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Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, that display heterogeneity in inflammatory and symptomatic burden between patients, and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients.This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK).A systematic review of 88,247 publications, and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence and expert opinion based-recommendations for pharmacological, nonpharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive, up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and post-operative management, as well as structure and function of the multidisciplinary team, and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2,379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.

The commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn's disease.To assess the impact of FOS in patients with active Crohn's disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn's disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn's Disease Activity Index of ≥ 70 points) in the intention-to-treat (ITT) population.103 patients were randomised to receive FOS (n = 54) or placebo (n = 49). More patients receiving FOS (14 (26%) vs 4 (8%); p = 0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p = 0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4-week intervention.An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn's disease, despite impacting on DC function. ISRCTN50422530.

Introduction The use of therapeutic drug monitoring (TDM) for anti-TNF drugs has become increasingly widespread over recent years. It is now used in many centres to guide clinical decisions regarding dose optimisation, the use of concomitant immunomodulators as well as switching or withdrawal of treatment. 1 TDM usually includes the measurement of serum trough levels of infliximab (IFX) or adalimumab (ADA) as well as anti-drug antibodies (ADAb). There are two different approaches to measuring ADAb; some techniques measure total ADAb (drug-ADAb complexes as well as free ADAb), whilst other measure only free ADAb. However, the clinical relevance of the differing data generated by these techniques is not yet fully understood. Methods A prospective evaluation of trough drug levels and ADAb was performed using our standard ELISA assay (LISA TRACKER, Theradiag) in 145 IBD patients on anti-TNF agents between January and May 2014. This technique measures only free ADAb. The samples were also anaylsed using an ELISA assay that measures total ADAb (IDKmonitor, Immundiagnostik). Long term outcomes were evaluated for 21 (17 IFX, 4 ADA) patients with Crohn’s disease (CD) who were found to have negative free ADAb but positive total ADAb. Outcome assessments were made by review of a prospectively maintained database, with a mean follow-up period of 22 months. Clinical outcome measures included; the need to escalate/switch/withdraw biologic treatment, infusion/injection-site reactions, documented clinical flare (HBI > 5) and need for steroid treatment. Biochemical outcome measures included; CRP > 5 mg/L and faecal calprotectin >150 ug/g. The subsequent development of positive free ADAb and subtherapeutic/undetectable drug levels were also collected as outcome measures. Results Anti-drug antibody (ADAb) detection: Of the 21 CD patients with positive total ADAb and negative free ADAb at the time of initial sampling, 3 (14%) went on to subsequently develop positive free ADAb during the follow-up period. Sixteen patients (75%) were taking concomitant immunomodulators, including all 3 patients who subsequently developed free ADAb. The mean IFX trough level in patients who went on to develop free ADAb was 1.05 ug/ml, compared to 4.04 ug/ml in those who did not. Outcomes: All 3 (100%) of the patients who developed positive free ADAb subsequently went on to have subtherapeutic or undetectable drug levels and required a switch in anti-TNF therapy. Two of the 3 (67%) had a flare in disease activity with an elevated faecal calprotectin. Two (67%) also developed significant infusion reactions. Of the remaining 18 patients who did not subsequently developed free ADAb, only one patient (6%) required a switch in anti-TNF, 4 (22%) developed clinical flares and 3 (17%) required steroid treatment. None of the 18 patients who remained free ADAb negative had undetectable drug levels during the follow-up period. Conclusion Long-term outcomes were not shown to be adversely affected by the presence of total ADAb, in the absence of free ADAb and adequate drug levels. However, patients who subsequently developed free ADAb and subtherapeutic or undetectable drug levels had unfavourable long-term outcomes. The presence of total ADAb does not appear to accurately predict the development of free ADAb. This data supports the use of ELISA techniques which measure free ADAb as well as drug levels. Our study and other similar work, 2 suggests that quantification of drug-ADAb complexes (total ADAb) appears to be less relevant to long-term clinical outcomes and therefore, less informative to clinical decision making. References 1 Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nature Reviews Gastroenterology & Hepatology 2014; 11 :243–255. 2 van schouwenburg, et al. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding tests shows predictive value and transient antibody formation. Ann Rheum Dis . 2013; 72 :1680–6. Disclosure of Interest None Declared

Background and aim Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. Methods To define the optimum population for Treg cell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA-Treg subsets were isolated from patients' blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. Results Tregs can be expanded from the blood of patients with CD to potential target dose within 22-24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA-Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. Conclusions CD4+CD25+CD127loCD45RA+Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials.

