistent loss in bacteria belonging to the Clostridiales order. This study has provided strong evidence of an early and persistent and disturbance of the bile acid-bacterial axis following

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 121 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease small bowel resection thereby furthering our understanding of the mecha- Table 1. CT and Endoscopy Findings nisms underlying SBS development. Suggested Diagnosis Findings on Subsequent Endoscopy on CT (n = 57)

Bowel wall thickening on computerised Malignancy = 13 Malignancy (colorectal 5, caecal 2) = 7 tomography- clinical and endoscopic Polyps = 1 significance Diverticular Disease = 2 SK CHAND,1,2 D LEWIS,1,2 D CHOMLAK, S BLOOM,1,2 Colitis = 2 J LUBEL1,2 Normal = 1 1Eastern Health Clinical School, Monash University, Diverticular Disease = 13 Diverticular Disease = 12 Melbourne, Victoria, Australia, 2Department of Malignancy (colorectal) = 1 Gastroenterology and Hepatology, Eastern Health, Colitis = 11 Crohn’s Disease = 2 Melbourne, Victoria, Australia Diverticular Disease = 3 Ischaemic Colitis = 1 Introduction: Bowel wall thickening is often noted on abdominal com- Indeterminate Colitis = 2 puterized tomography (CT); however, its clinical significance can present Normal = 3 a diagnostic and management challenge for physicians. Our aim was to Thickening without Diverticular Disease = 6 identify the correlation between bowel wall thickening on CT with findings radiological diagnosis Normal = 4 on subsequent colonoscopy. Furthermore, we aimed to examine any asso- =22 Malignancy (colorectal) = 4 ciation with hypoalbuminemia and the presence of bowel wall thickening. Colitis = 4 Methods: Patients with CT findings of bowel wall thickening were iden- Polyps = 1 tified from a radiology database at an inner city health service in Victoria, Other (volvulus, bowel obstruction) = 2 from January 2012 to January 2013. Patient files were then cross- Collapse = 2 Normal = 2 referenced for subsequent colonoscopy findings and likely final diagnoses. Age, gender and serum albumin levels at the time of CT were also Nb. some pts had more than 1 suggested diagnosis on CT recorded. Results: Of the 230 patients who were noted to have bowel wall thick- Table 2. Correlation with albumin and endoscopic diagnosis ening on CT, 58 patients had a colonoscopy; 1 patient was excluded from analysis as their colonoscopy was incomplete and further investigation was Endoscopic diagnosis Low albumin Very low albumin declined.. Patients who had a colonoscopy had an average age of 65.3 years (21–34 g/L) (<20 g/L) (range 20–93 years), 44.8% were female, and average serum albumin level was 32.8 g/L (range 16–43). Diverticular disease 1/16 1/16 CT findings suggesting malignancy were moderately accurate at predicting Malignancy 6/11 1/11 malignancy, with 61.5% (n = 8) confirming malignancy at endoscopy Colitis 3/10 3/10 (p = 0.001). Cancer was identified in 11.4% (n = 5) of those without Normal 4/6 0/6 mention of malignancy on CT (Table 1). There was a trend towards older Other 3/7 0/7 age in those diagnosed with cancer on endoscopy (mean 73.4 years com- pared to 62.6 years p = 0.12). Bowel wall thickening on CT attributable to diverticular disease accurately predicted its presence on endoscopy. Of those with diverticular disease on CT, 92.3% had diverticular disease on endoscopy; and of those whose CT did not mention diverticular disease To scope or not to scope: examining endoscopic 77.3% did not have diverticular disease as a cause of bowel wall thickening disease recurrence and outcomes in patients (p < 0.001). with Crohn’s disease post ileal surgery In those who had a colonoscopy who had albumin levels available (n = 51) RKY CHENG,1,2 J IRWIN,2 G RADFORD-SMITH1,2 there was no association between diagnosis and albumin level (p = 0.4) 1Department of Gastroenterology and Hepatology, Royal (Table 2). Brisbane and Women’s Hospital, Brisbane, Australia, Conclusion: Bowel wall thickening identified on CT is often not further 2Inflammatory Bowel Diseases Research Group, QIMR investigated depending on the clinical context; of those where clinicians Berghofer Medical Research Institute, Brisbane, Australia have decided to investigate further with endoscopy, there is often signifi- cant pathology. The commonest cause is diverticular disease, with malig- Introduction and aims: Approximately 70% of patients with Crohn’s nancy observed in a moderate number of patients. Hypoalbuminaemia Disease (CD) undergo an intestinal resection during their lifetime. Post- did not appear to have any correlation with the aetiology of bowel wall operative drug-therapy tailored to clinical risk together with early colonos- thickening. copy to determine need for step-up medication has been proposed as optimal management. The aims of this study are to evaluate post-operative management in an inception cohort of CD patients and explore the rela- tionships between endoscopic findings and disease outcomes following ileal resection. Method: CD patients undergoing bowel resection involving the ileum, with at least 365 days of follow-up between August 1995 and June 2012 were reviewed from a single tertiary center. The frequency and findings at colonoscopy within the first 12 months post-operatively were identified together with changes in management and outcomes. Results: 202 cases of ileal resection surgery occurred in 146 CD patients. (58% male, median age at diagnosis 25.5 years, mean period of observa-

122 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease tion post resection 8.2 years). 102 patients had a single resection, 44 ‘partial’ or ‘absent’ coverage of consensus statements derived from the patients had >1 ileal resection. Disease characteristics at diagnosis were as European Crohn’s and Colitis Organisation (ECCO), American College of follows: 58.2% ileal (85/146), 6.2% colonic (9/146), 34.9% ileocolonic Gastroenterology (ACG), and The Gastroenterology Society of Australia (51/146); 26% stricturing (38/146), 17.8% penetrating behavior (26/146); (GESA); comprehensiveness of data that could be entered; and, average 50.7% (72/142) were current or ex-smokers. Family history for IBD was pricing. present in 29.1% of patients (44/144). Results: Of the total 238 apps screened, a final 26 apps were assessed 43.1% of cases (87/202) had a colonoscopy within 1 year of resection (Figure 1), including 10 available on Android platforms, 8 on iOS plat- surgery [median time 7.5 months, range 1.9–11.9 months], 44.5% of cases forms and 8 on both. Fourteen of 26 (53.8%) apps had diary functionalities; (90/202) had colonoscopy after 1 year of resection surgery [median time ten of 26 (38.5%) provided health information about IBD. None of the apps 2.2 years, range 1.1–10.3 years] and 12.4% (25/202) of cases did not have offered decision support to facilitate the self-initiation of medical therapy. a post-operative colonoscopy [median observation period 7.5 years]. Five of 26 (19.2%) had professional medical involvement in their design. Patients not on an immunosuppressant in the 3 months immediately after Apps demonstrated ‘complete’ coverage of only 37.5% of the international surgery were more likely to undergo an early colonoscopy (p = 0.022). No consensus statements explored. The average price of the apps was other factors were associated with early colonoscopy; however, perforation AUD$1.37. at initial surgery (p = 0.060) approached statistical significance. When colonoscopy was performed, anastomotic macroscopic recurrence (Rutgeert’s Score ≥2) was found in 55.9% of cases (99/177), with histo- logical confirmation of disease in 84.5% of biopsies (74/81). In the 39.2% of cases without macroscopic recurrence (31/79), histological disease was still present in 58.6% of biopsies (27/46). Immediately after ileal resection surgery, 122/177 cases (68.9%) were not on immunosuppressant medication. The first post-operative colonos- copy resulted in 42 cases of immunosuppression commencement (23.6%). 19/42 patients were commenced on azathioprine, 20 patients on 6-mercaptopurine, 3 patients on methotrexate. 9 of these 42 patients with immunosuppression commencement still proceeded to a further ileal resection. Univariate analysis comparing early endoscopy within 12 months and after 12 months post-operatively did not demonstrate statistical difference in need for further surgery (p = 0.34), or immunosuppression commencement and cessation (p = 0.18). Post resection patients who had no colonoscopy during post-operative follow-up had higher rates of recurrent surgery (9/25, Figure 1. Flow diagram of search and selection process of apps. 36%) compared with those who had a colonoscopy (33/177, 19%), but this must be interpreted in context of low patient numbers in the subgroup. Conclusion: Apps may provide a useful adjunct to the management of Conclusion: Early post-operative colonoscopy was undertaken in less IBD patients. However, a majority of current apps suffer from a lack of than 50% of CD patients following ileal resection. The majority of these professional medical involvement and limited coverage of international patients had endoscopic and/or histologic recurrence of disease. Endos- consensus guidelines. Future studies and app design for IBD should copy resulted in medication commencement in 25% of post-operative include professional medical involvement, evidence based guidelines and patients but nevertheless a fifth of these had subsequent surgery. functionalities with decision support that are specifically tailored to patient self-managemen.

Smartphone apps for inflammatory bowel Comparison of dietary nutrient and food disease self-management: a systematic additive intake between patients with assessment of content and tools moderately active ulcerative colitis and healthy D CON,1,2 P DE CRUZ1,2 stool donors 1,2,3 1 1,3 1University of Melbourne, Department of Medicine, Austin S COSTELLO, C MASHEI, J ANDREWS 1 Academic Centre, Melbourne, Australia, 2Department of IBD Service, Department of Gastroenterology and Gastroenterology, Austin Hospital, Melbourne, Australia Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, 2Department of Gastroenterology, The Queen Background & Aim: The rising incidence of inflammatory bowel disease Elizabeth Hospital, Woodville, South Australia, 3School of (IBD) over the past decade has resulted in increased health care utilisation Medicine, Faculty of Health Sciences, University of and longer IBD outpatient waiting lists. ‘Self-management’ is recognised Adelaide. South Australia as an important aspect of chronic disease management but its application to IBD has been limited. The age of IBD onset in a majority of patients is in Background: The prevalence of UC is increasing worldwide with the their twenties to thirties. Smartphone apps are a technology familiar to highest rates noted in more developed countries. The aetiology of UC young adults and represent an opportunity to explore self-management as remains unclear but, given the increasing prevalence, it is likely caused by a new model of health-care delivery for IBD. We aimed to assess the environmental triggers in genetically predisposed individuals. There have suitability of the content and tools of existing IBD apps to facilitate patient been significant changes in the dietary intake of people in developed self-management. countries in recent decades and this, coupled with the intimate interaction Methods: Systematic assessment of apps targeted at IBD patients via food has with the gastrointestinal mucosa, has lead to the hypothesis that searches of Google (Android devices) and Apple (iOS devices) app stores dietary components play a role in disease pathogenesis. with pre-defined inclusion and exclusion criteria. Apps were assessed for: Aims: To characterise the nutrient and food additive intake of patients specific functionalities; presence of professional medical involvement; with moderately active ulcerative colitis (UC) and determine whether these consistency with international IBD guidelines based on ‘complete’, differ between patients and healthy stool donors.

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 123 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Methods: Participants with mild to moderately active UC (Mayo score IUFD at term, (on no therapy pre or during pregnancy) and one miscarriage 3–10, endoscopic subscore >1) were recruited for a randomised control trial (on combination 5-ASA and 6-MP therapy). of faecal microbiota transplant as a treatment for active UC. Faecal donors A total of 11 patients (45.8%) required steroids for a disease flare. 72.7% were healthy volunteers with no active medical problems as assessed by (8/11) of these had UC, whilst 27.3% (3/11) had CD. Of the three with CD, medical history, blood and stool screening. Patients with UC and faecal two had dosed reduced at the commencement of their pregnancy (AZA to donors each completed a 3-day diet diary, which was analysed using no therapy in one, AZA and adalimumab to adalimumab monotherapy in FoodWorks 7 software (Xyris, Australia) to yield macro and micronutrient the second). None of those with UC who required steroid therapy dose intake as well as dietary emulsifier and sulphate content for both groups. reduced at the commencement of their pregnancy. Results: A total of 37 diet diaries (24 patients and 13 donors) were Conclusions: 92% of the pregnancies reviewed resulted in healthy live analysed. The patients were significantly older than the donors with a mean infants with over 95% delivering at term, 82% of whom were on therapy. age of 40.0 years (34.4–45.7 years) vs 26.8 years (22.5–31.0 years) p < 0.01. All of those on biological therapy (12.5%) had healthy babies delivered at The UC group were 63% male (15M, 9F) and the donor group 42% male term. These results are reassuring for young women considering a preg- (5M, 7F). The intake of sugar was significantly higher in patients (mean nancy whilst on therapy for IBD. That steroids were mainly required for 108.0 g, 127.8–88.2 g) compared to donors (76.2 g, 88.9–63.5) P = 0.01. those with UC during pregnancy is consistent with known data suggesting The mean intake of saturated fat was also significantly higher in patients women with UC generally have more disease activity during pregnancy (30.0 g, 35.8–24.2 g) compared to donors (22.4 g, 27.2–17.5 g) p = 0.04. than women with CD3. Patients also had a numerically higher mean intake of total fats (77.5 g, References 90.8–64.2 g) compared to donors (60.7 g, 75.3–46.2 g) however this was not 1. tga.org.au website – accessed 11th May 2015 statistically significant (P = 0.11). The mean total energy intake in the UC 2. abs.gov.au website census data accessed 11th May 2015 patient group (8733 kj, 9708–7759 kj) was higher than in the donor group 3. Pedersen N, Bortoli A, et al. The course of inflammatory bowel disease (7295 kj, 5916–8676 kj) however again, this difference was not statistically during pregnancy and post-partum; a prospective European ECCO- significant (P = 0.11). There were no significant differences between the EpiCom Study of 209 pregnant women. Aliment Pharmacol Ther 2013; groups for mean fibre (P = 0.94), starch (P = 0.93), total carbohydrate 38: (5) 501–512. (P = 0.20), emulsifier (P = 0.09) or sulphate intake (P = 0.98). Conclusions: Patients with active UC had significantly higher intake of sugar and saturated fat than healthy faecal donors. These finding require corroboration with age and sex matched controls. Longitudinal studies Rising incidence of inflammatory bowel disease may determine whether the observed differences in these high energy in Canterbury, New Zealand nutrients are only seen during periods of active disease. The higher intake HSV GUPTA, AS DAY, RB GEARRY of sugar and saturated fat may contribute to the known higher cardiovas- Departments of Medicine and Paediatrics, University of cular morbidity in IBD patients and warrants further study. Otago (Christchurch), Christchurch; Departments of Gastroenterology and Paediatrics, Christchurch Hospital, Christchurch, New Zealand Pregnancy outcomes in patients with Aim: A population-based study of inflammatory bowel disease (IBD) in inflammatory bowel disease in a regional clinic the Canterbury province of New Zealand demonstrated an incidence of S ALLSOPP,1,2 AJ DAVESON1 Crohn disease (CD) in this region of 16.5 per 100,000 population in 2004, 1Mackay Inflammatory Bowel Disease Clinic, 2Mackay along with a high rate of IBD overall. At the time, this was one of the Hospital and Health Service highest rates of CD in the world. The current study aimed to ascertain the incidence of IBD in the same geographical area of New Zealand ten years Introduction: Many pharmacological therapies used to treat inflamma- later (during the 2014 calendar year). tory bowel disease (IBD) remain classified as potentially unsafe according Methods: Patients diagnosed with IBD between January 1st, 2014 and to the Therapeutic Goods Administration (TGA) pregnancy classification December 31st 2014 within the Canterbury region in the private and public scheme1. Despite this many young pregnant women with IBD require such sectors were identified and characterised. Diagnosis and disease classifi- therapy. cation was ascertained using standard accepted criteria. Projected popula- Aims: To assess the outcomes of pregnant women with IBD in a regional tion data for age and gender for the region were utilised to calculate IBD clinic. incidence rates for IBD overall and for CD, ulcerative colitis (UC) and Methods: Our unit is the only IBD service in a regional area with a inflammatory bowel disease-unclassified (IBDU). Incidence rates were population of 167,666, (47% of whom are female). 49% are aged between also age-standardized using the World Health Organization Standard Popu- 15–542. We conducted a retrospective analysis of all the pregnancies that lation. Furthermore, all patients were phenotyped according to the Mon- had occurred in patients attending our clinic between January 2010 and treal Classification. March 2015. Results: During the 2014 year, 205 patients were diagnosed with IBD in Results: A total of 24 pregnancies occurred in 15 women. The mean age Canterbury. This group comprised 134 patients with CD, 69 with UC and was 28.1, median age 30, with a mean of 1.6 pregnancies per female. 2 with IBDU. Patients were aged between 5 and 88 years, with most 45.8% had Crohn’s Disease (CD), whilst the remaining 54.2% had Ulcer- patients with CD and UC diagnosed between 20 and 54 years of age. The ative Colitis, (UC). Of the 24 pregnancies, treatment consisted of crude incidence rate for IBD for 2014 was 39.8 per 100,000 (95% CI, 34.4 infliximab monotherapy (8.3%), adalimumab monotherapy (4.2%), aza- – 45.3). In addition, the incidence rates for CD was 26.0 (95% CI, 21.6 – thioprine (AZA) monotherapy (8.3%), 5-aminosalicylic acid (5-ASA) 30.4), for UC 13.4 (95% CI, 10.2 – 16.6), and for IBDU 0.39 (95% CI, monotherapy (25%), 5-ASA and AZA combination therapy (8.3%), 5-ASA −0.15 – 0.93) per 100,000 population. For patients with CD, disease and 6-mercaptopurine (6-MP) combination therapy (25%) and no therapy location was evenly distributed (ileal 30%, colonic 36% and ileocolonic (21%). Biological therapy was used in a total of 12.5%, AZA in 16.6% and 34%) and 94% had inflammatory disease, with only 6% having stricturing 6-MP in 25% (a combined total of 54%). or penetrating disease at diagnosis. Twenty-two percent of patients with 92% of the pregnancies resulted in live healthy births, of which 82% were CD had upper gut involvement, whilst 13% had perianal disease at diag- on therapy. 95.5% of the live births went to term, (the single that didn’t was nosis. Similarly, patients with UC had even distribution of pancolonic, on 5-ASA monotherapy with confinement at 37 weeks). There was one left-sided and proctitis.

124 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Conclusions: This population-based study demonstrates further substan- Conclusions: Disease distribution and treatment exposure is similar to tial increases in the incidence of IBD in this well-delineated area of New previous reports. Despite the introduction of biological agents in the last 10 Zealand. Overall, incidence rates were 1.5 fold greater than when assessed years, surgical rates have not changed. This could be due to the more severe ten years earlier, with an even greater increase in the incidence of UC. The phenotype of paediatric CD and suggests a need for changes to the current reasons contributing to these continued increases remain unclear. However, approach of treatment. further increases in rates of IBD indicate growing health system demands in the coming years. Adverse events to thiopurines can be overcome and the majority of patients respond to therapy Surgery and medication exposure in paediatric – clinical outcomes from the EATME study Crohn’s disease AB FRIEDMAN,1 JDL BROOKES,1 MG WARD,1 1 2,3 2 2 W FAM, CH LEE, EV O’LOUGHLIN, S DUTT, B HEADON,1 LNW NIHILL,1 J REYNOLDS,2 2 2 2 2 M STORMON, A MAGOFFIN, A SHUN, M SPARGO, MP SPARROW,1 PR GIBSON1 2,3 1,4,5 K GASKIN, RW LEONG, 1Gastroenterology Department, The Alfred Hospital and 1 Faculty of Medicine, University of New South Wales, Monash University, Melbourne, Australia, 2Department of 2 Department of Gastroenterology, The Children’s Hospital Epidemiology and Preventative Medicine, Monash 3 at Westmead, James Fairfax Institute of Paediatric University, Melbourne, Australia Nutrition, University of Sydney, 4Department of Gastroenterology, Bankstown-Lidcombe Hospital, South Background: Thiopurines [azathioprine (AZA) and mercaptopurine Western Sydney Clinical School, 5Department of (MP)] are the mainstay of IBD treatment. There is poor correlation between standard weight-based dosing and the levels of thiopurine Gastroenterology, Concord Repatriation General Hospital metabolites: the efficacious 6-thioguianine nucleotides (6TGN) and the Background/Aims: To describe two decades of experience in the toxic 6-methylmercaptopurine (6MMP). 15% of patients are “thiopurine medical and surgical management of Crohn’s disease (CD) in a single shunters” with 6MMP:6TGN ratio ≥20. Patients start on a low dose and Australian tertiary paediatric centre. gradually escalate to full dose to avoid non-specific adverse events (AEs). Methods: All patients diagnosed with CD between 1991–2009 were AE rates leading to drug cessation are up to 40% and response rates are as identified from a departmental database. Medical records were reviewed low as 40%. retrospectively for patient demographics, disease phenotype, medications, Aims: to prospectively determine whether (a) AEs and inefficacy can be surgical procedures and post-surgical complications. Patients were divided overcome by switching thiopurines and/or adding low-dose allopurinol; into 3 eras by year of diagnosis (Era A 1991–1999, Era B 2000–2004 and and (b) these strategies alter real-world outcomes of patients on Era C 2005–2009). All data was analysed with SPSS 22.0 unless stated thiopurines. otherwise. Continuous variables are presented as median and interquartile Methods: In this single centre, prospective, open-label study of consecu- ranges (IQR), categorical as percentages and compared using Chi-square tive IBD patients commencing thiopurines, patients were commenced on or Fisher’s exact. Kaplan-Meier method was used to calculate cumulative 50 mg AZA or 25 mg MP daily. Doses increased fortnightly by 50 mg for risk and compared using log-rank test. Univariate/multivariate analysis AZA or 25 mg for MP until target dose was achieved, aiming for performed using cox regression. 2–2.5 mg/kg for AZA and 1–1.5 mg/kg for MP, with fortnightly monitor- Results: 250 patients were included, median follow-up time was 4.9 ing of haematology, CRP and liver function. Thiopurine metabolites were years (IQR 3.88). Median age at diagnosis was 12.1 years (<10 years old, considered in clinical decision-making once steady-state was achieved. If 33%; >10, 67%), male:female 1.2:1. Ileocolonic involvement was most a patient developed an AE requiring drug cessation, one or more of the prevalent (52%), followed by colon (40%) and isolated terminal ileum (TI) following interventions were used: switching to the other thiopurine, addi- (3.6%). Additionally, 27% had concomitant upper GI involvement, 17% tion of allopurinol with dose-reduced thiopurine, or use of thioguanine. small bowel and 34% perianal disease. Demographic variables and disease Clinical and biochemical outcomes were recorded. Mixed model analyses location remained similar throughout the three eras. Over the entire course were performed to estimate means and standard errors. McNemar’s test of their follow-up period, 51%, 63% and 27% were exposed to at least 6 was used to assess achievement of clinical remission. months of corticosteroid, 5 aminosalicylic acid (5ASA) and exclusive Results: Of 64 patients enrolled, 52 patients (81%) had Crohn’s disease enteral nutrition (EEN) respectively. Probabilities of receiving treatment at (CD), 11 (17%) ulcerative colitis (UC) and 1 (2%) IBD-U. 42 were 1, 3 and 5 years are 39, 53, 62% with immunomodulator (IM) and 16, 34, commenced on AZA and 22 MP (decision at physician discretion). 44% with biological agent. There were no significant differences in corti- 39 (61%) achieved full dose of their first thiopurine, 18 (28%) developed costeroids, EEN and IM exposure among the three eras. Era C received less an AE requiring initial thiopurine cessation and 7 (11%) were initially exposure to 5ASA (A80%, B66%, C52%; p = 0.001). Era C was more non-compliant. AZA tended to have a better AE profile than MP, with likely to be exposed to biological agent compared to Era A (p < 0.001) and 21% vs 41% requiring drug cessation (p = 0.10). Of the 18 patients with EraB(p= 0.039). Abdominal surgery was performed in 64/250. Cumula- AEs, 6 (9%) tolerated allopurinol/thiopurine combination, 3 (5%) toler- tive risk for first surgery resulting in a loss of length at 1, 3, 5 and 8 years ated the other thiopurine and 1 (2%) tolerated thioguanine. Another 8 were 5.7, 14.8, 27.2, 35.4%. In a multivariate analysis, ileal involvement (13%) patients required allopurinol because of thiopurine shunting. (isolated TI: HR 4.18, p = 0.029; ileocolonic: HR 2.34, p = 0.005) and Overall, this allowed an additional 27% of patients to tolerate female gender (HR 1.69, p = 0.05) were risk factors for surgery. Factors thiopurines. 8 (13%) could not tolerate thiopurines despite these that were not predictive of abdominal surgery included perianal involve- optimisation measures and 4 (6%) were lost to follow up. 23% of MP ment and age at diagnosis. Cumulative risk of perianal surgery at 1, 3, 5 and 14% of AZA patients were shunters (p = 0.395). Patients tolerating and 8 years were 9.4, 14.9, 16.2 and 20.4%. Repeat abdominal surgery was thiopurines had significant improvements in disease activity with 71% of performed in 18/64. Among those who have undergone prior surgery, CD patients achieving remission via Harvey-Bradshaw Index, (p = 0.001) cumulative risks at 1, 3 and 5 years were 24.5, 31.0, 35.6%. Unlike the first and 75% with UC via the Simple Clinical Colitis Activity Index surgery, disease location was not predictive for the risk of a repeat surgery. (p = 0.06). Early post-surgical complications after first abdominal surgery occur in Conclusions: Proactive monitoring and thiopurine optimisation during 9.4% of CD. initiation of thiopurine therapy allows the majority of patients to tolerate

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 125 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease and respond to thiopurines. This suggests that significantly more patients A specified oral vitamin d supplementation can benefit from thiopurines than previously published in recent literature. regimen is effective for increasing serum 25(oh) vitamin d and is associated with a reduction in Final thiopurine metabolite levels and shunter disease activity scores status can be predicted after six weeks of M GARG,1,2 A BARR,1 O ROSELLA,3 G ROSELLA,3 thiopurine therapy – biochemical outcomes from PR GIBSON,3 JJ LUBEL1,2 the EATME study 1Eastern Health Clinical School, Monash University, AB FRIEDMAN,1 JDL BROOKES,1 MG WARD,1 Victoria, Australia, 2Department of Gastroenterology, B HEADON,1 LNW NIHILL,1 J REYNOLDS,2 Eastern Health, Victoria, Australia, 3Department of MP SPARROW,1 PR GIBSON1 Gastroenterology, The Alfred Hospital, Victoria, Australia 1Gastroenterology Department, The Alfred Hospital and Monash University, Melbourne, Australia, 2Department of Background: There is emerging evidence that vitamin D may mediate Epidemiology and Preventative Medicine, Monash immunomodulatory effects in patients with IBD. We have previously University, Melbourne, Australia shown that serum 25(OH) vitamin D (25(OH)D) inversely correlated with intestinal inflammation as measured by faecal calprotectin in patients with Background: Dosing of thiopurines [azathioprine (AZA) and mercapto- IBD, with a possible threshold effect at 100 nmol/L. This project aimed to purine (MP)] in the management of IBD has been based upon patient assess a specific supplementation regimen of vitamin D to increase serum weight. However, it appears unreliable in predicting final levels of 25(OH)D to 100–125 nmol/L, and to evaluate change in disease activity. thiopurine metabolites. This leads to suboptimal clinical outcomes because Methods: Ten patients with isolated colitis, 5 each with Crohn’s disease of under- and over-dosing, and ‘shunting’ in 15% where toxic (CD) and ulcerative colitis (UC), with mild-moderately active disease as 6-methylmercaptopurine (6MMP) is preferentially produced over the effi- evidenced by faecal calprotectin > 100 μg/g and serum 25(OH)D level cacious 6-thioguanine nucleotides (6TGN), with 6MMP:6TGN ratio ≥20. of <75 nmol/L, were prescribed vitamin D supplementation over Aims: 1. To determine prospectively the clinical value and optimal 12 weeks (Table 1). They were evaluated for change in clinical activity timing of the measurement of thiopurine metabolites during dose- (Harvey-Bradshaw index [HBI] in patients with CD, Simple Clinical escalating regimen of thiopurine initiation in a consecutive cohort of IBD Colitis Activity Index [SCCAI] in patients with UC), and in intestinal patients being initiated on a thiopurine. 2. To determine if the (faecal calprotectin) or systemic markers of inflammation, as well as 6MMP:6TGN ratio changes during thiopurine dose escalation. adverse effects including serum calcium and urinary calcium excretion. Methods: In this single centre, prospective, open label study, patients Vitamin D supplementation was stopped at week 12, with further were commenced on either a daily dose of 50 mg AZA or 25 mg MP follow-up at week 16. (physician discretion). Doses increased fortnightly by 50 mg for AZA or Results: 5 patients each with colonic CD (mean age 51 [range 38–67] y, 25 mg for MP until target was achieved, aiming for 2–2.5 mg/kg for AZA 1 female), and UC (42 [24–54] y, 2 females) undertook the study. No and 1–1.5 mg/kg for MP. Haematology, CRP and liver function tests were significant differences in duration of disease (median 11 [range 2–15] vs 13 performed fortnightly to monitor toxicity. Thiopurine metabolites were [1–22] y, p = 0.647), ethnicity, Fitzpatrick skin type, sun exposure, or body measured fortnightly until steady-state was achieved, but these results were mass index (mean 29.8 [range 21.5–38.5] vs 29.9 [23.2–35.3] kg/m2) for not used for dosing decisions. Clinical and biochemical outcomes were patients with CD and UC, respectively, were noted. All patients completed recorded. Landmark analyses of shunter status used logistic regression the 12-week study protocol, except for one patient withdrawn at week 4 models and thiopurine metabolite levels were analysed using linear regres- due to a viral illness and increase in 24-hour urinary calcium excretion. 5 sion models. of the 9 patients who completed the study protocol–3of4with CD and Results: 64 patients (52 Crohn’s, 11 ulcerative colitis and 1 IBD-U) were 2 of 5 with UC – attained a 25(OH)D level of 100–125 nmol/L at week 12, enrolled. Final metabolite outcomes were: 11 (17%) patients were shunt- with the remainder achieving levels of 89–95 nmol/L. The mean rise in ers, 27 (42%) were underdosed (6TGN level of <260 pmol/8X108 RBCs), serum 25(OH)D from weeks 0 to 12 was 51 nmol/L (95% CI 5 (8%) patients’ levels were supratherapeutic (6TGN >450) and only 21 39–63 nmol/L, p < 0.001) across all participants, similar in patients with (33%) were therapeutic. 6MMP:6TGN ratios escalated over time in shunt- CD and UC. The mean total dose of vitamin D taken amongst the 9 patients ers, but not in others. After 2 weeks of therapy, a 6MMP:6TGN ratio above who completed the 12-week study period was 492 000 (range 280 000 – 9(p= 0.058) was suggestive of shunting, while after 6 weeks, a ratio ≥12 840 000) IU. (95% CI 7–28, p = 0.01) was predictive of shunting. 6TGN levels at week HBI in patients with CD declined from weeks 0 to 12 over the course of the 2 (median 106, range 0–328) predicted final 6TGN outcomes (median 282, study (median 2 [range 1–6] to 1 [0–1]; p = 0.019), and SCCAI declined range 50–746, r = 0.681, p < .001) and 6MMP levels at week 2 (median amongst patients with UC from weeks 0 to 12 (median 3 [1–5] to 0 [0–1]; 236, range 0–2163) predicted final 6MMP outcomes (median 1301, range p = 0.051). No changes in faecal calprotectin from week 0 to week 12 62–14600, r = 0.835, p < .001). 23% of MP and 14% of AZA patients were across all patients (median change +25 [range −1000 to +1100] μg/g; shunters (p = 0.395). At no time point did levels predict an adverse event to p = 0.975) or subgroups with CD or UC, or C-reactive protein, white cell thiopurines. No correlation was detected between the weight-based dose of and platelet count, and albumin were observed. No patient developed thiopurines and final ratios (r =−0.277), 6TGN (r = 0.044) and 6MMP hypercalcaemia or hyperphosphataemia during treatment. Mean 24-hour (r =−0.193) levels (all p values >0.10). An algorithm was developed using urinary Ca excretion also remained stable throughout the supplementation week 2 thiopurine metabolite levels to accurately determine the appropri- period for the whole cohort, but new hypercalciuria was noted in one ate final thiopurine dose. patient. There were no serious adverse events attributable to the therapy Conclusions: Weight-based dosing achieves therapeutic metabolites in and no patient required surgery or hospitalisation for deterioration of IBD. only one in three patients. 6MMP:6TGN ratios increase during dose esca- Conclusions: The oral high-dose vitamin D regimen successfully and lation in shunters only. Thiopurine metabolites after only two weeks of safely achieves target or near-target levels. Short-term effect of this therapy on either 50 mg AZA or 25 mg MP can be used in an algorithm to regimen on disease activity showed improved symptom-based activity determine the target thiopurine dose required. Patients with a 6MMP:6TGN scores, but had no impact on objective measures of intestinal or systemic ratio 12 or above after 6 weeks should be considered for optimisation with inflammation. Whether this represents a placebo response or was of insuf- allopurinol rather than waiting until 12 weeks of therapy. Weight-based ficient duration to significantly change inflammatory indices now requires dosing of thiopurines should no longer be used in standard practice. an adequately powered randomised placebo-controlled trial.

126 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Table 1. Daily vitamin D supplementation dose for subsequent 4 immunohistochemical VDR staining intensity across the three groups. weeks according to measured 25(OH)D level Analogous to PCR expression, VDR staining intensity in non-inflamed colonic segments was significantly higher than in inflamed colonic seg- Week Serum 25(OH)D (nmol/L) ments (p = 0.009) and non-IBD controls (p = 0.039). There was no signifi- <50 50 – <75 75 – <90 90 – <100 100 – <125 ≥125 cant correlation between serum 25(OH) D and either VDR gene expression 0 10,000 5000 N/A or staining intensity. Conclusions: VDR gene expression and protein localisation is similar in 4 10,000 5000 1000 Cease patients with CD, UC and non-IBD controls, but levels are higher in 8 10,000 5000 1000 Cease quiescent compared with active disease in patients with IBD. It is possible that VDR is upregulated as a compensatory mechanism, and an inability to upregulate may predispose to intestinal inflammation. Serum 25(OH)D Comprehensive characterisation of the vitamin d status is unrelated to intestinal VDR expression and staining intensity, so receptor in the terminal ileum and colon in novel VDR agonists may be required if activation of intestinal VDR is patients with and without inflammatory required for an immunomodulatory effect. bowel disease M GARG,1,2 C SHALLUE,1 SG ROYCE,3 P SLUKA,1 Medications blocking the renin-angiotensin H WARDAN,1 A MCFARLANE,2 PR GIBSON,4 system may influence disease outcomes in J S LUBEL1,2 patients with inflammatory bowel disease 1Eastern Health Clinical School, Monash University, M GARG,1,2 A JACKSON,2 K BRITTO,3 L BESWICK,2,3 Victoria, Australia, 2Department of Gastroenterology, M LUKIES,1 PR GIBSON,3 JS LUBEL1,2 Eastern Health, Victoria, Australia, 3Department of 1Eastern Health Clinical School, Monash University, Pharmacology, Monash University, Victoria, Australia, Victoria, Australia, 2Department of Gastroenterology, 4Department of Gastroenterology, The Alfred Hospital, Eastern Health, Victoria, Australia, 3Department of Victoria, Australia Gastroenterology, The Alfred Hospital, Victoria, Australia Background: There is emerging evidence that vitamin D may mediate Background: The renin-angiotensin system (RAS) is well-recognised in immunomodulatory effects in patients with IBD, possibly via the intestinal cardiovascular and renal homeostasis, but may regulate inflammation, vitamin D receptor (VDR). We have previously shown that serum total, fibrosis and angiogenesis in multiple other organs, including the gastroin- free and bioavailable 25(OH) vitamin D (25(OH)D) inversely correlated testinal tract. This study aimed to evaluate the association of the use of with intestinal inflammation as measured by faecal calprotectin in patients angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin with IBD. This project aimed to characterise the VDR gene and protein in receptor blockers (ARBs) with disease activity, requirement for patients with IBD in comparison with non-IBD controls. immunomodulatory and biologic therapy, and surgery and hospitalisations Methods: Terminal ileum, ascending and sigmoid colon from patients in patients with IBD by both population and case-control studies. undergoing intestinal resection and colonoscopy were surveyed for VDR Methods: Consecutive patients attending the IBD Clinics at two Mel- by mRNA expression by qRT-PCR, and immunohistochemical localisation bourne metropolitan hospitals were invited to list all medications currently and semi-quantification of particle density using microscope image pro- being taken together with duration of use. Demographic data and disease cessing software. Associations with markers of disease activity and serum characteristics were collected, with disease activity indices analysed for the 25(OH)D status were noted. previous 2-year period. Disease activity was graded along a scale as Results: 20 patients with CD (mean age 42 [range 22–69] y, 8 females), follows: 0 – quiescent disease,1–upto2flares per year with quiescent 15 with UC (40 [23–68] y, 5 F) and 14 non-IBD controls (50 [23–70] y, 7 disease in between, 2 – more than 2 flares per year or persistent disease F) underwent colonoscopy with biopsies. A trend towards older age of activity for less than 50% of the time, 3 – persistently active disease for non-IBD controls (p = 0.092), but no other demographic differences over 50% of the time, 4 – persistently active disease for over 50% of the including sex, ethnicity and Fitzpatrick skin type were noted. Body mass time with flares. Requirement for immunomodulators (IM) and/or biologic index and waist circumference were similar across the groups. Vitamin D therapy, surgery, and hospitalisations not requiring surgery were indepen- supplementation was more commonly noted in patients with IBD (71% vs dently assessed. Patients taking ACEi and/or ARBs (RAS blockers) were 21% non-IBD, p = 0.003, Chi-square), but serum 25(OH)D levels were compared with patients not taking these medications. Two case-control similar (mean 67, 65 and 65 nmol/L for patients with CD, UC and non-IBD studies evaluating clinical endpoints of surgery and hospitalisations due to respectively, p = 0.936). Full thickness tissue segments were obtained from IBD were performed, with cases matched with controls in a 1:2 fashion, 5 patients each with CD (46 [37–64] y, 4 F), UC (45 [23–62] y, 1 F) and and medication use evaluated. non-IBD controls (64 [44–83] y, 3 F), with no significant differences apart Results: Population study: 296 patients were analysed – 207 with from a trend towards higher age in non-IBD controls (p = 0.102). No Crohn’s disease (CD) and 89 with ulcerative colitis (UC). 26 of these significant differences in VDR gene expression across patients with CD, patients (8.8 %, 18 with CD and 8 with UC) were treated with ACEi (8 UC and non-IBD were noted in the terminal ileum, ascending or sigmoid perindopril, 1 ramipril), ARBs (7 candesartan, 5 irbesartan, 5 telmisartan) colon amongst cohorts undergoing colonoscopy or intestinal resection. In or both (one on perindopril and irbesartan). Patients treated with RAS the sigmoid colon, VDR expression was a median two-fold higher in blockers were significantly older than patients not treated with them (mean non-inflamed specimens than non-IBD control specimens (p = 0.020) and 61 vs 42 y, p < 0.001). Disease activity scores were lower in patients treated tended to be similarly higher than inflamed IBD specimens (p = 0.091). with RAS blockers over the previous two-year period amongst all patients There was an inverse correlation between faecal calprotectin and VDR with IBD (p = 0.016) and patients with CD (p = 0.040), but not UC expression in the terminal ileum in patients with CD (r =−0.796, (p = 0.252). Fewer patients treated with RAS blockers tended to require p = 0.002) and a similar trend noted in the sigmoid colon in patients with biologics in CD (39% vs 63%, p = 0.074, Fisher’s exact) and thiopurines UC (r =−0.568, p = 0.069). Immunohistochemical localisation of VDR for UC (25% vs 47%, p = 0.280). One of the 26 patients (4%) on RAS revealed diffuse nuclear staining throughout all layers of the intestinal wall blockers required surgery compared with 39 (14%) of patients with IBD in the terminal ileum and colon of all patient groups, most intensely in the (p = 0.225) and 38 (20%) of patients with CD (p = 0.206) not treated with epithelial layer. There was no significant difference in semi-quantitative these drugs. Rates of hospitalisation not requiring surgery were lower