Introduction There is a lack of evidence for a clear nutritional optimisation strategy of pre-surgical Crohn’s disease (CD) patients. Limited data suggests that pre-surgical enteral nutrition (EN) increases albumin and decreases CRP as well as reducing anastomotic leakage, intra-abdominal abscess formation and wound infection. We aimed to assess the effect of nutritional optimisation of pre-surgical CD patients with EN on peri- and post-surgical outcomes and anthropometrics. Methods CD patients (n = 32) requiring ileal or ileocolonic resection were identified and nutritionally optimised pre-surgery using a minimum of 6 weeks EN (Modulen IBD, Nestle, Vevey, Switzerland) providing 75–100% nutritional requirements. Peri-surgical (albumin and CRP) and post-surgical (total length of stay, complication rate, readmission days and stoma formation) outcomes were compared with a retrospective sample of control patients (n = 35) who had not been nutritionally optimised. A subset of nutritionally optimised patients underwent anthropometric analysis pre and post EN. Continuous data are presented as mean ± sd and paired and independent t-tests were used for comparison where appropriate. Categorical data were compared using Chi squared tests. p Results Nutritionally optimised patients had significantly shorter total length of stay compared with control patients (9.81 ± 9.97 d vs 16.34 ± 9.95 d, p = 0.009). Only 6 (19%) nutritionally optimised patients versus 19 (54%) control patients had stoma formation (p = 0.005). Nutritionally optimised patients had significantly fewer complication-related readmission days than control patients (0.69 ± 0.37 d vs 1.75 ± 3.64 d, p = 0.02). Twenty six (81%) nutritionally optimised patient had a normal albumin level pre-surgery versus 21 (60%) control patients (p = 0.002) and 20 (63%) nutritionally optimised patients had normal pre-surgery CRP versus 11 (31%) control patients (p = 0.001). Eleven patients (35.3 ± 13.3 years, 5 males) were included in the nutritionally optimised subset analysis. BMI did not change from pre to post EN (23.58 ± 5.04 kg/m2 to 23.03 ± 3.77 kg/m2; p = 0.336) nor did mid arm muscle circumference, waist circumference and handgrip strength. Conclusion Optimisation of nutrition pre-surgery in CD appears to reduce length of stay, stoma rate and additional hospital in-patient days for complications as well as improving albumin and CRP. However it is unclear what anthropometric measurements are useful to assess the effects of EN on nutritional status. Disclosure of Interest None Declared

Introduction There is an unpredictable relationship between thiopurine methyl transferase (TPMT) and hypermethylation. It is likely that cytochrome P450 (CYP450) enzymes play a role in the demethylation of methylated mercaptopurine (MMP), altering the MMP:Thioguanine nucleotide (TGN) ratio(Table 1). Smoking has been shown to induce CYP450 enzymes. One study on smoking and olanzapine demonstrated a 6 fold increase in CYP450 activity through smoking. 1 This might suggest that smoking could upregulate the demethylation process, reducing MMP. Methods Patients on thiopurines had their smoking status recorded as they attended the inflammatory bowel disease (IBD) clinic. Retrospective data on demographics was collected (Table 1). Only measurable TGNs after 6 weeks of therapy were used for analysis. Metabolites measured whilst on allopurinol were excluded. Average TGNs over the treatment period, MMP and MMP:TGN ratios were compared between smokers and non-smokers. Hypermethylators were defined as any patient with an MMP:TGN ratio of ≥11 during their treatment Results 230 patients were analysed(117 males). Table 1 shows comparison in demographics between smokers and non-smokers Mean MMP for smokers was 1683(SD 2565, median 840) versus 2041 in non-smokers(SD 2401, median 1340)(P = 0.713). Mean MeMP:TGN ratio for smokers was 6.15 (SD 9.06, median 2.22) versus 7.81 in non-smokers (SD 8.01, median 4.70)(P = 0.593). Conclusion There were more hypermethylators in the non-smoking cohort than in the smoking cohort (42.7% versus 28.3%(P Reference 1 Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol . 2003 Apr; 23 (2):119–27. Disclosure of Interest None Declared