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 127 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease amongst patients treated with RAS blockers (0 vs 15%, respectively; ileum, ascending and sigmoid colon from patients undergoing intestinal p = 0.033). No significant differences in most recent laboratory indices resection and colonoscopy were surveyed for these components by mRNA were seen, except faecal calprotectin measured in 96 patients within the expression by qRT-PCR, and immunohistochemical localisation and previous 3 months; lower values were seen in 8 who were concurrently semi-quantification of particle density using microscope image processing using RAS blockers (median calprotectin 34 vs 105 μg/g, p = 0.023). On software. bivariate correlation, age significantly correlated with use of RAS blockers Results: 56 patients with CD (mean age 41 [range 21–76] y, 27 (Spearman r = 0.33, p < 0.001), and inversely, albeit weakly, with disease females), 45 with UC (44 [22–82] y, 19 females) and 39 non-IBD con- activity (r =−0.15, p = 0.010), treatment with biologics (r =−0.27, trols (46 [22–83] y, 21 females) were studied. No significant differences p < 0.001) and combination therapy (r =−0.23, p = 0.001), but not require- in demographic features were noted across the three groups. Circulating ment for surgery or hospitalisations. After adjusting for age on hierarchal renin (mean 25.4 (95% CI 21.6–29.1) vs 18.6 (13.9–23.3) mIU/L, multiple regression, no significant effect of RAS blockers on disease activ- p = 0.026), ACE2:ACE ratio (mean 0.61 (95% CI 0.48–0.75) vs 0.40 ity scores in patients with IBD was seen (beta = 0.089, p = 0.152). (0.32–0.47), p = 0.028) and Ang (1–7) (mean 22.8 (20.1–25.4) vs 14.1 Case control study #1: 39 patients requiring surgery were compared 75 (10.8–17.4) pg/ml, p < 0.001) were higher, and ACE and Ang II similar in with age- and sex-matched patients with IBD not requiring surgery over the participants with IBD compared with controls. No significant correlations previous 2 years. Patients with CD having surgery were more likely to have between circulating RAS components and markers of disease activity stricturing or fistulising disease behaviour (31 of 38 vs 38 of 73, p < 0.001). (faecal calprotectin, C-reactive protein, platelet or white cell counts, or No significant differences in immunomodulator or biologic medication use albumin) were noted. Amongst patients undergoing colonoscopy (20 CD, were noted, but patients not requiring surgery were more likely to be on 15 UC, 14 non-IBD controls) and intestinal resection (5 each with CD, RAS blockers (12 of 75 vs 1 of 39, p = 0.034). UC and non-IBD), angiotensinogen, renin, ACE, ACE2, Ang II, Ang Case control study #2: 34 patients requiring hospitalisation were compared (1–7), AT1R, AT2R and Mas receptor were identified by qRT-PCR and/or with 68 age- and sex-matched patients not requiring hospitalisation. Dis- immunohistochemistry in healthy and diseased bowel, with significantly tribution of Montreal subtypes was similar between the groups. Disease higher gene expression of angiotensinogen (3–4 fold), ACE (30–40 fold) activity scores were higher in all IBD patients requiring hospitalisation and ACE2 (10 fold) expressed in the terminal ileum than colon (p = 0.002), but no differences in immunomodulator or biologic use were (p < 0.0001 for all). RAS components were consistently localised to the noted. RAS blocker use was less frequent amongst patients hospitalised (0 epithelium; variably in the lamina propria and submucosa, especially of 24 vs 8 of 58, p = 0.049). microvascular endothelium; and circular muscle myocytes. Expression of Conclusions: Patients with IBD concurrently treated with ACEi and/or mRNA of angiotensinogen was two-fold higher in inflamed IBD and ARBs have lower disease activity, but this may largely be related to older non-inflamed IBD or non-IBD control colonic segments (p < 0.001, age. However, their use was independently associated with fewer Kruskall-Wallis); immunohistochemical staining intensity for ACE2 was hospitalisations and less requirement for surgery in patients with CD. higher in the colon in patients with CD (p = 0.002), and that for Ang (1-7) Given physiological data to date, a prospective long-term study is war- lower (p = 0.001) in the colon in patients with IBD than non-IBD con- ranted to elicit any potential effect of ACEi or ARBs in patients with IBD. trols. Staining intensity of Mas receptor was higher in non-inflamed colon in patients with IBD than in inflamed colon or healthy control tissue (p = 0.045, Kruskall-Wallis). Alteration of the renin-angiotensin system in the Conclusions: All of the components of the classical and alternative RAS circulation, terminal ileum and colon in patients pathways are present in healthy intestinal tissue suggesting a role in normal with inflammatory bowel disease: a potential physiology, especially in epithelial cells. Circulating and mucosal compo- novel therapeutic target nents of the alternative RAS axis are upregulated in patients with IBD, but M GARG,1,2 C SHALLUE,1 SG ROYCE,3 C TIKELLIS,4 mucosal Ang (1-7) is reduced, suggesting dysregulation and a potential P SLUKA,1 H WARDAN,1 E VELKOSKA,5 LM BURRELL,5 role of the RAS in pathogenesis or perpetuation of inflammation in IBD. M THOMAS,4 A MCFARLANE,2 PR GIBSON,6 Novel therapies that increase mucosal Ang (1-7) may have a role in IBD. JS LUBEL1,2 1Eastern Health Clinical School, Monash University, 2 Victoria, Australia, Department of Gastroenterology, Outcomes post-liver transplant for primary 3 Eastern Health, Victoria, Australia, Department of sclerosing cholangitis: colitis activity and Pharmacology, Monash University, Victoria, Australia, malignancy 4 5 Baker IDI, Victoria, Australia, Department of Medicine, A-J GREENUP,1 G PAVENDRANATHAN,2,5 M KEEGAN,1 The University of Melbourne, Victoria, Australia, S GRIFFIN,1 D BOWEN,1,3,4 W SELBY,1,3 N SHACKEL,1,3,4 6 Department of Gastroenterology, The Alfred Hospital, S STRASSER,1,3 G MCCAUGHAN,1,3,4 D KOOREY1,3 Victoria, Australia 1A W Morrow Gastroenterology and Liver Centre, Royal Background: The renin-angiotensin system (RAS) has well-recognised Prince Alfred Hospital, Camperdown, Sydney, NSW, roles in cardiovascular and renal homeostasis, but may also regulate Australia, 2Department of Gastroenterology, St George inflammation, fibrosis and angiogenesis in multiple other organs, including Hospital, Kogarah, Sydney, NSW, Australia, 3University of the gastrointestinal tract. The recently recognised alternative RAS axis Sydney, Sydney, NSW, Australia, 4Centenary Institute of comprising angiotensin converting enzyme 2 (ACE2), the effector peptide Cancer Medicine & Cell Biology, Sydney, NSW, Australia, angiotensin (Ang) (1–7) and the Mas receptor, mediate anti-inflammatory 5University of New South Wales, Sydney, NSW, Australia and anti-fibrotic effects as opposed to the classical axis comprising ACE, Ang II and the AT1 receptor. This study aimed to prospectively characterise Background: The risk of colorectal cancer in patients transplanted for the RAS in the circulating and intestinal compartments in patients with primary sclerosing cholangitis (PSC) has been reported to be higher than in inflammatory bowel disease (IBD) and non-IBD controls. other transplant indications and non-transplanted patients with PSC1, while Methods: Circulating components of the RAS were measured in patients the activity of inflammatory bowel disease (IBD) in such patients varies with Crohn’s disease (CD), ulcerative colitis (UC) and non-IBD controls, despite immunosuppressive therapy2. Yearly endoscopic surveillance is and associations with markers of disease activity evaluated. Terminal recommended given the increased colorectal cancer risk.

128 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Aims: The aims of this retrospective observational study were to signalling and reduces synthesis and secretion of proteins forming the examine IBD colitis activity and rates of colonic dysplasia and cancer in protective mucus barrier. patients post-liver transplantation for PSC. Methods: We comprehensively analysed changes in mucus barrier com- Methods: Data for patients undergoing liver transplantation for PSC at ponents, ER/oxidative stress, and inflammation in the colon of mice fed Royal Prince Alfred Hospital from January 1986 to December 2014 was HFDs for 3, 11 and 22 weeks. We also examined the effect of suppressing collected by medical record review and was subsequently analysed accord- ER stress during a HFD with IL-22 (a potent stress suppressor) and ing to duration of follow up, pre or post-transplant colectomy, frequency of whether HFDs exacerbated acute and chronic murine colitis. colonoscopy, IBD activity and colonic dysplasia and cancer outcomes. Results: Obesity modulated the differentiation and function of intestinal Results: One hundred and fourteen patients were transplanted for PSC goblet cells via Kruppel-like Factor (KLF)-4 and down-regulated tran- during this 29-year period. Thirty-one patients were excluded for less than scription of Muc2 intestinal mucin. Long-term HFDs caused intestinal 2 years of follow up post-transplant (deceased (n = 20; 19 prior to 2008) or inflammation, ER stress and protein misfolding, which was resolved by transplantation since January 2013 (n = 11)). Of the remaining 83 patients, IL-22 (2wk treatment). In the ER-stress-driven Winnie colitis model, HFDs 14 patients had a pre-transplant colectomy, care of 4 patients was trans- did not exacerbate chronic disease. However, mice fed a 9 week HFD from ferred to another interstate transplant centre and 3 had limited available weaning showed significantly increased intestinal pathology. medical records. Eighteen of 62 patients did not have IBD pre-transplant, Conclusion: Prolonged HFD feeding significantly alters colonic barrier of whom 1 required a colectomy (for sporadic cancer) and 4 subsequently function by influencing ER stress and protein folding in mucosal secretory developed IBD. Accordingly, post-transplant IBD outcomes were available cells. for 48 patients with a mean age of 58 years, male to female ratio of 2:1 and a diagnosis of ulcerative colitis in 28 and Crohn’s disease in 20 patients. Mean follow-up was 11 years. Forty-seven of 48 patients had had at least one colonoscopy, with a median interval of 1.74 years. Colitis was histo- Correlation of intestinal ultrasound with faecal logically active in 68% of patients (n = 32) post-transplant, including 22 calprotectin in inflammatory bowel disease patients who had quiescent disease preceding transplant. Three patients N HEERASING, AK ASTHANA, AB FRIEDMAN, K, received tumour necrosis factor antagonist therapy, inducing remission in BRITTO, MP SPARROW, SL JAKOBOVITS, PR GIBSON two patients whilst the other required a colectomy. An additional 4 patients Department of Gastroenterology & Hepatology, Alfred also underwent colectomy for refractory colitis. In the remaining 15 Health and Monash University, Melbourne, Australia patients, colitis was quiescent post-transplant. Six further patients had a total or hemi colectomy for the indications of cancer (3), invisible dyspla- Introduction: We currently use a treat to target approach in the manage- sia (1), endoscopically unresectable polypoid dysplasia (1) and caecal ment of patients with Inflammatory Bowel Disease (IBD). Faecal volvulus (1). An additional 4 patients had a history of invisible dysplasia calprotectin is a non-invasive marker which has been shown to be a sur- and 4 endoscopically resectable polypoid dysplasia. rogate marker for mucosal healing. Limitations of this test include the lack Conclusions: Colitis has been active in 68% of patients post-transplant of information regarding disease location and the possibility of false posi- for PSC. Dysplasia and/or cancer have been detected in 14 patients. Col- tives with other conditions (such as malignancy, medications). Intestinal ectomy has been necessary in 11 patients overall. These findings emphasise ultrasound (IUS) is an alternative non-invasive imaging modality, which the need for aggressive surveillance and colitis management post- has the ability to provide information on both disease activity and location. transplantation, including vigilance for de novo IBD development. The Till date however, there have been no studies comparing the accuracy of median colonoscopic interval of 1.74 years remains longer than recom- IUS to faecal calprotectin. mended and is an opportunity for quality improvement. Aims: To assess the accuracy of IUS to faecal calprotectin in evaluating disease activity in IBD. References Methods: A prospective US database was established for IBD patients at 1. Sint Nicolaas J, de Jonge V, Steyerberg E, Kuipers E, van Leerdam M, The Alfred Hospital. Findings from IUS were compared to faecal Veldhuyzen-van Zanten, S. Risk of colorectal carcinoma in post-liver calprotectin within 7 days of the scan. Other captured data included clinical transplant patients: a systematic review and meta-analysis . Am J Trans- features such as disease phenotype, endoscopic findings (within 6 months plant 2010; 10: 868–76. of the scan) and biochemical tests (such as C-reactive protein). The 2. Singh S, Loftus E, Talwalkar J, MD. Inflammatory Bowel Disease after IUS were performed over a period of 8 months in 2014 and read by two Liver Transplantation for Primary Sclerosing Cholangitis. Am J IBD specialists with expertise in IUS. Statistical analyses were under- Gastroenterol 2013; 108:1417–1425. taken to assess the accuracy of IUS with different threshold levels of faecal calprotectin. These included 30 mcg/g, 50 mcg/g, 100 mcg/g and 250 mcg/g. Results: Forty-eight IUS patients (32%) had matched faecal calprotectin High fat diet and the colonic mucus barrier: levels – this was used as the gold standard test in this study. The different implications for obesity and inflammatory cut-off values used were 30 μg/g, 50 μg/g, 100 μg/g and 250 μg/g. For a bowel disease level of <30 μg/g, the PPV of the IUS findings was 100% and this dropped M GULHANE, L MURRAY, R WANG, H TONG, to 81% when a calprotectin level > 250 μg/g was used. Similarly, the M MCGUCKIN, S HASNAIN specificity of the IUS findings dropped from 100% to 76% for <30 μg/g Immunity, Infection and Inflammation Program, Mater and <250 μg/g respectively. One hundred and seven IUS patients had Research Institute – The University of Queensland, matched CRP results and in this cohort, 33 patients with positive IUS Translational Research Institute, Brisbane, Australia findings had an abnormal CRP with a sensitivity of 37% and a specificity of 75.5%. Forty-five patients in the database (30%) had both matched Background: The prevalence of obesity is increasing at an alarming rate calprotectin and CRP and in this group, all patients with calprotectin <30 worldwide. Prolonged high fat diets (HFDs) induce low-grade chronic and CRP <3(n= 6) had negative IUS findings. intestinal inflammation in mice, and HFDs are a risk factor for the devel- Conclusion: The combination of IUS and faecal calprotectin are ideal in opment of human inflammatory bowel diseases. We hypothesised that monitoring IBD patients non-invasively. The accuracy of IUS was high during HFD-induced obesity, endoplasmic reticulum (ER) and oxidative when using a faecal calprotectin cut-off value of 30 mcg/g. This study stress occurs in intestinal secretory cells, which triggers inflammatory illustrates that correlation between the two non-invasive tests are high in

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 129 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease excluding the presence of active disease. This is the first Australian study Concurrent infliximab and cyclosporin treatment to assess the accuracy of IUS in relation to faecal calprotectin. The results for severe colitis of this study make a strong case for further prospective research into the P HENDY,1,3 TH FLORIN1,2,3 comparison of IUS with faecal calprotectin. 1School of Medicine, University of Queensland, Brisbane, Australia, 2Mater Research-University of Queensland, Brisbane, Australia, 3Gastroenterology Department, Mater Idelalisib-induced acute proctocolitis: clinical Health Services, Brisbane, Australia and histological findings P HENDY,1 C ROSTY,2 J BASHFORD,4 A CLOUSTON,2 Introduction: Cyclosporin and infliximab are medical rescue strategies D BURGER3 for acute severe and steroid refractory colitis. Sequential use of cyclosporin 1School of Medicine, University of Queensland, Brisbane, and infliximab is considered risky by many although there is evidence ∼ 2 showing colectomy rates of 40% at 12 months and relatively low serious Australia, Envoi Pathology, Brisbane, Australia, 1 3 infection rates . Concomitant infliximab and cyclosporin has been reported Gastroenterology and Liver Diseases, Wesley Hospital, in rheumatoid arthritis2, but concomitant cyclosporin-anti-TNFa therapy in 4 Brisbane, Australia, Haematology and Oncology Clinic, IBD has not been reported. Wesley Medical Centre, Brisbane, Australia Methods and results: Here we report three female patients (22–43 years Background: Idelalisib (Zydelig®) is a highly specific small-molecule old) prescribed concurrently cyclosporine and infliximab for episodes of phosphatidylinositol-3-kinase (PI3K-delta) inhibitor with recent United severe colitis. Two patients were intolerant of steroids due to psychiatric States’ FDA and European Union approval as an oral treatment for side-effects. The other patient had steroid refractory disease. All three relapsed B cell haematological cancers1. Phase 2 and 3 registration studies patients met Truelove and Witts’ criteria for acute severe colitis. Two have demonstrated fatal and/or serious and severe diarrhoea or colitis in up patients had ulcerative colitis (one left-sided and one with pancolitis con- to 14%, however the histological findings have not been well docu- firmed on colonoscopy). The other patient had distal Crohn’s colitis with a C. mented2,3. Here we report the clinical and histological features associated new-onset rectovaginal fistula allowing passage of whole faeces. CMV, difficile with Idelalisib gastrointestinal toxicity. infection and infectious colitis were excluded in all cases by faecal C. difficile Methods: Two cases of Idelalisib associated colitis were identified from culture, PCR and antigen testing prior to concomitant treatment a single centre, information on their clinical management and outcomes with cyclosporine and infliximab. were reported by the treating gastroenterologist and haematologist. Histol- Infusions of 2 mg/kg daily cyclosporin were given for 3–5 days followed ogy was reviewed by two expert gastrointestinal pathologists. by oral therapy with liposomal cyclosporin (Neoral™) for 3 months. Due Results: Both patients presented with non-bloody, severe (grade III) diar- to lack of satisfactory early clinical response, infliximab 5 mg/kg induction rhoea and weight loss following 3 months of Idelalisib therapy. Both doses were prescribed while continuing therapy with cyclosporin. patients had negative stool culture, faecal multiplex PCR, and C. difficile Infliximab was continued as maintenance therapy in two cases. Each PCR with elevated faecal calprotectin >1000 ug/g. Both patients failed to patient received concomitant thiopurines. Despite a gratifying initial improve despite Idelalisib withdrawal and empiric loperamide. Colonos- response, the left-sided ulcerative colitis patient developed severe infec- copy demonstrated patchy left-sided colitis in one patient and confluent tious complications with herpetiform gingivostomatitis secondary to para- pancolitis in the second patient. Upper gastrointestinal tract, proximal influenza III infection and disseminated bacterial folliculitis. All small bowel and terminal ileum were endoscopically normal in both immunomodulatory therapy was ceased and the patient came to colectomy patients. Colonic biopsies showed acute colitis with oedematous lamina for severe left-sided colitis 10 weeks after commencement of the combi- propria, mixed inflammatory infiltrate comprising numerous eosinophils, nation treatment. The other two patients achieved clinical remission. A crypt abscesses and crypt dropout, lymphocyte exocytosis in the crypts colonoscopy at 19 months showed complete healing of the fistula and with apoptotic bodies. CMV was not found. Both patients responded colonic mucosal healing in the Crohn’s patient. A colonoscopy at two rapidly to intravenous hydrocortisone with resolution in diarrhoea and months showed macroscopic mucosal healing in the patient with pan- normalisation of CRP. Follow-up biopsies on one patient demonstrated ulcerative colitis. Conclusion: features of resolving colitis five months later. It is worthwhile to consider treatment with concurrent Conclusions: Idelalisib may cause an acute toxic inflammatory reaction infliximab and cyclosporin in select, well-informed patients with severe in the colon resembling infective proctocolitis with a marked eosinophilic colitis wanting to avoid surgery and in whom concomitant steroids are infiltrate. Given the likely incorporation of this medication into the thera- contraindicated. peutic approach for relapsed B-cell haematologic malignancies, clinicians References may encounter an increasing number of such cases and should be aware of 1) Narula N, Fine M, Colombel JF, et al. Systematic Review: Sequential this potentially fatal and severe complication. Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh References the Risks? Inflamm Bowel Dis. 2015 Apr 1. [Epub ahead of print] 1. Markham A. Idelalisib: first global approval. Drugs 2014 PMID: 25839775. Sep;74(14):1701–7. 2) Temekonidis TI, Georgiadis AN, Alamanos Y, et al. Infliximab treat- 2. Gopal AK, et al. PI3K-delta inhibition by Idelalisib in patients with ment in combination with cyclosporin A in patients with severe refrac- Ann Rheum Dis 61 relapsed indolent lymphoma. NEJM 2014;370(11):1008–18. tory rheumatoid arthritis. 2002; :822–825. 3. Furman RR, et al. Idelalisib and Rituximab in relapsed chronic lym- phocytic leukaemia. NEJM 2014;370(11):997–1007.

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Low muscle mass at treatment initiation is bowel disease; this identifies baseline muscle wasting as an important associated with early loss of response to negative prognostic indicator. anti-TNF therapy for Inflammatory Bowel References Disease 1. Bultman E, de Haar C, van Liere-Baron A, Verhoog H, West RL, D HOLT,1,2,3 P VARMA,1 B STRAUSS,3 G MOORE1,3 Kuipers EJ, et al. Predictors of dose escalation of adalimumab in a 1Gastroenterology and Hepatology Unit, 2Clinical Nutrition prospective cohort of Crohn’s disease patients. Alimentary Pharmacol- and Metabolism Unit 3Department of Medicine, School of ogy & Therapeutics. 2011 Dec 22;35(3):335–41. Clinical Sciences, Monash University, Melbourne, Victoria, 2. Baracos VE, Reiman T, Mourtzakis M, Gioulbasanis I, Antoun S. Body Australia composition in patients with non-small cell lung cancer: a contempo- rary view of cancer cachexia with the use of computed tomography Introduction: Inflammatory bowel disease (IBD) is associated with image analysis. Am J Clin Nutr. 2010 Apr 1;91(4):1133S–1137S. altered body composition, with reductions of skeletal muscle mass and 3. Hanna JS. Sarcopenia and Critical Illness: A Deadly Combination in the bone mass common. A correlation between anti-TNF refractory inflamma- Elderly. JPEN J Parenter Enteral Nutr. 2015 Jan 15. tion and increased body mass index has previously been noted in Crohn’s Disease1, rheumatic and dermatological conditions. Low skeletal muscle 2 has been associated with poor outcomes in cancer chemotherapy patients Bone health in inflammatory bowel disease 3 and patients with critical illness . We sought to examine whether body patients – management by australian composition analysis using routinely-obtained CT images at around the gastroenterologists is variable and poorly time of anti-TNF induction correlated with loss of response to these drugs. We have previously shown that single slice analysis of abdominal scans has consistent with current guidelines 1 1 1 a high degree of correlation with total body measures of body composition. Y KO, S PARAMSOTHY, K SARATHY, P SHAN, 1 1 Methods: A retrospective audit was conducted of all patients with IBD W NG, S CONNOR receiving anti-TNF therapy at our centre. All patients on anti-TNF therapy 1Department of Gastroenterology & Hepatology, Liverpool with an accurate date for TNF commencement, an abdominal MRI or CT Hospital, Liverpool NSW 2170 Australia scan within 12 months of induction, and adequate correspondence to deter- Background and Aims: Data is lacking regarding gastroenterology prac- mine end-points were included. Analysis was performed at the level of the tice in preventing and treating osteoporosis in inflammatory bowel disease third lumbar vertebra and at the fourth-fifth lumbar intervertebral disc by a (IBD). We surveyed Australian Gastroenterologists (GEs) to assess osteo- single experienced operator using SliceOMatic software to measure areas porosis screening and management practices in IBD. of skeletal muscle, subcutaneous fat, and visceral fat. Patients with prior Methods: We conducted an anonymous online survey of GEs regarding exposure to any anti-TNF agent were excluded. Loss of response was bone health in IBD, collected over an 18-month period. defined by an admission or surgery post-induction, escalation of TNF dose Results: 164 responses were obtained (response rate 25%). The majority or immunosuppressants for clinical LOR, emergence of a new fistula or (90%) practiced in urban centres. For newly diagnosed Crohn’s disease rising Crohn’s Disease Activity Index >150 (CDAI). Statistical analysis patients, 27% of GEs always screened for bone health and osteoporosis; was performed with GraphPad Prism v6. Kaplan-Meier analysis was 53% did so if there was clinical suspicion. For ulcerative colitis, rates were undertaken, with Log-Rank test to compare curves, and chi-square testing 16 % and 58% respectively. Significant variation was found in the numbers of categorical variables. A p value of <0.05 was considered significant. of GEs utilising osteoporosis screening tests: 75% ordered a dual-energy Results: 35 patients were identified; 16 female, 19 male. 34 patients had x-ray absorptiometry scan, only 26% investigated for secondary causes of Crohn’s Disease, 1 had ulcerative colitis. 9 patients received adalimumab osteoporosis, and 16% assessed bone turnover markers. In terms of treat- induction therapy, 26 received infliximab. 14 patients (45%) experienced ment practices, only 18% of GEs attempted to manage osteoporosis inde- loss of response (LOR), with a median LOR-free survival of 1100 days. pendently. 41% of GE referred to an Endocrinologist. 70% of respondents Patients in the lowest quartile of L3 skeletal muscle area were significantly initiated calcium and vitamin D treatment, compared with only 30% for more likely to have loss of response, with a median survival of 386.5 days oral bisphosphonate therapy, and 6% for intravenous bisphosphonate. After compared with 1219 in the highest quartile (p = 0.0021). Those patients in bisphosphonates, responders were most comfortable using Strontinum the lowest quartile of L4-5 visceral adipose tissue area had a median ranelate (59%) and Selective Estrogen Receptor Modulators (45%), fol- survival of 636 days, compared with 1100 days in the median 50% lowed by Teriparitide (28%) and Denosumab (18%). Importantly, only (p = 0.0457). The median time to loss of response was shorter for the 67% advocated non-pharmacological measures in bone health lowest quartile of skeletal muscle area than for the lowest quartile of body optimisation. weight or visceral adipose tissue area. Crohn’s Disease Activity Index and Conclusions: Practices among Australian Gastroenterologists regarding C-reactive protein were not predictors of loss of response, but those in the bone health in IBD vary widely. Issues identified include lack of knowl- lowest quartile of albumin and haemoglobin measures had a shorter mean edge of current guidelines, lack of uniformity in utilising screening tests, time to loss of response (p = 0.024 and 0.037 respectively). suboptimal advocacy for lifestyle measures, and inadequate awareness of pharmacological therapies. L3 Muscle area 100 Lowest quartile Highest quartile Middle 50%

50 LOR-free survival LOR-free p = 0.0021 0 0 500 1000 1500 2000 Days

Summary: These data suggest that baseline low skeletal muscle mass may be a predictor of loss of response to anti-TNF therapy in inflammatory

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 131 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Inflammatory bowel disease environmental risk Conclusions: Significant differences exist in IBD environmental factors factors: a multi-centre cross-sectional control between Australia and Lebanon, evident in both populations of Caucasians study on differences between Australia and the and migrant Middle Easterners. Specifically, there is increased OCP use, Middle East increased antibiotics use and greater hygiene markers in Australia com- Y KO,1,3 V KARIYAWASAM,1,2 M KARNIB,4 R BUTCHER,5 pared to the Middle East. These factors may be important IBD risk factors in migrant populations, contributing to greater their greater IBD risk upon D SAMUEL,2,6 A ALRUBAIE,2,6 N RAHME,6 immigration. On the other hand, smoking was less likely in controls of 1,6 1,6 1,6 C MCDONALD, J COWLISHAW, P KATELARIS, migrant and native populations compared with Lebanon, suggesting 1,6 3,6,7 6,8 G BARR, B JONES, S CONNOR, G PAVEN, smaller role in contributing to IBD risk in developed countries. Diet was G CHAPMAN,1,6 G PARK,6 R GEARRY,9 RW LEONG1,2,3,6 also not significantly different between developing and developed country ON BEHALF OF THE IBD SYDNEY ORGANISATION environments. 1Gastroenterology and Liver Service, Concord Hospital, Sydney, Australia, 2Gastroenterology and Liver Service, Bankstown Hospital, Sydney, Australia, 3Faculty of Increased mucosal cytokine expression in Medicine, UNSW Australia, 4American University of Beirut patients with inflammatory bowel disease Medical Center, Lebanon 5Central Manchester University corresponds to severity of disease activity Hospitals, Manchester Royal Infirmary, Department of G IYNGKARAN,1 A KARNOWSKI,2 M NG,2 Gastroenterology, Manchester, United Kingdom, 6IBD M CHRISTIE,3 F MACRAE1 Sydney, Sydney, Australia, 7Liverpool Hospital, 1Royal Melbourne Hospital, Colorectal Medicine and Department of Gastroenterology and Hepatology, Sydney, Genetics, Parkville, Australia, 2CSL Bio 21, Immunology, New South Wales, Australia, 8St George Hospital, Parkville, Australia, 3. Royal Melbourne Hospital, Gastroenterology and Hepatology, Kogarah, New South Pathology, Parkville, Australia Wales, Australia, 9University of Otago, Christchurch, New Zealand Background: The aetiology of inflammatory bowel disease (IBD) is unknown but an imbalance between pro and anti-inflammatory Background: The incidences of the inflammatory bowel diseases (IBD) cytokines is thought to play a role. Gut microbiota (GM) can stimulate Crohn’s disease (CD) and ulcerative colitis (UC) are increasing, indicating pro and anti-inflammatory cytokines[1]. Indigenous Australians (IA), in gene-environment interactions. Generally, IBD incidence and prevalence whom IBD is rare, have different GM profiles compared to Caucasian are lower in developing nations compared to developed countries, suggest- controls and IBD patients [2]. The GM of IA may potentially stimulate ing protective environmental factors in developing countries. Migrants regulatory cytokines and confer some resistance to chronic mucosal from low IBD prevalence countries to high prevalence country may help inflammation. Studying mucosal cytokine expression in IBD patients, con- identify the relative contribution of environmental risk factors compared trols and low risk groups may lead to the discovery of novel therapeutic with native Caucasians. Australia provides suitable opportunity for using options. migrant groups for epidemiological study of IBD environmental factors. Aims: To study mucosal cytokine profiles in patients with IBD, controls Aims: To investigate the differences in IBD environmental risk factors and IA. between developing (Lebanon) and developed (Australia) countries using Methods: Mucosal biopsies were obtained from healthy controls (HC), matched controls. Comparison using native and migrated groups of same IA and patients with active Crohn’s disease (CD) and Ulcerative colitis ethnicity (Middle Eastern) is made, as well as comparison with Australian (UC). Samples were graded histologically as having no, mild or severe Caucasian controls. inflammation by 2 pathologists. Quantitative cytokine mRNA analysis was Methods: This is a multi-centre cross-sectional comparative control performed using Taqman Gene expression cards. study which evaluated 104 IBD environmental risk factors of Middle Results: 183 samples from 74 patients (26 CD, 21 UC, 12 Controls, 15 Eastern migrants (MEM) in Australia compared with matched Caucasian IA) were analysed. IBD patients with active inflammation had increased IBD subjects, controls and controls in the Middle East (Lebanon). A pro-inflammatory cytokine mRNA expression (IL-1β, IL6, IL17A, IL17F, multivariate model was produced using logistic regression for statistical IL21, IL23A, TNF-α, IFN-γ, CSF-2 and CSF-3). There was a linear analysis. Adjusted odds ratios (aor) were produced for each risk factor. increase in mRNA expression of IL-1β, IL6, TNF-α and IFN-γ correlating Results: 153 MEM controls, 173 Caucasian controls and 153 controls in with severity of inflammation. Cytokine mRNA expression in CD and UC Lebanon were recruited. On comparing Australian ME controls to Leba- were similar apart from a relative increase in IL23R in CD patients and an nese controls, antibiotics and OCP use were more likely in Australian ME increase in IL-13 in UC patients. Increased mRNA expression of IL10 and controls (aor 3.22 95% CI: 1.81–5.71 & aor 3.23 95% CI: 1.46–7.60 IL-22 were seen in active IBD but not in IA, who had a similar cytokine respectively). Rural dwelling in infancy (aor 0.20 95% CI: 0.08–0.47) and mRNA expression profile to controls. TNF-α was expressed in all groups bedroom sharing for infancy, childhood and adolescence (p < 0.05) were with a higher expression noted in inflammed mucosa. There was higher less likely, while pet feeding in childhood (aor 2.07 95% CI: 1.21–3.53) expression of Thymic stromal lymphopoeitin (TSLP) mRNA in several IA was more likely. Smoking was also less likely in MEM controls (aor 0.88 but this was not statistically significant. 95%CI 0.24–0.76). On comparing Australian Caucasian controls to Leba- Conclusion: There is a higher expression of several pro-inflammatory nese controls, smoking was less likely (aor 0.30 95% CI: 0.17–0.52), as cytokines in patients with IBD. The mRNA expression of IL-1β, IL6, well as rural dwelling in infancy, childhood and adolescence (p < 0.05) and TNF-α and IFN-γ correlate directly with the severity of mucosal inflam- bedroom sharing for all ages under 16 (p < 0.05). On the other hand, OCP mation. There was no difference in mRNA expression between IA and use (aor 2.99 95% CI: 1.33–6.72) increased. There was no significant controls although a trend in increase of TSLP is seen in IA. TSLP has been differences found for takeaway consumption and vegetarianism between shown to be protective against IBD in mouse models and further research controls in Lebanon and controls in Australia (p > 0.05). on this cytokine may be worthwhile.

132 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

TNF CSF3 IL6 rank correlation (rs) was applied to determine the magnitude of the rela- 3 6 15 tionship between 6-TGN concentration, absolute dose (mg) and weight 2 4 10 based dose (mg/kg) of AZA and 6MP. In the 6MP cohort, there was a

1 2 5 poor correlation between absolute dose of 6-MP and 6-TGN level (r [arbitrary unit] [arbitrary s [arbitrary unit] [arbitrary [arbitrary unit] [arbitrary gene expression gene gene expression gene expression gene

0 0 0 0.197). When correlated further using weight-based dosing (mg/kg) a l d o s o s l d o s o s l d o s o s o e e ro n N e N e o e e tr In N Y N Y t I Y Y tr In N Y N Y n l D C n l D D C C n l D C o o C D U C o ro C U o o C D U C tr C U C t C U tr C U slightly more significant relationship was identified (r 0.257). Findings C n n C n s o o o C C C differed in the AZA cohort, absolute dose in (mg) showed a strong cor-

TSLP IL17A IL22 relation with 6-TGN concentration (rs 0.314) and a slightly weaker rela- 5 4 2.5 tionship when analysed using a weight-based dose (mg/kg) comparison 4 2.0 3 3 1.5 (rs 0.273). 2 2 1.0 Conclusion: In this study conventional weight-based dosing of [arbitrary unit] [arbitrary unit] 1 [arbitrary unit] gene expression gene expression 1 gene expression 0.5 thiopurines did not reliably predict 6-TGN concentration levels. 0 0 0.0 l d o s o d o s o s l o e es rol n N e N e o d o s o s In N N Y t Y Y r n N e N e Thiopurine metabolite testing is a valuable clinical tool to inform dosage l D C n l I D C t I Y Y ntr DY C o o C D U C n l D D C C ro C C U U tr C U o ro C U Co t C n C t C U n o n C o Co C across the adult IBD population. We feel that when initiating a thiopurine, using a standard absolute dose is just as likely as a weight based dose to yield thiopurine metabolite levels in the therapeutic range. References: 1. Martin, R., et al., The Commensal Bacterium Faecalibacterium prausnitzii Is Protective in DNBS-induced Chronic Moderate and Severe Colitis Models. Inflamm Bowel Dis, 2014. 20(3): p. 417–30. 2. Iyngkaran G, et al., (2013), Indigenous Australians have a distinctive gut microbial profile compared to patients with inflammatory bowel disease and non Indigenous controls, European Crohn’s and Colitis Vienna 2013

References: Weight-based dosing of thiopurines and 6-TGN 1. Dignass, A., Van Assche, G., Lindsay, J. O., Lémann, M., Söderholm, concentrations in an adult cohort of patients J., Colombel, J. F., . . . European Crohn’s and Colitis Organisation with Inflammatory Bowel Disease (ECCO). (2010). The second European evidence-based Consensus on 1 1 1 A MCMAHON, K SEWELL, M HOWLETT, GL the diagnosis and management of Crohn’s disease: Current manage- RADFORD-SMITH,1–3 J IRWIN2–4 ment. Journal of Crohn’s & Colitis, 4(1), 28–62. doi:10.1016/ 1Dept of Gastroenterology, RBWH; 2QIMR Berghofer MRI; j.crohns.2009.12.002 3University of Queensland School of Medicine, Herston 2. Dubinsky, M. C. (2004). Azathioprine, 6-mercaptopurine in inflam- Campus, 4Dept of Gastroenterology, Palmerston North matory bowel disease: pharmacology, efficacy, and safety. Clinical Hospital, New Zealand Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association, 2(9), 731– Background: Current practice guidelines endorse weight-based dosing 743. of 6-Mercaptopurine (6-MP) 0.75–1.5 mg/kg/day and Azathioprine (AZA) 1.5–2.5 mg/kg in the adult Inflammatory Bowel Disease (IBD) popula- tion1. Serum levels of the thiopurine metabolites, 6-thioguanine nucleotide Beta-lactam associated eosinophilic colitis 1 2 3 (6-TGN) and 6-methylmercpatopurine (6-MMP) have been shown to cor- T MOGILEVSKI, D NICKLESS, S HUME relate with risk of toxicity and efficacy2. These levels are utilised by 1Department Gastroenterology and Hepatology, Austin clinicians to guide and optimise thiopurine treatment in the clinical Health, Melbourne, Victoria, Australia, 2Department of setting2. Thiopurines are a mainstay in the medical management of IBD Healthscope Pathology, The Northern Hospital, and as such, appropriate dosing, efficacy and risk minimisation are impor- Melbourne, Victoria, Australia, 3Department of Infectious tant treatment considerations. Diseases, The Royal Melbourne Hospital, Melbourne, Aim: To examine the relationship between weight-based dosing of Victoria, Australia thiopurines and 6-TGN concentrations in an adult cohort of patients with IBD. We report the case of a 42-year-old man with a history of childhood asthma Methods: A total of 176 adults, with established IBD and treated with who presented with a two week history of watery diarrhoea and marked thiopurines were included in this retrospective observational study. peripheral eosinophilia in the setting of recent use of cephalexin. His Patients were reviewed in a dedicated IBD clinic between 24/02/2013–31/ colonoscopy revealed patchy colitis. Biopsies were consistent with eosino- 03/2015. Those with 6-TGN concentration levels performed within 3 philic colitis. Two months later he received a course of amoxycillin result- months of the clinic review were included in the analysis. All subjects on ing in recurrence of peripheral eosinophilia. Given the time-frame of an allopurinol-thiopurine combination were excluded. Additionally, those beta-lactam administration to symptom onset and elimination of all other with a 6-TGN & 6-MMP level < 50 pmol/8 x 108 were excluded from the precipitating causes he was diagnosed with beta-lactam associated eosino- analysis with assumed non-adherence. philic colitis. The patients’ symptoms resolved and peripheral eosinophil Results: Thiopurine distribution within the patient cohort consisted of count decreased with no specific treatment. 115 patients treated with 6-MP and 61 patients treated with AZA. There Eosinophilic colitis is an exceptionally rare condition thought to be part of were 116 males and 60 females, disease distribution within the group a larger spectrum of eosinophilic gastrointestinal disorders. It is a hetero- consisted of 119 patients with Crohn’s disease and 57 patients with geneous disorder, both in its clinical presentation and histopathological Ulcerative colitis. There were 7 patients in the 6-MP cohort and 3 appearance, and can affect both infants and adults. patients in the AZA cohort that did not have a recorded weight, these The pathogenesis of eosinophilic colitis is incompletely understood, but patients were not included in the final statistical analysis. Spearman’s thought likely to be a combination of genetic predisposition and environ-

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 133 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease mental exposure. This theory is supported by a large multinational registry, Current belief and practice of Victorian which showed that amongst patients with eosinophilic gastrointestinal gastroenterologists regarding perioperative disease, 80% had coexisting atopic disease and 16% had an immediate immunomodulator therapy in the perioperative family member with a similar disorder.[1] period in patients with IBD The diagnosis of eosinophilic gastrointestinal disease is made from the J NG,1 A TING,2 D DOWLING1,3 presence of gastrointestinal symptoms, peripheral eosinophilia, endoscopic 1Department of Gastroenterology, University Hospital and histological findings, and eosinophilic ascites, with no well-defined 2 causes of eosinophilia on thorough evaluation. [2] Geelong, Victoria, Australia, Department of To our knowledge this is the first report of beta-lactam associated eosino- Gastroenterology, Monash Medical Centre, Victoria, philic colitis in the literature to date. Australia, 3School of Medicine, Deakin University, Victoria, Australia Background: Immunomodulatory therapy (thiopurines, TNF antagonists and corticosteroids) is extensively used in the medical management of inflammatory bowel disease (IBD). Patients treated with these agents fre- quently require surgery for both refractory disease and non-IBD indica- tions. Whilst extensive evidence exists for corticosteroids increasing the risk of post-operative infectious complications, conflicting evidence exists regarding the effects of thiopurine therapy and TNF antagonists (biologics) on post-operative infection risk. 1 There has been no prior Australian studies examining Gastroenterologists’ practice with respect to perioperative management of immunomodulator therapy in patients with IBD. Figure 1 – Sigmoid colon Aim: To gain insight into current belief and practice of Victorian Gas- troenterologists with respect to perioperative use of immunomodulator therapy in IBD patients. Methods: An online survey was sent to Victorian Gastroenterologists with appointments at major public hospitals. The survey consisted of 15 questions focused on current belief and practice regarding perioperative use of thiopurines, biologic therapy and prednisolone in IBD patients. All replies were anonymous. Results: We obtained 41 responses from the online survey. The percent- ages of respondents who believed thiopurines, biologic therapy and corti- costeroids are associated with an increased post- operative infection risk were 20%, 45% and 95% respectively. In the setting of non – emergent abdominal surgery, 10%, 22.5%, and 72.5% of gastroenterologists recom- mend stopping thiopurines, biologic therapy and corticosteroids respec- tively prior to surgery. With respect to elective non-abdominal surgery, 5.1%, 10.3% and 56.4% of the respondents recommended ceasing thiopurines, biologic therapy and corticosteroids respectively prior to surgery. Among those who recommended ceasing thiopurines prior to surgery, most recommend ceasing the medication 1–30 days prior to surgery and restarting 1–7 days after surgery. Among those who recom- Figure 2 – Colonic biopsy mended ceasing biologic therapy, the majority of the respondents recom- mended ceasing it 8–30 days prior and restarting it 8–30 days after surgery. References Conclusion: The majority of gastroenterologists do not believe 1. Guajardo JR, Plotnick LM, Fende JM, Collins MH, Putnam thiopurines and biologic therapy increases post-operative infection risk. PE, Rothenberg ME. Eosinophil-associated gastrointestinal dis- This is consistent with the findings of most studies which have examined orders: a world-wide-web based registry. J Pediatr. 2002 Oct;141(4): the post-operative infection risk associated with these agents. 2 Most gas- 576–81. troenterologists, including many who believe thiopurines and biologic 2. Yan BM, Shaffer EA. Primary eosinophilic disorders of the gastroin- therapy increases post-operative risk, continue with these medications testinal tract. Gut. 2009 May;58(5):721–32. through the perioperative period. References 1. Ali T, Yun L, Rubin DT. Risk of post-operative complications associ- ated with anti-TNF therapy in inflammatory bowel disease. World Journal of Gastroenterology. 2012;18:197–204. 2. Rosenfeld G, Qian H, Bressler B. The risks of post-operative compli- cations following pre-operative infliximab therapy for Crohn’s disease in patients undergoing abdominal surgery: a systematic review and meta-analysis. J Crohns Colitis. 2013;7:868–877