Introduction Thioguanine nucleotides (TGNs) are the biologically active metabolites of thiopurines. Methylated thiopurine metabolites (MeMPs) formed via thiopurine-S-methyltransferase (TPMT) may also have immunosuppressive properties through inhibition of de novo purine synthesis (DNPS).1 Individuals with intermediate TPMT activity do not produce significant levels of methylated metabolites, with predictably less inhibition of DNPS and therefore may tolerate higher levels of TGNs. If confirmed this suggests that the therapeutic range of TGNs (240–450 pmol/8x108) may differ between patients with intermediate Vs normal TPMT activity. Methods All IBD patients at Guy’s and St Thomas’ Hospitals treated with either azathioprine or mercaptopurine who had TGNs measured from 2002–2013 were included. Patients receiving low dose thiopurine with allopurinol were excluded. Data was collected using the electronic patient record system and statistical analysis was completed in GraphPad Prism version 5.0. Results 2193 TGN measurements were included in the analysis, 340 (15.5%) from patients with intermediate TPMT activity and the remaining 1853 had normal TPMT activity. The average normalised thiopurine doses between groups was 1.13 Vs 1.87 mg/kg/day respectively, reflecting standard dose adjustment in intermediate TPMT patients. The median TGNs levels were significantly higher in patients with intermediate Vs normal TPMT activity; 370 Vs 277 pmol/8x108 (P = Conclusion Despite significantly higher TGN levels in patients with intermediate as compared to normal TPMT activity, there was no difference in levels of Hb, WBCs, neutrophil or platelets counts. This suggests a greater tolerance to TGNs in patients with intermediate TPMT activity and may indicate that a different TGN therapeutic range is needed in these patients. The likely reason is that methylated metabolites are biologically active and also play a role in overall thiopurine immunosuppression. Reference 1 Tay BS, Lilley RM, Murray AW, et al. Inhibition of phosphoribosyl pyrophosphate amidotransferase from Ehrlich ascites-tumour cells by thiopurine nucleotides. Biochemical Pharmacology. 1969;18(4):936–8. Disclosure of Interest None Declared

Introduction Small intestinal bacterial overgrowth (SIBO) negatively affects both the structure and function of the small intestine leading to a number of acute and chronic symptoms. The lactulose hydrogen breath test (LHBT) is commonly used to detect SIBO. However, little is known to what extent the diagnosis made by this method can affect the patient’s clinical state. The aim of this study was to assess whether patients diagnosed with SIBO using LHBT respond clinically to SIBO treatment. Methods All the patients who were diagnosed with SIBO by LHBT within the last 12 months prior to December 2016 were retrospectively contacted. A visual analogue scale (VAS) on a scale of 0–10 was used to score the severity of their top 3 symptoms pre and post treatment. 0 being the lowest and 10 being the highest severity of each symptom. Positive LHBT was considered as raise of hydrogen >12 ppm against baseline within the first 60 min of the study. A paired t-test was conducted to evaluate the significance of the differences; P value Results 17 patients were included (10 female, median age 40.5, age range 26–70). All these patients were prescribed antibiotics (AB). Reduction of the symptom 1 and 2 were significant pre vs post treatment but not the symptom 3 (P values respectively: Conclusion The findings of this study suggest that patients diagnosed with SIBO using LHBT effectively respond to treatment (i.e. AB). Using raise of hydrogen >12 ppm against baseline within the first 60 min of the study is a reliable criteria to diagnose SIBO. Further studies with larger number of patients is required to confirm the findings of this study. Disclosure of Interest None Declared