134 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

The first prospective Australian Comparing colectomy rates in treatment naïve population-based study of newly diagnosed IBD vs. treatment experienced patients with acute identifies outpatient resources as the major cost severe ulcerative colitis (ASUC) driver, including medications and investigations D PATRICK,1,3,4 E BALLARD,2 P O’ROURKE,2 O NIEWIADOMSKI,1 C STUDD,2 C HAIR,3 J WILSON,2 M HOWLETT,1 GL RADFORD-SMITH1,3 J MCNEILL,4 R KNIGHT,3 E PREWETT,3 P DABKOWSKI,3 1Department of Gastroenterology and Hepatology, Royal D DOWLING,3 S ALEXANDER,3 B ALLEN,3 M TACEY,5 Brisbane and Women’s hospital. Brisbane Queensland, W CONNELL,1 P DESMOND,1 S BELL1 Australia, 2Department of Statistics, QIMR Berghofer 1Gastroenterology Dept, St Vincent’s Hospital, Melbourne, Medical Research institute, Herston campus, Brisbane, 2Royal Hobart Hospital, Tasmania, 3Barwon Health, Queensland, Australia, 3Inflammatory bowel disease Geelong, 4Dept of Epidemiology & Preventative Medicine, group, QIMR Berghofer Medical Research Institute and Monash University, 5Melbourne Epicentre & Northern University of Queensland School of Medicine, Herston Clinical Research Centre, Melbourne Campus, Brisbane, Queensland, Australia 4Department of Medicine, University of Queensland, St Lucia, Brisbane, There is limited prospective population based data on the health care cost of IBD in the post-biologic era. A prospective registry that included all Queensland, Australia incident cases of Inflammatory Bowel disease (IBD) was established to Background: ASUC is a colon and life threatening condition with a study disease progress and health cost. colectomy rate of 30 % and mortality of 1–2 % with the colectomy rate Aim: To prospectively assess health-care costs from a health system unchanged over the last 30 years. No study has evaluated using prospective perspective in the first year of diagnosis among a well-characterized cohort data the effect of treatment prior to presentation on colectomy rate. of newly diagnosed IBD. Aims: To evaluate colectomy rate at discharge and 1 year post admission Method: Incident cases of IBD were prospectively identified in 2007– in treatment naïve versus treatment experienced patients with ASUC. 2008 and 2010–2013 from multiple health care providers and enrolled into Method: Data was collected prospectively on 196 patients admitted to the population-based registry. Health care resource utilization for each the Royal Brisbane and Women’s hospital from Jan 1996 – May 2014 with patient was collected through active surveillance of case notes and cost of a first presentation of ASUC meeting Truelove and Witt’s criteria. Patients all investigations, specialist visits, diagnostic tests, medications, medical were divided into 3 groups for analysis: Treatment naïve, oral steroid and hospitalizations, and surgery. immunomodulator. Patients received intravenous hydrocortisone for 3 days Results: 252 of 276 incident cases of IBD (91%) were recruited to the followed by rescue therapy with infliximab or ciclosporin if they failed registry, and health care cost was calculated for 242 (146 Crohn’s disease, initial therapy and underwent colectomy if refractory to maximal medical CD, and 96 Ulcerative colitis, UC). The median cost in CD was higher at therapy or developed toxic mega colon or perforation. Clinical, biochemi- A$5905 per patient (Inter-quartile range (IQR): A$1571- $91,324), than in cal, endoscopic and colectomy data were recorded and analysed up to at UC A$4752 (IQR: A$1488- A$58,072), p = 0.003. The majority of cost in least 1 year. both groups stemmed from outpatient rather than inpatient resources (55% Results: Eighty eight (44.9 %) patients were treatment naïve on admis- and 71% of total CD and UC cost, respectively). Medication was the most sion with a colectomy rate of 29.5 % (26/88) at discharge and 36 % (32/88) expensive resource (32% and 39% of CD and UC cost, respectively). In at 1 year. Sixty three patients (32.1%) were on oral steroids alone at CD, high medication cost is driven equally by 5ASA(aminosalicylates) presentation with a colectomy rate of 40 % (25/63) at discharge and 49 % (49%) and biological therapy (50%). In UC, over 90% of medication cost (31/63) at 1 year. Oral steroids on admission was associated with a higher is due to 5ASA’s. Surgery followed closely in CD (31% of total cost), see colectomy rate at 1 year compared with steroid naïve patients (p = 0.027). Figure 1. High cost outliers were identified; in CD 11% of patients Forty five patients (23 %) were on an immunomodulator on admission accounted for 42% of total cost, and in UC 10% accounted for 36% of total with a colectomy rate of 28.9 % (13/45) at discharge and 48.9 % (22/45) cost. These patients contribute to the right skew in the distribution of cost at 1 year which was not statistically significant compared with among the cohort. Clinical predictors at diagnosis of high cost included immunomodulator naïve patients (p = 0.83). ileocolonic, stricturing and penetrating phenotype in CD, and extensive Conclusion: Patients on oral corticosteroids at the time admission with colitis as well as an elevated CRP in UC. ASUC have a higher late colectomy rate than those who are naïve to Conclusion: In the first year of diagnosis, outpatient resources account steroids. Immunomodulator therapy on admission was not associated with for the majority of cost in both CD and UC. Medications are the main cost an increased risk of colectomy. Patients on oral steroids at presentation driver in IBD. should be considered a particularly high risk subgroup and a low threshold for early rescue therapy and intensive post discharge immunosuppression should be pursued to try and reduce the long term chance of colectomy.

Medication non-adherence in inflammatory bowel diseases is significantly associated with disability J PERRY,1 A CHEN,2 G COLLINS,3 J CHANG,2,3 F KOHLER,2 RW LEONG1,2,3 1Faculty of Medicine, Sydney University, Sydney, Australia, Figure 1 The distribution of costs in Crohn’s Disease and Ulcer- 2Faculty of Medicine, University of New South Wales, ative Colitis in the first year of disease. KEY: Hospital- medical Sydney, Australia, 3Concord Repatriation Hospital, admissions. Surgery-including surgical admissions. Diag- diagnos- Gastroenterology and Liver Services, Sydney, Australia tic test. Meds-medications. O/pt- specialist outpatient reviews. Background: Adherence to therapy in inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) is critical to the

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 135 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease effective maintenance of remission, prevention of disease progression, Case Study: The patient was diagnosed with very early onset inflamma- development of disease complications and moderation of symptoms. Poor tory bowel disease at 5 years old with the background of several atopic adherence may drive ongoing IBD activity resulting in disability, which is diseases. At presentation he had peri-oral disease consistent with oral facial defined as objective impairment, activity limitation, and participation granulomatosis, whereas his gut disease was relatively mild with anal restriction. The IBD Disability Index score has recently been validated as fissures, microscopic colitis and no upper gastrointestinal tract involve- a consistent measure of functional disability or wellbeing. Whether non- ment. Over the next 3 years, his colonic disease worsened and was recal- adherence to IBD therapy is associated with functional losses and disabil- citrant to medical treatments including sulfasalazine, prednisolone, ity has never been elucidated. azathioprine, methotrexate, infliximab and tacrolimus. Eventually he had Aims: To examine the relationship between non-adherence to medication diversion ileostomy. Post operatively, despite exclusive enteral nutrition, therapy and functional outcomes in IBD patients. The impact of patient cyclosporine and adalimumab, he continued to be symptomatic mainly specific demographic, clinical and attitudinal factors will be assessed to with peri-oral disease. determine whether any of these are significant predictors of adherence or At 13 years old, he was investigated for several months’ history of a disability. nocturnal dry cough and hoarseness. Consultation with a respiratory phy- Methods: Patients were recruited from the IBD clinic of an Australian sician and investigations including chest X-ray and spirometry did not tertiary hospital and administered three validated questionnaires. Medica- reveal the cause of his symptoms. ENT nasendoscopy examination of the tion Adherence Rating Scale (MARS) which measured non-adherence larynx revealed marked swelling of the tissues adjacent to the supraglottic (defined as score <17), Inflammatory Bowel Disease Disability Index and hypopharyngeal region and ulceration of the pharyngeal mucosa. He (IBD-DI) which assessed functional outcomes of their illness and the underwent microlaryngoscopy, biopsy and right supraglottoplasty along Beliefs about Medicines Questionnaire (BMQ) which characterises atti- with upper oesophagoscopy. Microlaryngoscopy showed bulky, thickened tudes regarding the ‘necessity’ of taking therapy and ‘concerns’ regarding and indurated arytenoids, supra-arytenoid mucosa and epiglottis, com- their use. A high ‘necessity’(>15) and low ‘concerns’(<15) score is defined pletely obstructing the view of the vocal cords. Circumferential oesopha- as ‘acceptance’ of therapy by the patient. Chi square, Mann Whitney U and geal ulceration was also noted during the same procedure. Histopathology logistic regression statistical analyses were performed using SPSS. showed chronic inflammation with granuloma formation in the arytenoids Results: In total 100 patients were recruited of whom 22% were classi- and epiglottis consistent with extraintestinal CD. fied as non-adherent. Patient mean age was 41 (SD: 14.8) and 53% were The patient also had symptoms suggestive of obstructive sleep apnoea with females. There were 63 CD and 37 UC cases. 28% have had exposure to snoring, drooling during sleep and excessive daytime fatigue. biological agents and 27% have had previous surgery. All respondents Polysomnography revealed severe obstructive sleep apnoea, with an completed all three assessments. Disability was strongly correlated with apnoea/hypopnoea index of 16.2 that rose to 63.5 in REM sleep. He also medication non-adherence (r = 0.366, median difference of IBD- demonstrated an elevated arousal index of 28.6 with multiple desaturations DI = 13.5, P < 0.01). Non-adherence was associated with rectal bleeding to 82%. (OR: 6.3, 95% CI: 2.3–17.5, P = 0.04), arthralgia (OR: 4.9, 95% CI: Following the diagnosis of otolaryngeal CD, the patient was commenced 1.64–14.71, P = 0.03) and difficulty regulating bowel movements (OR: on prednisolone and azathioprine in addition to his regular adalimumab 7.6, 95% CI: 2.34–24.40, P = 0.01). Patients perceiving mild or no maintenance therapy; sleep apnoea was managed with nocturnal CPAP. improvement from medications were more likely to be non-adherent (OR: Adalimumab and azathioprine levels were monitored and optimized. Pred- 5.6, 95% CI: 1.97–16.1, P < 0.01). High ‘concerns’ over medications nisolone doses were titrated according to monthly flexible nasendoscopic (P < 0.01) and female gender (P < 0.01) were independent predictors of findings (see Figure 1). He was successfully weaned off prednisolone by poorer functional outcomes. Shorter duration of illness (P < 0.01) and one year and remained on combination therapy with adalimumab and perceived ‘acceptance’ of therapy (P < 0.01) were predictors of adherence azathioprine. however did not impact upon IBD-DI on regression analysis. Conclusion: Ortolaryngeal CD causing obstructive sleep apnoea is Conclusions: This is the first study demonstrating that poor adherence to extremely rare. This case highlights the importance of a multidisciplinary IBD medications is significantly associated with impaired functional out- approach in the management of ortolaryngeal CD. The ease of repeated comes and disability. Non-adherence may result in disease progression and nasendoscopy examinations enables titration of medications to achieve development of complications that result in disability. Targeted interven- (ortolaryngeal) mucosal healing. tions need to be developed that focus on the identified risk factors of high ‘concern’ and low ‘acceptance’ of therapy. Screening questionnaires such as the BMQ and MARS should be adopted in clinical practice to identify non-adherers that are at high risk for poor functional outcomes.

Obstructive sleep apnoea in a paediatric patient with otolaryngeal Crohn’s disease T PERVEZ,1 CH LEE,2 C SETON,2 M RAFTOPULOS,2 C BIRMAN,2 EV O’LOUGHLIN2 1Nepean Hospital, Sydney, Australia, 2The Children’s Figure 1. Nasendoscopy view of the inflamed supraglottic region post Hospital Westmead, Sydney, Australia supraglottoplasty. Background: Extraintestinal Crohn’s disease (CD) involving the airway is a rare phenomenon. We report a case of extraintestinal CD involving the supraglottic and hypopharyngeal regions leading to obstructive sleep apnoea in a child.

136 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Associations between oral contraceptive pill Differences in clinical course, treatment and use and inflammatory bowel disease in an outcomes in elderly patients with inflammatory Australian cohort bowel disease S SANAGAPALLI,1,2 Y KO,1 S GOPIKRISHNA,2 S SANAGAPALLI,1,2 P WIDANA PATHIRANA,1,2 R LEONG1,3 R LEONG1,3 1Gastroenterology & Liver Services, Concord Repatriation 1Gastroenterology & Liver Services, Concord Repatriation General Hospital, Sydney, Australia, 2University of New General Hospital, Sydney, Australia, 2University of New South Wales, Sydney, Australia, 3University of Sydney, South Wales, Sydney, Australia, 3University of Sydney, Sydney, Australia Sydney, Australia Background and Aims: An association between oral contraceptive pill Background: Previous studies have not consistently found major differ- (OCP) use and the risk of developing inflammatory bowel disease (IBD) ences in the clinical course of IBD in elderly patients compared with has been suggested in previous overseas studies, and the purported link has younger adults. However, none distinguished between elderly-onset received significant media attention recently. In February 2015, the Aus- patients and those elderly patients with longstanding IBD; we hypothesised tralian Therapeutic Goods Administration announced a proposal to that these two groups would behave differently. Our study therefore aimed mandate that the association with IBD be declared on the Product Infor- to compare differences in disease phenotype, outcomes and treatment in mation sheet for all OCPs. In light of this, we sought to determine if such IBD patients based on age at diagnosis as well as duration of disease. an association held true in an Australian cohort, and to compare it to other Methods: A retrospective cohort study using patients recruited from both risk factors for IBD. tertiary hospitals and private consulting rooms was conducted. The diag- Methods: A case-control study using a cohort of patients from the nosis of IBD was confirmed by review of clinical, endoscopic and patho- Sydney area was performed. Consecutive IBD cases (confirmed by logic findings. Patients were categorised into 3 groups: those diagnosed medical records) were recruited. Age and sex matched non-IBD controls from 18 to 40 years of age were classified as ‘young-onset’ (YO); patients from the same community were randomly recruited. A validated, face-to- diagnosed at age 60 or older were defined as ‘elderly-onset’ (EO); a third face questionnaire was used to determine the nature of exposure to a group of patients diagnosed prior to age 60 but were older than 60 years at number of environmental variables. Statistical analysis was performed most recent follow-up was classified as ‘long-standing’ (LS). with SPSS for Mac version 23.0. Results: 1342 patients were included. These were distributed into: 268 Results: 316 IBD cases (168 CD, 148 UC) and 479 controls were EO (119 CD, 149 UC), 433 LS (157 CD, 276 UC) and 641 YO (332 CD, included. 12 IBD cases were excluded as OCP was used only after the 309 UC). Groups were well matched in terms of sex and follow up duration diagnosis of IBD. IBD cases and controls were well matched in terms of (measured post age 60 in the LS group) and differed in median age at clinical and demographic characteristics. OCP use was associated with the diagnosis (28 y in YO, 67 y in EO, 44 y in LS, p < 0.001). development of IBD, with 45.0% of OCP users in the cohort having IBD, The 3 groups had different disease phenotypes. In CD, EO patients more = = versus 33.3% of never users (p 0.025, OR 1.63, 95% CI: 1.06–2.51). often had colonic phenotype (59.0%), and had higher rates of this com- The association also held true for Crohn’s disease, with 31.7% of OCP pared with YO (32.5%, p < 0.001). YO had predominantly ileocolonic = users having the diagnosis of CD versus 20.2% of never users (p 0.022, phenotype (41.4%) and had higher rates of this compared with in EO OR 1.84, 95% CI: 1.09–3.11); the association did not reach significance for (25.6%, p < 0001). LS patients were intermediate between the other UC (OR 1.42, 95% CI: 0.81–2.50). On multivariate analysis using logistic groups, having predominantly colonic phenotype but less so compared regression, the association between OCP use and IBD was no longer with EO (41.0 vs 56.0%, p = 0.001). Perianal CD was significantly more significant, while other factors showed far stronger associations (Table 1). common inYO versus EO patients: present in 13.7%, 16.0% (p = 0.59) and Of note, breastfeeding was found to be protective against the development 22.6% (p = 0.04) of EO, LS and YO patients respectively. of IBD. Of OCP users, the mean duration of use was not significantly YO patients had more progression of disease compared to both elderly different in IBD cases compared to controls (7.4 versus 8.7 years; groups. In CD, disease localisation remained stable in 96.6% of EO patients = p 0.605). For the same group, age of first OCP use was no different in and 98.1% of LS patients (p = 0.45), but only in 85.5% of YO patients = IBD cases versus controls (19.9 years versus 21.4 years, p 0.18). (p = 0.001). In UC, localisation progressed in 8.1% of EO and only in 2.5% Conclusions: The use of OCP had a significant association with the (p = 0.009) of LS patients, but progressed in 21.7% (p < 0.001) of YO. diagnosis of Crohn’s disease only and not ulcerative colitis. However the Medication use was more conservative in EO patients compared with both effect size was small, and less than that seen with other environmental other groups. 5-ASAs were the most commonly used drug overall; usage factors. Neither the duration nor age of first OCP use had a significant rates were similar in all groups. In CD, immunomodulators were used less association with diagnosis of IBD. The protective effect of breastfeeding often in both older groups (47.5% in EO and 48.6% in LS) compared with observed suggests hormonal factors may be involved. YO (70.5%, p < 0.001). Anti-TNF therapies were used infrequently in EO (7.8%) compared with both YO (23.2%) and LS (20.5%) groups Table 1: (p = 0.005). In UC, immunomodulators were used infrequently in EO (14.9%), compared with both YO (33.7%) and LS (27.0%) groups Risk factor OR 95% CI p-value (p = 0.002). Anti-TNF use for UC was low in all groups without a signifi- Family history of IBD 11.4 4.9–26.7 0.000 cant difference being observed. Breastfed in infancy 0.389 0.21–0.71 0.002 In CD, EO patients were less likely to have surgery than YO patients Antibiotics in childhood 2.40 1.38–4.19 0.002 (33.9% vs. 43.4%, p = 0.02); LS patients were even less likely to (18.7%, = Smoking 1.44 0.87–2.36 0.16 p 0.004). YO patients had a higher rate of multiple surgeries than the OCP use 1.22 0.71–2.08 0.475 other groups. Surgery rates in UC were lower, and there was no significant difference in the rates between the 3 groups. Conclusion: We found 2 distinct subtypes of elderly patients with IBD – those developing IBD at an older age, and those who have aged with IBD. These groups had distinct differences in disease phenotype, rate of pro- gression, and also in their management compared with each other and also with young-onset patients.

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 137 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

High prevalence of perianal Crohn’s disease in and smoking cessation. We aimed to characterise the uptake of existing patients of Indian ancestry preventative health measures in IBD patients attending a metropolitan M SANDHU, F YEAMAN, G MOORE teaching hospital in order to identify factors that may limit the uptake of Department of Gastroenterology, Monash Health, such measures. Melbourne, Victoria, Australia Methods: A retrospective audit of IBD outpatient clinic records together with a prospective cross-sectional survey were undertaken. The retrospec- Background: Inflammatory bowel disease (IBD) has traditionally been tive audit focused on past serological screening results as an indicator of thought to be uncommon in patients of Indian subcontinent ancestry, vaccination status. The prospective cross-sectional survey of patients however, recently, an increased incidence has been observed, particularly attending the IBD clinic in March-May 2015 focused on the past experi- with Westernisation of lifestyles and migration. There is limited data on the ence and current attitudes of patients towards preventative health measures. phenotype of Crohn’s Disease (CD) in this population. We therefore per- Chi-squared and logistic regression analysis were used to determine factors formed a retrospective analysis to compare the difference in demographics, that affected uptake rates. CD location [Montreal Classification: L1 (ileal) L2 (colonic) and L3 (ileo- Results: The retrospective study identified 441 patients of whom less colonic disease)] and the prevalence of perianal CD in patients of Indian than 50% had previous serological screening tests. 41% (62/150), 44% ancestry compared with Caucasian patients. (102/230) and 93% (113/121) of patients tested were protected against Methods: Patients on biologic therapy for CD were identified through hepatitis A, hepatitis B, and varicella zoster respectively. The prospective our IBD database. Information on demographics, disease presentation study surveyed 100 outpatients (73% of whom were taking immunosup- (including perianal disease) and disease behaviour were obtained from pressive medications). Despite 71% of patients regarding vaccination as medical records. Patients were then stratified based on ethnicity: Cauca- important, self-reported vaccination rates ranged between 19% (pneumo- sian, Indian ancestry, East Asian, Middle Eastern, Mediterranean and other. nia vaccine) and 64% (flu vaccine). Serological screening and vaccination Patients’ demographics and CD behaviour were analysed retrospectively were recommended by treating clinicians in less than 50% of cases. Com- and the prevalence of perianal disease was determined in each group. pared to no recommendation, patients were more likely to have their Analysis was performed using Chi squared and Mann Whitney testing. hepatitis A (p < 0.01) and hepatitis B vaccinations (P = 0.02) if this was Results: Of the 144 patients with CD on biologic therapy with complete recommended by their gastroenterologist. However, this was not observed data that were identified, 118 (82%) patients were Caucasians and 17 for influenza (p > 0.05) and varicella zoster vaccines (p > 0.05). Similarly, (12%) patients were of Indian ancestry. The remaining were Middle patients were more likely to have their hepatitis A vaccination (p = 0.01) if Eastern (6 patients), Mediterranean (2 patients) and East Asian (1 patient). this was recommended by their general practitioner. In contrast, attitudes The majority of patients of Indian ancestry were born in Australia (8 about vaccines cost, efficacy, perceived side effects and its impact on patients) and India (4 patients). The remaining were from Sri Lanka (2 disease activity did not significantly affect the uptake rates of any vaccine patients), Fiji (2 patients) and England (1 patient). The majority of patients (p > 0.05). In addition, 33% and 7% of Crohn’s disease and ulcerative of Indian ancestry were males compared to Caucasian patients (14 patients colitis patients were current smokers respectively. Only 63% (27/41) of (82%) vs 62 patients (53%), respectively; p 0.03). The median age of smokers and ex-smokers were given verbal advice to stop smoking and of disease onset in patients of Indian ancestry was 28 years (IQR 16:32 years) these, 42% (11/27) were successful. A minority 19% (8/41) had been and 20 years (IQR 14:27 years) in Caucasian patients (p value 0.3). A referred to a formal QUIT program. Dual-energy X-ray absorptiometry higher proportion of patients of Indian ancestry had perianal disease com- (DEXA) and skin cancer screening were performed in 55% and 14% of the pared to Caucasian patients (11(65%) vs 38 (32%), respectively; p value patients respectively. Paradoxically, bone mineral density screening rate 0.01). There were more Caucasian patients with L3 disease compared to was significantly lower in patients currently taking oral steroids than those patients of Indian ancestry (62% vs 35% respectively; p value 0.12). The who did not (p = 0.04). Pap smears were performed in 74% (33/46) of proportion of Caucasian patients with L1 and L2 disease was 16% and 22% female patients. Compared to no recommendation, uptake of DEXAs and respectively. The proportion of Indian ancestry patients with L1 and L2 pap smears were higher if it was recommended by gastroenterologists disease was 24% and 35% respectively. (DEXA, p < 0.01) and general practitioners (DEXA, p = 0.02; Pap smear, Conclusion: In this small population of Crohn’s patients on biologic p < 0.01). therapy, there was a high incidence of perianal Crohn’s Disease in the Conclusion: This study reinforces that current preventative health prac- patients of Indian ancestry. This need to be confirmed in wider population tices in IBD is suboptimal. Vaccination rates, smoking cessation, bone based studies but may suggest different genetic or environmental influ- density and skin cancer screening were inadequate. Physician input ences specific to this ethnicity. appeared to be important in the uptake of preventive health measures by patients. Strategies to improve the uptake of such preventive health mea- sures are required. Better than cure: improving preventative health measures for patients with inflammatory bowel disease Efficacy of vedolizumab as induction therapy in YT SHAO,1,2 S GRANT,3 T CATO,3 K MARION,3 refractory IBD patients: a multicentre cohort P DE CRUZ,1,2 C LEUNG1,2 E SHELTON,1,2 J ALLEGRETTI,2,3 B STEVENS,1 1Melbourne Medical School, The University of Melbourne, M LUCCI,3 A ANANTHAKRISHNAN,1,2 V YAJNIK1,2 Melbourne, Australia, 2Department of Gastroenterology, 1Division of Gastroenterology, Massachusetts General Austin Health, Melbourne, Australia, 3School of Hospital, Boston, MA, 2Harvard Medical School, Boston, Mathematical and Geospatial Sciences, RMIT University, MA, 3Division of Gastroenterology, Brigham and Women’s Melbourne, Australia Hospital, Boston, MA Background and Aims: Preventative health measures are an integral Background: Vedolizumab (VDZ), an α4β7 integrin inhibitor, aspect of chronic disease management yet previous studies have suggested demonstrated efficacy in Crohn’s disease (CD) and ulcerative colitis that the uptake of such strategies in patients with inflammatory bowel (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at disease (IBD) is suboptimal. Such measures include vaccination against week 14 in inflammatory bowel disease (IBD) in a multicentre cohort of opportunistic infections, bone mineral density and skin cancer screening, patients.

138 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Methods: Patients at two academic referral hospitals in Boston were Methods: A retrospective review of case-notes of patients undergoing considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6 treatment with Ipilimumab and anti PD-1 therapy from 2009–2015 was and 14. Efficacy was assessed using the Harvey Bradshaw index (HBI) for conducted across two tertiary referral facilities, Westmead Hospital and the CD, the simple clinical colitis activity index (SCCAI) for UC and physi- Melanoma Institute Australia. Multiple variables related to the develop- cian assessment, along with C-reactive protein (CRP) and decrease of ment of colitis, doses of immunotherapy, time from therapy to colitis and corticosteroid therapy. Clinical response was defined as decrease in treatment of colitis were documented. Patients received treatment with HBI ≥ 3 and SCCAI ≥ 3 and remission HBI ≤ 4 and SCCAI ≤ 4 and phy- steroid alone or steroids plus infliximab. Symptom resolution was defined sician assessment of response and remission. no episodes of diarrhea as per patient survey on follow up. Statistical Results: Our study included 172 patients (107 CD, 59 UC, 6 IBD-U, analysis was with SPSS version 23 using t-test analysis. male 48%, mean age 40.0 years and disease duration 14.0 years). Fourteen Results: 19 patients (11 male, 8 female) developed IRC. Mean age of patients had an end ostomy and 9 an ileoanal pouch. Only 35.5% of onset was 62 years (41–83 yrs). Of these, 16 received treatment with patients in our study would have been eligible to participate in the GEMINI Ipilimumab (15 melanoma, 1 renal cell carcinoma) while three received studies. Previous treatment failures with ≥2 anti-TNFs occurred in 70.9%, anti PD-1 therapy alone (2 melanoma, 1 lung cancer). 17 patients had one-third were on an immunomodulator and 46% systemic steroids at documented endoscopic and histopathological evidence of colitis. All baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had patients received high dose steroid either as intravenous, oral (1–2 mg/kg) clinical response and clinical remission at week 14. (Figure 1) Elevated or combination. baseline CRP was negatively associated with week 14 response/remission. 14/16 patients treated with Ipilimumab were documented to have mild- Adverse events occurred in 9.9%. moderately active disease, with a mean Mayo Endoscopic Score of 1.78 Conclusions: In refractory IBD patients in clinical practice VDZ is safe (0–3) with presence of cryptitis, crypt abscesses and lymphocytic infiltra- and well tolerated with efficacy in both UC and CD with responses similar tion on histopathology. Colitis was predominantly limited to distal colon to what was seen in clinical trials. (proctitis n = 4, left colon n = 7, pancoltis n = 2, R. sided n = 1). Mean onset of colitis from first dose of Ipilimumab was 72 days (8–146 days). 10 patients received high dose steroid therapy only, while 9 patients, with persistent symptoms despite steroid therapy received further treatment with infliximab, as per physician discretion. The mean time to resolution for those treated with corticosteroids only was 61 days whereas those treated with corticosteroids then infliximab was 12 days from the initiation of rescue therapy (p = 0.0873). Of the 16 patient’s treated with Ipilimumab it was noted three patients developed colitis upon being changed rapidly from Ipilimumab to PD-1 therapy (2–26 days). These were though unlikely to be attributable to the addition of PD-1 therapy, given the timing of symptom onset. Three patient’s developed IRC while being treated with anti-PD-1 monotherapy. Anti PD-1 associated IRC, was limited to a L. sided colitis, and were recorded to have Mayo Endoscopy scores of 1,1 and 1 respectively consistent with mild disease. In this group two patients had symptom resolution with steroid therapy alone with one patient Figure 1: Efficacy of vedolizumab at week 14 in Crohn’s disease and requiring rescue therapy with infliximab. The mean time to resolution of symptoms for treatment with steroids only was 36 days, while the mean ulcerative colitis time to resolution after initiation of rescue therapy was also noted to be 36 days. Infliximab for the treatment of Ipilimumab (anti Conclusions / Discussion: Immunotherapy-related colitis is an impor- CTLA-4) and Nivolumab/Pembrolizumab (anti tant emerging clinical entity and has clinical and histologic similarities to PD-1) associated colitis idiopathic inflammatory bowel disease. Infliximab appears to induce M SIDHU,1 T MERSAIDES,2 E LINIKER,3 D TATE,1 earlier resolution of symptoms in patient’s refractory to steroid treatment, and this result trends towards significance. Future research implications G LONG,3 A NAGRIAL,2 V KARIYAWASAM,4 include immune-pathogenic analysis of IRC to improve insight into the 5 2 2 N SANDANYAKE, R KEFFORD, M CARLINO, pathogenesis of idiopathic inflammatory bowel disease. VKWAN1 1Department of Gastroenterology, Westmead Hospital, 2Crown Princess Mary Cancer Institute, Westmead Inflammatory bowel disease phenotype and Hospital, 3Melanoma Institute Australia, 4Department of disease course in Middle Eastern and Caucasian Gastroenterology, Blacktown Hospital, 5Department of patients Gastroenterology, Royal North Shore Hospital THOMAS A, LEONG R, BUTCHER O, RAHME N, SAMUEL D, ALRUBAIE A, MEREDITH C, Introduction: Immunotherapy with anti CTLA-4 (Ipilimumab) or anti REDMOND D. PD-1 (Pembrolizumab, Nivolumab) antibodies are now the standard of Gastroenterology Department, Bankstown-Lidcombe care for metastatic melanoma and other malignancies. These drugs have Hospital, Bankstown been associated with various immune related adverse events, including autoimmune colitis with marked similarity to idiopathic inflammatory Background and Aims: The impact of ethnicity on inflammatory bowel bowel disease. Current literature regarding immunotherapy related colitis disease (IBD) phenotype and disease course is understudied. Anecdotally, (IRC) are scarce and very little treatment-related data exist. patients of Middle Eastern descent have more aggressive cases of IBD with Aims: To describe the clinical spectrum of immunotherapy-related greater treatment requirements and earlier need for surgery. Our aim was to colitis (IRC) and treatment response to systemic steroids alone or a com- compare the phenotype and disease course in Middle Eastern patients and bination of systemic steroids and infliximab therapy. age and sex-matched Caucasians.

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 139 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Methods: We conducted a multi-centre, retrospective case-control study comparing disease characteristics and treatment outcomes of both 250 Middle Eastern IBD patients and 250 Caucasian controls. Outcomes of interest were disease phenotype for Crohn’s disease (CD) and ulcerative colitis (UC), medical management (steroids at present- ation, 5-ASA, immunomodulator, anti-TNF, and surgery (resection, peri- anal). The Middle Eastern cohort was further subdivided into second gen- eration or first generation. Outcomes were presented as survival curves and log rank score, Chi square and Mann Whitney score for statistical significance. Results: 250 Middle Easterners and 250 Caucasian age and sex-matched Results: Patients were followed up for a median for 4 months. The controls were recruited. No statistical difference was seen between their median baseline CDAI at baseline was 330 and the median end CDAI was age at diagnosis (26.0 vs 26.0, p = 0.30) or their disease duration (7.0 years 119 with a median change in CDAI 215. CRP was elevated at baseline in vs 7.5 years, p = 0.33). Middle Easterners were more likely to have a 50% patients and there was a significant decrease at the end of treatment to family history of IBD (31.5% vs 15.6%, p < 0.005) and more likely to be 5% of the cohort . On baseline MREs, 74% patients had strictures (6% current smokers (24.5% vs 13.0%. p = 0.003). Similar phenotype in CD fibrous, 13% inflammatory and 55% mixed), 47% patients (n = 13) had location and behaviour were observed (stricturing, penetrating, non- fistulising disease and 87% had CE on MRE. The degree of severity of CE stricturing or penetrating p = 0.22). Perianal disease was more common in is shown on the graph. the Middle Eastern population (59% vs 42%, p = 0.04). There was no On CDAI criteria, 73% (n = 22) patients responded to Infliximab and 47% difference in incidence of change of disease location or behaviour were (n = 14) achieved clinical remission. Those who failed to respond had seen between the two groups. Middle Easterners were more likely to severe stricturing disease at baseline: 1 patient had fibrous strictures and 2 require steroids (90.2% vs 73.2%, p = 0.0005) and more likely to receive had mixed fibrous and inflammatory strictures. methotrexate (14.7% vs 5.6%, p = 0.01). Use of thiopurines, anti-TNF and There was a significant correlation between baseline CDAI score and rates of surgery was similar. length of bowel involved (p = 0.03), contrast enhancement (p = 0.025), Conclusion: Smoking is significantly common in the Middle Eastern wall thickness (p = 0.03) and mural oedema (P < 0.0005). CRP correlated population and may be responsible for some indicators of increased disease with mural oedema (P < 0.005) but did not correlate significantly with the activity including increased perianal disease, use of methotrexate and other MRE parameters studied. There was no significant correlation steroids. In contrast to anecdotal impression of increased complications, between CDAI and CRP. our study demonstrated no significant increase in need for surgery or Conclusions: Our results support that Infliximab is an effective treat- disease progression. ment for CD even in a cohort of patients with moderate-severe disease at baseline. The correlation between CDAI and MRE findings is significant supporting the validity of the CDAI as a measure of active disease. In our Magnetic resonance enterography in Crohn’s experience, stricturing disease assessed as including a fibrotic component disease: Relationship between imaging, disease on MRE may be a predictor of poor response to Infliximab but larger activity and response to Infliximab studies are needed to further investigate the association. Z VALAYDON,1 Z KHAN,1 K MARION,2 D STELLA,1 F MACRAE1 1Department of Gastroenterology, Royal Melbourne Immunomodulators provide no reduction in loss Hospital, 2RMIT University, Melbourne of response for inflammatory bowel disease patients starting anti-TNF-alpha therapy Background: Magnetic resonance enterography (MRE) is a valuable P VARMA, F YEAMAN, D HOLT, G MOORE tool in the evaluation of Crohn’s disease (CD) especially to examine the Department of Gastroenterology, Monash Health, Clayton, extent and severity of disease in the small bowel. MRE could potentially Victoria, Australia also be useful to stratify risk and response to treatment. Infliximab has revolutionized the treatment of CD. However response rates are only Aims: In Inflammatory Bowel Disease (IBD), large registration studies approximately 65%, and it is expensive. Currently there are no reliable have not shown a significant difference in clinical endpoints in patients predictors of response that may help rationalize its use. treated with anti-tumour necrosis factor alpha (anti-TNF) monoclonal anti- Objective: To determine the MRE features that correlate with disease body alone versus with immunomodulator co-therapy, however from recent severity and predict the response to Infliximab in CD. data, there is a trend towards co-therapy to reduce immunogenicity to Study design: 30 patients with CD were recruited. The diagnosis of CD anti-TNFs. Given the risks of immunomodulators, particularly thiopurines, was confirmed on colonoscopy and by histology for all patients. At base- we queried the long-term therapeutic benefits of immunomodulator line, disease activity was assessed by the Crohn’s Disease Activity Index co-therapy. Our aim was to assess whether anti-TNF monotherapy was (CDAI), C-reactive protein (CRP) levels and an MRE. Patients were the associated with earlier loss of response (LOR) in patients with Inflammatory treated with 3 Infliximab infusions at 5 mg/kg after which CRP, CDAI Bowel Disease (IBD) versus combination therapy in a real world cohort. assessment and MRE were repeated. An elevated CRP was defined as Methods: A retrospective audit was conducted of all patients with IBD CRP > 6. Response was defined as CDAI drop by 100 and remission was receiving anti-TNF therapy in a tertiary centre. All patients on anti-TNF defined as an end-CDAI < 150. MRE were performed and reported by therapy with an accurate date for TNF commencement and adequate cor- two independent, blinded radiologists. The following MRE parameters respondence to determine end-points were included. Patients with prior were studied: Number and length of inflamed segments of bowel, exposure to any anti-TNF agent were excluded. Outcomes measured Number of strictures, contrast enhancement (CE), mural oedema, bowel included weight and body mass indices pre and post anti-TNF and days to wall thickening, regional lymphadenopathy, fistulae and strictures. Stric- first loss of response; defined by an admission or surgery post-induction, tures were categorised as fibrotic, inflammatory or mixed and contrast escalation of TNF dose or concurrent immunomodulators for clinical LOR, enhancement was graded 0–5 to ensure internal consistency in the report- emergence of a new fistula or rising Crohn’s Disease Activity Index > 150 ing of MREs. (CDAI). Statistical analysis was performed with GraphPad Prism v6.