Introduction We have shown that Tregs expanded with rapamycin from FACS-sorted Crohn’s Disease (CD) peripheral blood (PB) CD4+CD25hiCD127loCD45RA+ precursors, yield an epigenetically stable FOXP3+ cell population that is resistant to pro-inflammatory cytokine expression.1 We will utilise this for a first in man clinical trial of Treg therapy for Crohn’s disease. We wished to optimise the expression of gut homing molecules on these cells as Tregs are required at the site of action for optimal suppressive ability. Methods Tregs were isolated from peripheral blood of CD patients and healthy controls. Retinoic acid (RA) and Rapamycin supplementation was tested in standard culture conditions as well as the addition of short chain fatty acids (SCFA). The effect of SCFA was assessed on ex-vivo expanded Tregs from CD4+CD25hiCD127loCD45RA+ precursors and induced Tregs (iTreg) from naive T cell precursors. The expression of gut homing molecules integrin b7 and GPR15 was assessed by flow cytometry. Suppressive ability was tested in vitro using autologous effector T cells (Teff). Parametric and non-parametric data were calculated as the mean±s.d. and median (interquartile range, IQR) respectively. For comparison of parametric and non-parametric data, t- test, one- or two-way ANOVA. Results In comparison to Rapamycin treated cells, the addition of RA significantly increased the expression of integrin beta 7 (38.7%±11.78% Rapamycin alone vs 72.26%±8.98% Rapamycin + RA p = 0.04, N = 7). RA treatment also significantly increased GPR15 expression. Cells treated with RA maintained their superior suppressive ability compared to Rapamycin treated Tregs (95.8%±3.5% vs 91.15%±10.1% p=ns; at Treg:Teff 1:1 ratio). SCFA treatment led to diminished cell viability and did not induce the expression of colonic homing molecule GPR15 in CD4+CD25hiCD127loCD45RA+ Tregs (74.4%±13.2% Rapamycin and RA treated culture vs 43.4%±17% with the addition of SCFA). Conclusion Contrary to existing evidence in mouse, SCFA did not increase the proportion of CD4+FOXP3+ Tregs in human iTreg cultures. In conclusion, the addition of Retinoic acid not SCFA provides the optimal conditions for ex-vivo Treg expansion for cell based therapy of Crohn’s disease. Reference 1 Canavan JB, Scotta C, Vossenkamper A, Goldberg R, Elder MJ, Shoval I, et al. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn’s disease. Gut. 2015. Disclosure of Interest None Declared

Introduction Although deranged liver function tests(LFTs) are seen in around 1/3 of patients with IBD at some point during the course of their disease,there is a lack of clarity over how this should be investigated and managed. Methods IBD patients attending clinic between September 2014 and December 2015 were analysed for previously elevated alanine transferase((ALT) defined as >56 IU/L). Analyses,where there were derangement of gamma glutamyl transferase and alkaline phosphatase (ALP) only,were not performed. Data was collected for disease activity,medication,time to ALT normalisation(in months) and ALP. Results Data on 236 patients with elevated ALT were collected(50.4% male, mean age 40 years(range 16 to 83)). 64% had Crohn’s disease(CD). 61% had active disease at the time of elevated ALT. Liver injury was predominantly hepatitic(mean ALT:ALP ratio 1.52). Mean ALT was 159 (maximum 1980). Of the patients with PSC,81% had ulcerative colitis(UC) of whom 75% had pancolitis. The mean ALT:ALP ratio was 0.47 and therefore cholestatic(SD 0.29). Overall,70% of patients had an ALT which normalised completely(mean of 2.4 months(SD 2.7)). 37% were due to thiopurines and 35% due to disease flares. 6% were other drug related (methotrexate in 8 cases, mesalazines in 2). Where ALT did not normalise,21% were diagnosed with a chronic liver disease. 2/3 of thiopurine-induced hepatotoxicity were associated with hypermethylation(Methylmercaptopurine to thioguanine nucleotide ratio >11) and mean ALT:ALP was 1.74 and therefore hepatitic(range 0.15–11.57,SD 1.67). Median time for normalisation of thiopurine-induced hepatotoxicity was 2 months(SD 3.9) where as it was 0.5 months(SD 15.5) due to flares. Conclusion Liver disease in IBD is common but rarely severe. Thiopurines are the commonest cause. Liver injury associated with active disease is also common. ALT normalised completely in over 95% of drug related cases. Where deranged LFTs continue for over 2 months,then a liver screen is indicated to exclude a chronic liver disease. Where liver derangement is cholestatic and the patient has UC, investigations should be carried out to exclude PSC. Disclosure of Interest None Declared

Introduction Iron deficiency anaemia (IDA) is common in inflammatory bowel disease (IBD), can be hard to treat and has a negative impact on quality of life (QOL). Because of previous concerns about the efficacy and safety of oral iron, particularly in young people with IBD, we undertook a trial to assess whether ferrous sulphate is as effective and well-tolerated in adolescents as in adults with IBD. Methods Prospective phase IV, open-label, parallel group, 6 week non-inferiority clinical trial to compare the effects of oral ferrous sulphate 200 mg twice daily on Hb, iron status, serum hepcidin, symptoms, disease activity (Harvey-Bradshaw Index, Simple Colitis Clinical Activity Index, C-reactive protein (CRP), faecal calprotectin (FCP), QOL, mood and fatigue psychometric scores in 43 adolescent (age 13–18 years) and 45 adult (>18 years) IBD patients with IDA who were either oral iron-naive or previously iron-tolerant. Results On intention-to treat analysis, ferrous sulphate produced similar small but statistically significant rises in serum Hb in the adolescent (before treatment 10.3 g/dl [0.2] (mean [SEM]); after 11.7 [0.2]: p Conclusion Oral ferrous sulphate is no less effective or well-tolerated in adolescents than in adults with IBD, and does not increase disease activity. Baseline serum hepcidin level is inversely related to the increase in Hb produced by oral iron in patients with IBD: its measurement could indicate which patients would do better with intravenous than oral iron. Change in Hb had no effect on QoL, mood or fatigue scores. Disclosure of Interest None Declared

Introduction Vedolizumab was recently granted NICE approval for moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC). Novel pathways agreed by our CCG meant that patients at Guy’s & St. Thomas’ and King’s College Hospitals had early access to vedolizumab. Methods Records of patients commencing vedolizumab between Nov 2014–15 were screened. Those completing at least 14 weeks of treatment were included. Clinical activity was assessed using Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) at baseline, 14 and 30 weeks. Response: HBI/SCCAI reduction ≥3. Remission: HBI Results 60 patients (CD: 32, 53%, UC 25, 42%, IBD-U 3, 5%) commenced vedolizumab (m:f 29:31, age: 39 (18–74), follow-up: 5 months (1–13)). 19 were excluded from our analysis (3 IBD-U, 5 stomas, 11 treated for Of 32 patients with active disease at baseline, 17 (53%) responded and 11 (34%) achieved remission by week 14. The response and remission rates for CD were 8/15 (53%) and 6/15 (40%). In UC they were 9/17 (53%) and 5/17 (29%). Response and remission rates in anti-TNF experienced patients were 12/26 (46%) and 6/36 (35%) compared to 5/6 (83%) and 5/6 (83%) in anti-TNF naive patients, respectively. 7/11 (64%) with active disease at baseline who completed 30 weeks of treatment responded and achieved remission. Faecal calprotectin fell significantly (pre-induction: 1076 (90–4800), post-induction: 478 (10–3184), p = 0.029 for n = 14) and CRP remained stable (pre-induction: 4 (1–70), post-induction: 4 (1–72), p = 0.28 for n = 40). Rates of steroid use at each time point: 19/41 (46%) at baseline, 11/41 (21%) at week 14 and 3/15 (20%) at week 30. Surgery was required in 4/41 (10%, CD:3 and UC:1). Conclusion Our experience mirrors a previously reported real-world cohort 1 and demonstrates similar efficacy to the GEMINI trials. This data demonstrates a meaningful reduction in clinical and biochemical disease activity as well as a steroid-sparing effect in patients with complex and previously refractory disease. We did not see a significant difference in efficacy between patients with UC and CD. Reference 1 Christensen B. et al . Post-marketing experience of vedolizumab for IBD: The University of Chicago experience . ECCO; Barcelona, 2015. Disclosure of Interest None Declared