140 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Results: A total of 94 patients were included for analysis; 53 induced (343 ± 470 pg/ml) was significantly elevated compared with 16 age- with Infliximab (IFX) and 41 induced with Adalimumab (ADA). 91 matched healthy individuals (p = 0.002). Baseline faecal OPG levels were patients were treated for Crohn’s Disease and 3 patients treated for correlated with CRP (p = 0.004), IGF-1 (p = 0.011) and Crohn’s disease Ulcerative Colitis. 81 patients received co-therapy and 13 patients activity index (p = 0.018). Thirteen patients completed EEN, 12 had a received monotherapy. 42 (45%) patients had loss of response during positive response and OPG significantly reduced (p = 0.008) to levels follow-up; 23 (55%) IFX patients and 19 (45%) ADA patients (p = ns). observed in healthy controls (Figure 1). Upon reintroduction of usual diet Causes for LOR included hospital admission (n = 13, 31%), clinical LOR faecal OPG increased significantly (p = 0.018) to levels not significantly (n = 21, 50%), surgery (n = 6, 14%) or new fistula (n = 2, 5%). The different from baseline (Figure 1). median time to loss of response in patients with concomitant Conclusion: Faecal OPG is elevated in adults with active Crohn’s immunomodulator therapy was 1027 days, compared to 980 days in disease and is correlated with existing disease activity measures. Faecal patients treated with anti-TNF monotherapy. (p = 0.78) (Figure 1) There OPG normalises during treatment with EEN. was no difference between the type of immunomodulator co-therapy and time to loss of response. There was no correlation between baseline p = 0.008 CDAI or body mass index and time to loss of response. Baseline hae- 2000 moglobin, albumin and C-reactive protein were no different between 1000 p = 0.018 those who experienced loss of response and those who did not. No dif- ference was found in the type of anti-TNF agent used and time to loss of 800 response. 600 400

100 OPG (pg/ml) 200 IM No IM 0

50 Baseline Treatment On usual completed diet

Percent survival Percent Figure 1. Change in osteoprotegerin during exclusive enteral nutrition (n = 13) 0 0 500 1000 1500 2000 Time

Figure 1: Survival in patients on anti-TNF monotherapy (no IM) versus Use and expenditure of biological drugs for combination therapy (IM), with standard error (broken line). Crohn’s disease and ulcerative colitis under the pharmaceutical benefits scheme (PBS) of Conclusion: In this Australian ambulatory specialist care setting, Australia patients treated with anti-TNF therapy had similar rates of loss of response LC WANG,2 G COLLINS,1 C CORTE,1 P KATELARIS,1 and outcomes, regardless of immunomodulator use, at both short-term and RW LEONG1 extended follow-up. 1Concord Repatriation Hospital, Gastroenterology and Liver Services, Sydney, Australia, 2Faculty of Medicine, Exclusive enteral nutrition alters Sydney University, Sydney, Australia faecal osteoprotegerin Introduction: Tumour necrosis factor (TNF) antagonists infliximab 1 2,3 1,4 C WALL, R GEARRY, ADAY (IFX) and adalimumab (ADA) successfully induce and maintain remission 1Department of Paediatrics, University of Otago, in refractory Crohn’s disease (CD) and ulcerative colitis (UC). Anti-TNF Christchurch, New Zealand, 2Department of Medicine, are associated with high costs and PBS has set a per annum cap. Analyses University of Otago, Christchurch, New Zealand, of the temporal trends and geographical distribution of anti-TNF usage and 3Department of Gastroenterology, Christchurch Hospital, costs may identify disequity in access to drug and ensure cost-containment New Zealand, 4Department of Paediatrics, Christchurch and sustainability of this drug class. Hospital, New Zealand Aims: to examine the Australian and state-based use and cost of IFX and ADA for treatment of luminal and fistulising CD and acute severe UC Introduction: The role of osteoprotegerin (OPG) in bone health is well under the PBS and RPBS over January 2007 to July 2014. characterised, however it is now known to also be involved in the inflam- Methods: Prospectively collected PBS data from January 2007 to July matory process. OPG has been proposed as a potential faecal biomarker of 2014 were analysed. Data contained monthly number of prescriptions and Crohn’s disease activity in children however faecal OPG in adults with expenditure for each PBS item code specific for disease indication and active Crohn’s disease has not been investigated. separated into Australian states and territories. Methods: Adults aged 16 – 40 years with active Crohn’s disease involv- Results: From 2007 to 2014, total of 167,213 prescriptions were ing the ileum were referred for an eight week treatment with exclusive made for combined CD and UC (IFX: 49,956; ADA: 117,257) with total enteral nutrition (EEN). Patients had blood tests and provided stool expenditure of $380 million (IFX: A$158 million; ADA: A$222 million; samples at baseline, fortnightly during treatment and three and six months Fig. 1). Drug expenditure increased linearly by a mean of $15 million after treatment initiation. Blood was tested for markers of inflammation every year. IFX annual prescription numbers increased 4-fold over the and nutrition. OPG was measured in stool using enzyme-linked study period whereas ADA by 6-fold. ADA prescription exceeded IFX immunosorbent assay. Faecal OPG was also measured in a healthy age- after Dec 2008 (Fig. 2) with expenditure rising from 51% (2008–2009) to matched cohort. 57% (2013–14) of total cost. A 4-fold increase in annual number of ADA Results: Twenty-four adults were referred for EEN. At baseline Crohn’s prescriptions for continuation treatment and a 5% increase for initiation disease activity index ranged from 39 to 498 and mean faecal OPG treatment.

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 141 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Southern latitude is associated with higher anti-tumour necrosis factor usage in Australia LC WANG,1 G COLLINS,2 C CORTE,2 P KATELARIS,2 RW LEONG2 1Faculty of Medicine, Sydney University, Sydney, Australia, 2Concord Repatriation Hospital, Gastroenterology and Liver Services, Sydney, Australia Introduction: Increasing latitude is associated with higher prevalence of inflammatory bowel diseases (IBD) in the northern hemisphere. Whether this is observed in the southern hemisphere is not known due to a lack of nationwide prevalence databases. The use of tumour necrosis factor (TNF) antagonists infliximab (IFX) and adalimumab (ADA) for Crohn’s disease (CD) and ulcerative colitis (UC) is governed by the national Pharmaceu- tical Benefits Scheme (PBS). Geographic trends of anti-TNF prescriptions under the PBS may identify any relationship between latitude and refrac- Figure 1. Moving annual total for IFX and ADA costs toriness to conventional treatment in Australia. Aims: to examine the association between geographical latitude and Australian state-based use and cost of IFX and ADA for the treatment of refractory luminal and fistulising CD and acute severe UC under PBS and RPBS over January 2007 to July 2014. Methods: Prospectively collected PBS data from January 2007 to July 2014 were analysed. Data contained monthly number of prescriptions and expenditure for each PBS item code specific for disease indication, sepa- rated into Australian states and territories and controlled for by the esti- mated IBD population. Correlations were made with latitude of the geographical centre, capital city and population centre for each of the 8 states and territories. State-based IBD population was obtained from Crohns and Colitis Australia. Results: From 2007 to 2014, a total of 167,213 prescriptions were made for combined refractory CD and UC (IFX: 49,956; ADA: 117,257). Marked geographical heterogeneity in anti-TNF usage was observed (Fig 1). Controlling for estimated IBD patient population, the most prescrip- Figure 2. Three-monthly prescription numbers for IFX and ADA tions were made in the southern states of Tasmania (TAS), Victoria, South Australia, with least prescriptions in Northern Territories (NT). Latitude strongly predicted for the annual anti-TNF prescriptions per IBD patient (R2 = 0.86; P = 0.001). Use of anti-TNF in TAS was 3.3-fold higher than in the NT. The annual prescription numbers per 1,000 IBD patients increased 25-fold for TAS and 4-fold for NT across the study period. The linear trend was most evident for luminal CD (R2 = 0.71) and fistulizing CD (0.78) than UC (0.43), but was irrespective of whether the latitude of the state geographical centre, capital city or population centre was used (Table 1a).

1200 TAS VIC 1000 SA 800 QLD Figure 3. Three-monthly number of prescriptions per 1,000 IBD 600 NSW patients for IFX and ADA across states and territories 400 WA ACT 200 Conclusion: Both IFX and ADA usage are increasing expontentially with ADA increasing more rapidly than IFX. Prescription numbers for 0 13 12 11 ADA continuation therapy is greater than initiating therapy and ADA pens Prescripons per 1000 IBD paents - - - -08 -09 -11 preferred over pre-filled syringes. Heterogenecity of biologic access was Jun-12 Jun-14 Jun Jun-09 Jun-13 Jun-08 Jun-10 Dec Dec Dec Dec Dec-07 Dec Dec-10 observed across Australian states and territories. Actual biologic usage and costs remain within PBAC predictions. Addition of new indications for Figure 1. Moving annual total of prescriptions per 1,000 IBD patients biologics did not lead to large escalations of use with persistent linear trend for IFX and ADA across states 2007–14 intact, supporting PBS sustainability.

142 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Intrapatient variability in adalimumab drug levels within and across cycles in patients with Crohn’s disease M WARD,1,2 L BESWICK,2 P THWAITES,1 J HOGG,1 G ROSELLA,1 J REYNOLDS,3 D VAN LANGENBERG,2 P GIBSON,1 M SPARROW1 1Department of Gastroenterology, Alfred Hospital, Melbourne, 2Department of Gastroenterology, Eastern Health, Melbourne, 3Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne Background: Therapeutic drug monitoring, (TDM) of infliximab, (IFX) and adalimumab (ADA) is utilized in the management of Crohn’s disease (CD). TDM is traditionally performed at trough, defined as the day of next Figure 2. Prescriptions per IBD patient for IFX and ADA against latitude scheduled dose. Whereas this is easy to perform with IFX, it is often of population centre of each state 2013–14 impractical with ADA which frequently mandates a return to the clinic for blood collection. We hypothesised that the narrow peak/trough 3.5 concentration-time profiles seen with ADA pharmacokinetics may corre- late with little intrapatient drug level variation, permitting TDM to be 3 y = 0.0933x - 0.6329 performed at other time points in a treatment cycle. R² = 0.8643 difference 2.5 Methods: Prospective observational pilot study of CD patients on main- tenance ADA (40 mg subcutaneous fortnightly) attending the outpatient Fold in prescripons 2 clinic of two centres. Concomitant immunomodulator dose was stable for 1.5 3 months. Patients were evaluated at day 4–6, (visit 1) day 7–9, (visit 2) and day 13–14, (trough) across two consecutive treatment cycles with 1 TDM (Matriks Biotek ELISA, Turkey). Patient characteristics (ADA deliv- 15 25 35 45 Latude (degrees south) ery device, concomitant immunomodulation) and disease activity (Harvey Bradshaw Index,(HBI) ≥ 5, CRP ≥ 3 ng/mL, FCP ≥ 150 μg/g defined as Figure 3. Fold difference in IFX and ADA prescription number (NT as 1) active disease) were recorded. ADA drug level (DL) < 4.9 μg/mL was against latitude of state geographical centres for 2013–14 defined as sub-therapeutic. Linear mixed model analyses of log- transformed DL were performed to investigate inter and intrapatient varia- Table 1a. Latitude in degrees south for geographic centre, capital city tion (within and between cycles). A recursive partitioning analysis was and population centre of states; 1b.R2 value for correlation between performed to determine the likelihood of a therapeutic trough DL based on DL at visits 1 and 2 and other covariates. each latitude value and prescriptions per IBD patient for 2007–14 and Results: 15 patients, (8 male) underwent 87 evaluations, (1 patient did 2013–14. not attend second cycle). Active disease was observed in 11/28 (39%) of 1a) Latitude (degrees south) visits as defined by FCP. Mean DL are shown in Table 1 and patient DL over time in Figure 1. 19/29 (66%) trough levels were sub-therapeutic. NSW VIC QLD SA WA TAS ACT NT There were no significant differences in mean DLs of paired visits across = Geographic 32.2 36.9 22.5 30.1 25.3 42.0 35.5 19.4 cycles, (p 0.69). DL did not significantly decline between visits 1 and 2, but declined 20% between visit 2 and trough (p < 0.05). There was no Capital city 33.9 37.8 27.5 34.9 32.0 42.9 35.3 12.5 difference in DL decline according to disease activity (elevated CRP, FCP Population 33.4 37.7 25.6 34.9 31.6 42.1 35.3 14.5 or HBI). DL ≥ 6.25 at visit 1 predicted therapeutic trough DL and 1b) Prescriptions per IBD Prescriptions per IBD DL < 4.87 predicted sub-therapeutic trough DL, both with 100% accuracy. patient (2007–14) patient (2013–14) DL between these values misclassified 2/10 cases (overall error rate = 6.9%). DL ≥ 6.29 at visit 2 predicted therapeutic trough DL with 2 2 Geographic R = 0.63 R = 0.86 100% accuracy, DL < 6.29 misclassified 2/21 cases (overall error 2 2 Capital city R = 0.71 R = 0.76 rate = 6.9%). After removing DL at visit 1 and 2, patient weight was the Population R2 = 0.71 R2 = 0.78 only variable that predicted sub-therapeutic trough DL, (19/23(83%) evaluations weight ≥67.5 kg = sub-therapeutic DL, 6/6 evaluations Conclusion: In line with data from the northern hemisphere, latitude in weight < 67.5 kg = therapeutic DL). the southern hemisphere is a strong predictor of refractory CD and UC with Conclusions: There is little variation in DL between cycles, suggesting a 3.3-fold increase in anti-TNF usage observed in southern- compared to the results of a single DL can be interpreted with confidence and do not northern Australia. This may indicate higher disease prevalence or more need to be repeated. DLs do not significantly decline between day 4–6 and severe disease in the southern states. Possible confounders include differ- day 7–9 and a DL > 6.2 μg/ml at these time points was able to classify ing patient access to care and state-based treatment practices, but specu- therapeutic vs sub-therapeutic trough DL with an observed error rate of lative IBD environmental risk factors include geographical differences in 6.9%. Increased patient weight was associated with sub-therapeutic DL temperature, sunlight exposure, microbiome and vitamin D level. although sample size was small. Larger population based pharmacokinetic studies are required before TDM with ADA in CD can be performed at any time point with confidence.

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 143 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Patients in CR and PR had significantly lower (better) scores on all Visit Cycle 1 DL (μg/mL) Cycle 2 DL (μg/mL) WPAI:UC domains than did NR patients at both time points (P < 0.05 and 1 5.67 5.25 P < 0.001, respectively). Further, at both induction and maintenance end- 2 5.31 4.70 points, WPAI:UC domain scores did not statistically differ between CR ≥ 3 (trough) 4.14 3.91 and PR patients (all P 0.415). Estimated parameters and means from the RMMM indicated that patients in CR or PR showed similarly larger improvements and better maintenance of improvements in OWI over time 14 than did NR patients. 12 Conclusion: Patients whose UC was in CR or PR following both short- 10 term and long-term daily treatment with multimatrix mesalazine exhibited 8 better WRO than NR patients. Furthermore, WRO was equivalent for 6 patients in CR and PR groups, indicating that improvement and mainte- 4 nance of WRO for patients who achieved PR was just as good as for those

ADA DL μg/mL 2 in CR. 0 References: Day 4-6 Day 7-9 Day 13-14 Day 18-20 Day 21-23 Day 27-28 1. Gibson PR, Vaizey C, Black CM, Nicholls R, Weston AR, Bampton P et al. Relationship between disease severity and quality of life and assessment of health care utilization and cost for ulcerative colitis in Australia: a cross-sectional, observational study. J Crohns Colitis. 2014; 8(7):598–606. Remission status predicts work-related 2. Reinisch W, Sandborn WJ, Bala M, Yan S, Feagan BG, Rutgeerts P outcomes for patients with mild-to-moderate et al. Response and remission are associated with improved quality of ulcerative colitis receiving short-term and life, employment and disability status, hours worked, and productivity long-term daily therapy with multimatrix of patients with ulcerative colitis. Inflamm Bowel Dis. 2007; mesalazine 13(9):1135–1140. A YARLAS,1 G D’HAENS,2 D WILLSHIRE,3 M TEYNOR4 1Optum, Lincoln, Rhode Island, USA, 2Academic Medical Center, Amsterdam, The Netherlands, 3Shire, North Ryde, Health-related quality of life varies as a function Australia, 4Shire, Lexington, MA, USA of remission status in patients with Introduction: Studies have shown that increased disease activity for mild-to-moderate ulcerative colitis receiving patients with ulcerative colitis (UC) predicts impairment in work-related short-term and long-term daily therapy with outcomes (WRO), such as decreased productivity and increased absentee- multimatrix mesalazine ism. In addition, patients whose UC is in complete (clinical and endo- A YARLAS,1 G D’HAENS,2 D WILLSHIRE,3 M TEYNOR4 scopic) remission (CR) demonstrate less impairment in WRO than patients 1Optum, Lincoln, Rhode Island, USA, 2Academic Medical whose UC is not in remission (NR).1,2 The objective of the current study Center, Amsterdam, The Netherlands, 3Shire, North Ryde, was to examine WRO of UC patients in partial remission (PR) relative to Australia, 4Shire, Lexington, MA, USA WRO of patients in CR or NR. Methods: Data were from a multinational, open-label, prospective trial Introduction: Studies have shown an inverse relationship between of multimatrix mesalazine (NCT01124149). In the induction phase, disease activity and health-related quality of life (HRQL) for patients with patients with active mild-to-moderate UC received 4.8 g of multimatrix ulcerative colitis (UC), such that decreases in disease activity predict better mesalazine once daily (QD) for 8 weeks. Patients in CR or PR after HRQL. Consistent with this are findings that patients with UC in complete induction were enrolled in the maintenance phase, during which they (clinical and endoscopic) remission (CR) exhibit better HRQL than received 2.4 g of multimatrix mesalazine QD for 12 months. Remission patients not in remission (NR).1,2 What has not been established is whether status at induction endpoint (Week 8 or early withdrawal [EW] visit) and at HRQL for UC patients in partial remission (PR) is more similar to patients maintenance endpoint (Month 12 or EW visit) was determined by a in CR or NR. patient’s score on a modified UC-Disease Activity Index (UC-DAI). CR Methods: Data were from a multinational, open-label, prospective trial was defined as UC-DAI ≤ 1 with scores of 0 for both rectal bleeding (RB) of multimatrix mesalazine (NCT01124149). During induction treatment, and stool frequency (SF) components, and ≥1-point reduction from base- patients with active mild-to-moderate UC received 4.8 g multimatrix line for the endoscopy component. PR was defined as UC-DAI ≤ 3, mesalazine once daily (QD) for up to 8 weeks. Patients in CR or PR at RB+SF ≤ 1, and not in complete remission. Patients who did not complete Week 8 were eligible to receive 12 months of maintenance treatment with the full course of treatment were classified as NR. 2.4 g multimatrix mesalazine QD. Remission status at Week 8 or early A UC-specific version of the Work Productivity and Activity Impairment withdrawal (EW) visit during the induction phase (induction endpoint) and (WPAI:UC) questionnaire measured the impact of UC on 4 WRO domains at Month 12 or EW visit of the maintenance phase (maintenance endpoint) – absenteeism, presenteeism, overall work impairment (OWI), and activity was determined using a modified UC-Disease Activity Index (UC-DAI). impairment – at baseline, Week 8, and Month 12 (including EW patients at CR was defined as UC-DAI ≤ 1 with scores of 0 for both rectal bleeding all time points). Analysis of variance models compared WPAI:UC scores at (RB) and stool frequency (SF) components and ≥1-point reduction from these time points among CR, PR, and NR patient groups. Changes in OWI baseline for the endoscopy component. PR was defined as UC-DAI ≤ 3, scores over time as a function of remission status was examined using a RB+SF ≤ 1, and not in complete remission. All EW patients were classified repeated-measures mixed-effects model (RMMM). All tests used as NR. Patients completed measures of generic HRQL (12-item Short- Bonferroni-adjusted P values to control for multiplicity. Form survey [SF-12v2]) and disease-specific HRQL (Shortened Inflam- Results: The numbers of patients in CR, PR, and NR (including EW matory Bowel Disease Questionnaire [SIBDQ]) at baseline and at the end patients) were, respectively, 186 (26.6%), 282 (40.3%) and 231 (33.0%) at of induction and maintenance treatment. Analysis of variance models Week 8, and 159 (39.7%), 103 (25.7%) and 139 (34.7%) at Month 12. tested if HRQL scores at both endpoints differed as a function of patients’

144 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease remission status. Repeated-measures mixed-effects models (RMMM) or weekly adalimumab. Endoscopic recurrence was assessed at the study tested if changes in HRQL over time varied by maintenance endpoint endpoint of 18 months. Faecal calprotectin (FC) measurement was per- remission status. All tests used Bonferroni-adjusted P values to control for formed post-operatively at 6, 12 and 18 months. Healthcare utilization data multiplicity. were collected post-operatively over 18 months, based on administrative Results: The numbers of patients in CR, PR, and NR (including EW data maintained by the Clinical Costing Unit at one secondary and tertiary patients) were, respectively, 186 (26.6%), 282 (40.3%) and 231 (33.0%) at hospital, chart review and patient questionnaires. Unit costs were based on Week 8, and 159 (39.7%), 103 (25.7%) and 139 (34.7%) at the end of published Australian health care sources. maintenance (Month 12). At both time points, patients in CR and PR Results: 174 patients (median age 38, 55% female) were enrolled. Of scored significantly better on all 8 SF-12v2 and all 4 SIBDQ domains than these, 60 patients (active care n = 43, standard care n = 17) from 1 centre NR patients (all P < 0.0001). Including EW patients in all analyses, there were included in this anaysis. Median total health care cost was $6440 per were no statistical differences between scores of CR and PR patients on 7 patient. Active care cost $4824 more than standard care over 18 months. of 8 SF-12v2 domains (all but bodily pain, P = 0.013) or any SIBDQ Medication accounted for 78% of total cost, of which 90% was for domains at Week 8, while at Month 12, there were no statistical differences adalimumab. Median health care cost was higher for those with endoscopic between CR and PR patients on any SF-12v2 or SIBDQ domains (all recurrence compared to those in remission ($26,347 [IQR 25,045–27,485] P ≥ 0.251). Estimated parameters and means from RMMM indicated that vs $2,729 [IQR 1,182–5,215], P < 0.001). FC to select patients for colo- patients in CR or PR showed similarly larger improvements and better noscopy could reduce cost by $1010 per patient over 18 months. Active maintenance of HRQL over time than did NR patients. care was associated with 18% decreased endoscopic recurrence, costing Conclusion: HRQL was similar for patients whose UC was in CR or PR $861 for each recurrence prevented. following both short-term and long-term daily treatment with mesalazine. Conclusion: Post-operative strategies to prevent disease recurrence after Furthermore, at both endpoints, CR and PR patients exhibited better intestinal resection are associated with high healthcare costs, the majority HRQL than NR patients. These results indicate that improvement and of which is medication driven. Endoscopic recurrence when compared to maintenance of HRQL for patients with UC in PR was comparable with remission is associated with significantly higher healthcare costs. The those in CR. POCER strategy, as illustrated in the active care arm of this study, is based on risk-related medication, monitoring for early disease recurrence, and References treatment intensification when needed. It is associated with a reduction in 1. Reinisch W, Sandborn WJ, Bala M, Yan S, Feagan BG, Rutgeerts P post-operative endoscopic recurrence without a significantly greater cost et al. Response and remission are associated with improved quality of than standard care. Strategies that prevent endoscopic recurrence may life, employment and disability status, hours worked, and productivity therefore be associated with substantial healthcare savings downstream, of patients with ulcerative colitis. Inflamm Bowel Dis. 2007; making the POCER algorithm a potentially cost effective strategy. Further, 13(9):1135–1140. using FC to select patients appropriate for colonoscopy reduces costs 2. Casellas F, Arenas JI, Baudet JS, Fabregas S, Garcia N, Gelabert J et al. significantly. The long term cost-benefit of these strategies remains to be Impairment of health-related quality of life in patients with inflamma- evaluated. tory bowel disease: a Spanish multicenter study. Inflamm Bowel Dis. 2005; 11(5):488–496. What causes post-operative Crohn’s disease Structured post-operative treatment and recurrence? Evaluation of gut microbiota, monitoring to prevent Crohn’s disease anti-TNF non-response and smoking recurrence is cost effective. Results from the EK WRIGHT,1 MA KAMM,1 P DE CRUZ,1 F PRINCEN,2 POCER study F SELVARAJ,2 J WAGNER,4 SM TEO,3 AL HAMILTON,1 EK WRIGHT,1 MA KAMM,1 P DE CRUZ,1 K RITCHIE,1 EO KREJANY,1 A GORELIK,1 D LIEW,1 AL HAMILTON,1 K RITCHIE,1 SJ BELL,1 SJ BROWN,1 L PRIDEAUX,1 IC LAWRENCE,1 JM ANDREWS,1 WR CONNELL,1 PV DESMOND,1 D LIEW2 PA BAMPTON,1 SL JAKOBOVITS,1 TH FLORIN,1 1Department of Gastroenterology, St Vincent’s Hospital PR GIBSON,1 H DEBINSKI,1 FA MACRAE,1 D SAMUEL,1 and University of Melbourne, Melbourne, Australia, I KRONBORG,1 G RADFORD-SMITH,1 RB GEARRY,1 2Melbourne EpiCentre, University of Melbourne and W SELBY,1 MJ JOHNSTON,1 R WOODS,1 PR ELLIOTT,1 Melbourne Health, Melbourne, Australia SJ BELL,1 SJ BROWN,1 WR CONNELL,1 1 2 3 Background: Healthcare costs for Crohn’s disease are high. Active PV DESMOND, S SINGH, M INOUYE, 4 disease, surgery, hospitalisations and anti-TNF use are key cost drivers. CD KIRKWOOD 1 70% of patients with Crohn’s disease require at least one surgical resec- Department of Gastroenterology, St Vincent’s Hospital, tion, and of these most develop disease recurrence. Post-operative strate- Melbourne, Australia, 2Department of Research and gies to prevent disease recurrence, which include endoscopic assessment Development, Prometheus Laboratories, Inc., San Diego, and patient-tailored prophylactic drug therapy, are therefore desirable. California, USA, 3Centre for Systems Genomics, School of However, the cost-effectiveness of such strategies is unknown. Biological Sciences and Department of Pathology, Methods: In a randomised trial, patients undergoing intestinal resection University of Melbourne, 4Enteric Virus Group, Murdoch of all macroscopically diseased bowel were treated with post-operative Children’s Research Institute drug therapy to prevent disease recurrence. All patients received 3 months of metronidazole therapy. Patients at high risk of recurrence also received Background: Crohn’s disease (CD) usually recurs after intestinal resec- a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients tion. Smoking more than doubles the risk of early recurrence, while were randomly assigned to parallel groups: colonoscopy at 6 months adalimumab prevents recurrence in a majority of patients, but not in all; the (active care) or no colonoscopy (standard care). Computer-generated block cause of recurrence while on anti-TNF therapy is unknown. The intestinal randomisation was used to allocate patients to active or standard care in a microbiota is an antigenic drive in Crohn’s disease, and is likely to be 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥ i2) at 6 months responsible for disease recurrence after intestinal resection. We aimed to patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, identify the cause of post-operative recurrence of CD after intestinal resec-

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 145 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease tion by examining longitudinally changes in the gut microbiome, recur- drugs as above would decline after long-term use while the disease could rence in relation to adalimumab drug concentration and the presence of break out repeatedly. Advances in our understanding of the cell populations anti-adalimumab antibodies (AAA), and the effect of smoking on involved in the pathogenetic processes and recent findings on the regen- microbiota and adalimumab pharmacokinetics. erative, trophic and immunoregulatory potentials of stem cells open new Methods: 174 patients were included in the POCER study, comparing paths for UC therapy. This study is to analyze the therapeutic effect of the strategies to prevent disease recurrence. Bacterial 16S ribosomal profiling umbilical cord blood stem cell transplantation on the patients with ulcer- was performed on tissue from the resection specimens and samples taken ative colitis. at colonoscopy at 6 and 18 months post-operatively. Profiling was per- Methods: The cases of UC were enrolled from Shandong Qianfoshan formed using the Illumina MiSeq platform and bioinformatic analysis Hospital between December 2009 and December 2013. The treatment conducted using the QIIME software package. Serum adalimumab levels group (81 patients) were given stem cell therapy based on the traditional and AAA were measured by homogenous mobility shift assay in treatment while the control group (66 patients) were only treated with adalimumab treated patients at 6, 12 and 18 months post-operatively. traditional treatment. The umbilical cord blood stem cells, which were Endoscopic assessment was performed at 6 and/or 18 months post- separated from 70 ml to 100 ml umbilical cord blood, were transplanted operatively and recurrence assessed using the Rutgeert’s score. into the intestinal tract through inferior mesenteric artery. The changes of Results: 141 mucosal biopsy samples from 34 Crohn’s disease patients clinical, endoscopic and pathological characteristics were recorded care- were obtained at surgical resection (baseline) and from the ileum at colo- fully, and statistical analyses were carried out according to the disease noscopy 6 and/or 18 months post-operatively. Gut microbial diversity activity score index. (alpha diversity) and overall composition (beta diversity) did not differ Results: One week after the transplantation, the clinical symptoms and significantly, but there were significant taxonomic differences, between signs were significantly improved. After four weeks, the clinical symptoms patients with and without endoscopic recurrence at 18 months. Patients and signs had almost disappeared and never relapsed in 24 weeks. Colo- with recurrence had elevated Proteus genera (P = 0.008) and multiple noscopy examinations displayed that the intestinal inflammation disap- decreased genera from the Firmicutes phylum, including Faecalibacterium peared and the blood vessels texture became clear, while inflammatory (P < 0.001) in the ileal mucosa post-operatively. Adalimumab levels and polyps reduced. There were two patients who suffered from low fever after AAA were measured over time from the time of surgery in 126 samples transplantation. Not any other adverse reaction occurred in 24 weeks. The from 52 patients. Adalimumab concentration did not differ significantly patients in control group were also becoming better, but most of them between those in endoscopic remission compared to recurrence relapsed in 24 weeks. According to statistical analysis, stem cell therapy is (10.0 μg/mL vs 8.4 μg/mL, p = 0.387). An adalimumab level of 9.3 was more effective than traditional treatments. determined as the optimal cut-off for the prevention of endoscopic recur- Conclusions: Umbilical cord blood stem cell transplantation in the treat- rence (Sensitivity 0.71, Specificity 0.51, PPV 0.33, NPV 0.84, AUROC ment of ulcerative colitis can significantly reduce inflammation, repair the 0.56). AAA were more prevalent in those on monotherapy versus combi- injured intestinal mucosa and reduce the complications. It will greatly nation therapy (34% vs 13%, p = 0.012). Median adalimumab levels were improve the patients’ life quality while its long-term outcome is better than lower in patients with detectable AAA compared to those without traditional treatments. Therefore, the stem cell therapy is of high value in (3.6 μg/mL vs 12.0 μg/mL, p < 0.001). Smoking was associated with sig- use for UC. nificantly elevated levels of Proteus (p = 0.013) post-operatively. Low abundance of Faecalibacterium (<0.01%) and detectable Proteus in the post-operative ileal mucosa were associated with higher risks of recurrence Horses for courses? comparing adalimumab and [OR 14 (1.7–110), P = 0.013 and 13 (1.1–150), P = 0.039] respectively, infliximab in an Australian IBD centre – Does when corrected for smoking status. A predictive model of endoscopic recurrence comprising ileal mucosa Proteus, Faecalibacterium abundance, the choice matter and what can we tell and smoking status showed moderate accuracy (AUC 0.740, 95% CI prospective anti-TNF patients regarding long [0.69–0.79]). term outcomes? Conclusion: Combined evaluation of the gut microbiota, drug therapy B YE,1 D LEWIS,1 K NALANKILLI,1 SW YEOH,1 and smoking has provided key insights into the understanding of recurrent DR VAN LANGENBERG1 disease. Specific microbial factors have been identified that are associated 1Department of Gastroenterology, Eastern Health, Victoria, with early disease recurrence and open the possibility of targeted therapy. Australia, 3128 Adalimumab drug levels post-operatively do not correlate with endoscopic recurrence after CD resection; disease recurrence in adalimumab-treated Background: Real world, head-to-head comparative data of the two anti- patients is therefore not simply a result of sub-therapeutic drug concentra- TNF therapies available for Crohn’s disease (CD) in Australia tion. AAAs had a high prevalence and are associated with lower drug (adalimumab (ADA) and infliximab (IFX)) are scarce, yet are integral to levels. Smoking independently influences post-operative CD recurrence. informed decision-making for patients. Here we evaluated long term out- Elucidating these factors will lead to precise prediction of disease recur- comes of patients with CD receiving anti-TNF therapies, comparing ADA rence and targeted therapies. and IFX, and assessed the interactions of other factors putatively affecting durable outcomes. Methods: Data from patients with confirmed CD attending Eastern Health IBD clinics between 2010–2015 and who received PBS-funded Umbilical cord blood stem cell transplantation adalimumab and/or infliximab were retrospectively collected, including for the treatment of ulcerative colitis time to loss of response (LOR) and at LOR, the subsequent change in HL YANG,1 J YANG,1 CQ XU,1 K LI,1 JN ZHANG1 anti-TNF management performed (e.g. switching to other anti-TNF, 1Department of Gastroenterology, Shandong Qianfoshan reinduction or dose escalation of same anti-TNF, ceasing or surgery). Hospital, Jinan, China Outcomes were assessed until lost to follow-up or 30/4/2015. Both physician-assessed (as per clinical records) and ‘definite’ (as per occur- Introduction: Ulcerative colitis (UC) is a chronic non-specific intestinal rence of anti-TNF switch/ cessation/ reinduction or dose escalation) inflammatory disease, while up to now the etiology and pathogenesis are LOR were captured. Other data including concomitant medications at not entirely clear. The traditional treatments are 5-aminosalicylic acid, anti-TNF start, smoking status and body mass index (BMI) were also glucocorticoid and immuno-suppressors, but the safety and efficacy of collected.

146 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Results: 221 CD patients received PBS-subsidised ADA or IFX (or 2015 at a tertiary hospital. Screening colonoscopies were defined as those both), median age at diagnosis 24 years (range 5, 81), median disease in which caecal intubation and random biopsies from both left and right duration 6 years (0, 40), 110 (50%) were females and 66 (30%) were colon were completed, or those performed in cases of previous colonic smokers at start of anti-TNF. Head to head, there was no significant resection where representative biopsies were taken throughout the residual difference in time to LOR for adalimumab vs infliximab (median 523 vs colon. 471 days, log rank test p = 0.9). However based on a multiple regression Results: Of 600 IBD patients reviewed, 396 were excluded- 197 had IBD model accounting for other factors below, infliximab (versus adalimumab) diagnosed <8 years ago, 146 had no colonoscopy during study period, 23 resulted in a more rapid onset of LOR on average by 386 days (beta 0.29, had colonoscopies that were incomplete or inadequately biopsied and 30 p = 0.001). Other factors included in the model and associated with shorter had previous total colectomy. The remaining 204 patients had 310 colo- duration to LOR included more extensive disease involvement (beta 0.34, noscopies; 106 (52%) were females, 178 (58%) with CD. At time of p < 0.001), higher BMI (>25 kg/m2, beta 0.23, p = 0.004), and smoking at colonoscopy mean age was 47 years (range 17–88), mean IBD duration of time of starting anti-TNF and younger age at diagnosis (<18 y, trends only 16 years (range 8–40), 67 (21%) were on a TNF-inhibitor, 159 (52%) on an for latter two, each p = 0.1). Moreover in all comers (both ADA and IFX), immunomodulator, 22 (7%) on maintenance prednisolone and 72 (23%) on those with no LOR through to end of follow-up (i.e. ‘long term respond- 5-aminosalicylates alone. ers’, n = 122, 55%) were more likely on concurrent immunomodulator Dysplasia was found in 15 (5%) colonoscopies, 11 (73%) in males, 9 when anti-TNF started (OR 2.5 [1.4, 4, 5]), did not have extensive CD (OR (60%) with CD. 11 (73%) were low grade adenomas, 1 (7%) a high grade 0.50 [0.26, 0.95]) and were older at diagnosis (per year, OR 1.03 [1.0, 1.1], adenoma, 2 (13%) high grade dysplasia in random flat biopsies and 1 (7%) each p < 0.05). The rate of primary anti-TNF non-response was 13%, with an adenocarcinoma. Compared to those without dysplasia, those with secondary LOR rates at 1, 3, 5, 10 years of 17, 31, 42, 46% respectively, dysplasia were significantly older (mean = 63 vs 46 years, p < 0.01), more with no significant differences between ADA or IFX (at any time point). likely to be above the age of 45 (14/15, 93% vs 54%, p < 0.01), have Post-first LOR in all comers, switching anti-TNF tended to provide more extensive colitis (E3, 26% vs 7%, p = 0.03), yet less likely to have had durable outcomes than either reinduction or dose intensification of same bowel resections (0% vs 24%, p = 0.02). They tended to have longer anti-TNF (median time to next LOR 605 vs 343 vs 287 days respectively, disease duration (mean 19 vs 16 years, p = 0.09) yet lower smoking rates ANOVAp = 0.08), with no significant differences between ADA or IFX (or (7% vs 29%, p = 0.07). They exhibited an unfavourable treatment profile order thereof). Finally, regardless of type of anti-TNF change(s) made, with lower rates of TNF-inhibitor (7% vs 22%) and immunomodulator use there was no apparent drop-off in response duration per successive change (40% vs 51%) and higher prednisolone use (26% vs 6%, p = 0.01). made, with median duration to next LOR for 1st→2nd,2nd→3rd,3rd→4th, Excluding post-colectomy patients, the mean number of random colonic 4th→5th change of 366, 382, 499, 156 days respectively (p = 1.0, ANOVA). biopsies was 14 (range 4–42). The 2 patients with dysplasia detected on Conclusions: This largest Australian head-to-head comparison of ADA colonic biopsies had a higher number taken (22 and 24 respectively) and IFX for CD in a single IBD centre to date suggested no significant compared to the mean (p = 0.06) but dysplasia was found only in biopsies differences in duration of response.Yet when accounting for adverse cofac- of endoscopically visible inflammation. Of the 4 patients developing high tors such as extensive disease, smoking and higher BMI, infliximab was grade dysplasia or carcinoma, 2 had distal colitis (E2) but were ≥78 years associated with reduced response duration. This however may represent old. The other 2 had uncontrolled, steroid dependent pancolitis–a33year clinician bias in selecting IFX for those with more severe CD and/or other old with TNF refractory CD for 19 years plus primary sclerosing cholan- adverse factors. To regain anti-TNF response post-LOR, switching to gitis, and a 65 year old with UC for 17 years refractory to another anti-TNF appears more effective than reinduction or dose escala- immunomodulators. Compared to a background population adenoma tion, yet regardless, ongoing anti-TNF response may be more durable than detection rate of 24.5%1, this cohort had a far lower rate of 4.8% perhaps expected after one or even multiple LOR events when appropriate (p < 0.001). management is undertaken. Conclusions: Rates of IBD-related dysplasia are very low in this centre, with the majority of cases being macroscopically visible (likely sporadic) adenomas. Those developing high grade dysplasia were older and/or had extended periods of poorly controlled IBD. Non-adenomatous dysplasia Rates of dysplasia on screening colonoscopies was only detected in endoscopically inflamed mucosa. The yield of screen- in patients with inflammatory bowel disease ing colonoscopies in well-controlled IBD patients under the age of 45, and after 8 years of diagnosis are low in the 21st routine biopsies of macroscopically normal mucosa, is negligible in this century Australian setting population. S YEOH,1 A BOHRA,1 D LEWIS,1 K NALANKILLI,1 1,2 Reference D VAN LANGENBERG 1 Barclay R et al. Colonoscopic Withdrawal Times and Adenoma 1 Department of Gastroenterology and Hepatology, Eastern Detection during Screening Colonoscopy. N Engl J Med 2006; 355:2533– 2 Health, Monash University 2541. Background/Aims: Guidelines recommend screening colonoscopies for patients with inflammatory bowel disease (IBD) from the 8th year post- diagnosis to assess for dysplasia. However these recommendations are based on data predating the current practice of applying early, aggressive therapies (e.g. inhibitors of tumour necrosis factor [TNF]) to alleviate colonic inflammation, the major driver of carcinogenesis. Furthermore, regular colonoscopies increase risk and morbidity to patients and health- care costs. We aimed to document the rates of dysplasia found on screening colonoscopies in a major Australian IBD centre and elucidate characteris- tics associated with dysplasia. Methods: Demographic, IBD-related, surgical, medication, smoking, procedural and histological data were extracted from records of patients with Crohn’s disease (CD) or ulcerative colitis (UC), ≥8 years post- diagnosis, who had screening colonoscopies from January 2011 to March

Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 147 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Inflammatory Bowel Disease

Bile induces the release of zonula occludens Methods: C. concisus strains were cultured with and without the pres- toxin by Campylobacter concisus: a unique ence of bile. The presence of Zot toxin in C. concisus bacteria and in the pathogenic mechanism by which oral supernatant was detected using Western-blot. N-terminus of C. concisus E. coli Campylobacter species initiate a subgroup of Zot was expressed in and its effects on intestinal epithelial barrier was assessed using Caco2 cells by measuring transepithelial electrical human IBD resistance (TEER) and passage of paracellular marker FD4. The effects of 1 1 1 2 3 F LIU, R MA, H LEE, SM RIORDAN, MC GRIMM, C. concisus Zot on Caco2 cell actin rearrangement was measured using 4 1 RW LEONG, LI ZHANG * confocal microscopy. 1School of Biotechnology and Biomolecular Sciences, Results: Bile induced C. concisus to release Zot toxin into the superna- University of New South Wales, Sydney, New South tant. The N-terminus of C. concisus Zot significantly reduced TEER and Wales, Australia, 2Gastrointestinal and Liver Unit, Prince of increased the passage of paracellular marker FD4 in Caco2 cells as com- Wales Hospital, Sydney, NSW 2052, Australia, 3St George pared to vector control. C. concisus also induced actin rearrangement in and Sutherland Clinical School, University of New South Caco2 cells. Wales, Sydney, NSW 2052, Australia, 4Concord Hospital, Conclusion: This study shows that C. concisus releases Zot toxin in enteric environment and C. concisus Zot toxin damages intestinal epithelial Sydney, University of New South Wales, Sydney 2052, barrier function. These data reveal a unique pathogenic mechanism by Australia which oral Campylobacter species may use to initiate enteric inflammatory Introduction: Recent evidence supports the role of oral Campylobacter diseases. species such as Campylobacter concisus in initiating a subgroup of human IBD1. The pathogenic mechanisms by which oral Campylobacter species Reference initiate inflammation at the lower parts of the gastrointestinal tract remain 1. Zhang L. Oral Campylobacter species: Initiators of a subgroup of inflam- elusive. We hypothesize that some enteric environmental factors stimulate matory bowel disease? World J Gastroenterol 2015:21:9239–9244 C. concisus to release toxins in the intestinal tract. In this study, we have examined the effects of bile on the release of zonula occludens toxin (Zot) by C. concisus and the impact of C. concisus Zot toxin on intestinal epithelial barrier.

148 Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 3): 117–148 © 2015 The Authors. Journal of Gastroenterology and Hepatology © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd