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ObjectiveIBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and project future, prevalence in Lothian, Scotland.DesignWe conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997–2018), IBD pathology coding (1990–2018), primary and secondary care prescribing data (2009–2018) and a paediatric registry, (1997–2018) to identify ‘possible’ IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028.ResultsIn total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn’s disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture–recapture methods identified an additional 427 ‘missed’ cases (95% CI 383 to 477) resulting in a ‘true’ prevalence of 832/100 000 (95% CI 827 to 837).Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p80 years of age.ConclusionsWe report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide.

Objective Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials. Design The Paediatric European Crohn9s and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement. Results Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8–12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn9s Disease Activity Index in Crohn9s disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn9s disease), faecal calprotectin, quality of life scales, and a patient-reported outcome. Conclusions It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal.

Background Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn’s disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD. Methods 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and ‘doubly robust’ weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups. Results 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test). Conclusions In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

Objective Although polymorphisms of the NOD2 gene predispose to the development of ileal Crohn's disease, the precise mechanisms of this increased susceptibility remain unclear. Previous work has shown that transcript expression of the Paneth cell (PC) antimicrobial peptides (AMPs) α-defensin 4 and α-defensin-related sequence 10 are selectively decreased in Nod2−/− mice. However, the specific mouse background used in this previous study is unclear. In light of recent evidence suggesting that mouse strain strongly influences PC antimicrobial activity, we sought to characterise PC AMP function in commercially available Nod2−/− mice on a C57BL/6 (B6) background. Specifically, we hypothesised that Nod2−/− B6 mice would display reduced AMP expression and activity. Design Wild-type (WT) and Nod2−/− B6 ileal AMP expression was assessed via real-time PCR, acid urea polyacrylamide gel electrophoresis and mass spectrometry. PCs were enumerated using flow cytometry. Functionally, α-defensin bactericidal activity was evaluated using a gel-overlay antimicrobial assay. Faecal microbial composition was determined using 454-sequencing of the bacterial 16S gene in cohoused WT and Nod2−/− littermates. Results WT and Nod2−/− B6 mice displayed similar PC AMP expression patterns, equivalent α-defensin profiles, and identical antimicrobial activity against commensal and pathogenic bacterial strains. Furthermore, minimal differences in gut microbial composition were detected between the two cohoused, littermate mouse groups. Conclusions Our data reveal that Nod2 does not directly regulate PC antimicrobial activity in B6 mice. Moreover, we demonstrate that previously reported Nod2-dependent influences on gut microbial composition may be overcome by environmental factors, such as cohousing with WT littermates.

Introduction There is an unmet need for novel blood based biomarkers that offer timely and accurate diagnostic and prognostic testing in Inflammatory Bowel Diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD Methods A total of 156 patients (82 IBD and 74 non-IBD) were sampled within 90 days from diagnosis (median 0 days; IQR 0–7). A multibiomarker diagnostic and prognostic model was derived using multivariable logistic regression analysis. Treatment escalation was defined as the need for escalation and establishment of 2 or more immunomodulatory therapies and/or surgery for disease flare after initial induction of disease remission (criteria previously used by Lee et al) (1). Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes Results SC correlated strongly with current biomarkers including CRP (rho = 0.60, p = 1.4x10−16) faecal calprotectin (FC) (rho = 0.51, p = 1.6x10−4). Paired FC was available within 30 days (median 0 days, IQR: -4 to5 days) of SC in 50 patients (IBD n = 30, non-IBD n = 20).The area under receiver operating characteristic discriminating IBD from controls was similar for FC and SC(0.95, 95% CI 0.87–1.00 and 0.89, 95%CI 0.81–0.98 respectively;p = 0.36). SC was the strongest individual predictor of IBD diagnosis (odds ratio (OR): 12.33 (95% CI 4.48–38.33, p = 3.5×10−6) compared with other markers (CRP: OR 4.44, CI 1.58–12.90; albumin: OR 5.65, CI 1.98–17.16). At follow up (median 342 days; IQR: 88–563),a total of 1 (2%), 16 (47%),23 (51%) patients required treatment escalation in the IBDU, CD and UC group respectively.SC predicted treatment escalation and/or surgery in IBD (HR 2.4, 95% CI: 1.1–4.9), in particular CD (HR 4.1, 95% CI 1.1–14.7). A model incorporating SC, CRP and albumin has a positive likelihood ratio of 20.03 for IBD.At 1 year, our prognostic model can predict treatment escalation in IBD in 65% of cases (95% CI: 43–79%) and 80% (95% CI: 31–94%) in CD if 2 or more blood marker criteria are met. Conclusion Sampling faeces can be a hurdle for patients and some individuals can decline FC testing. These factors impact on the practical utility of FC.SC shows promise as a diagnostic and prognostic biomarker in IBD. Our findings warrant further exploration and validation within large multicentre cohorts. Reference 1 Lee JC, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011;121:4170–9. Disclosure of Interest None Declared

In recent years the inflammatory bowel diseases (IBD)—Crohn's disease and ulcerative colitis—have emerged as a model for all complex traits in the successful dissection of the molecular basis of inherited susceptibility by non-parametric linkage analysis1 2 and genome-wide association studies (GWAS).3–5 The recent meta-analyses of GWAS carried out by the International Inflammatory Bowel Disease Genetics Consortium have now reported the identification of 99 susceptibility loci involved in the pathogenesis of Crohn's disease and ulcerative colitis.4 5 These successes in candidate gene discovery have provided new insights into the pathogenetic mechanisms involved in the chronic intestinal inflammation associated with IBD. These data provide strong evidence that Crohn's disease and ulcerative colitis are related complex diseases, sharing some, but not all, susceptibility loci.5 It is clear that while some pathogenic pathways are implicated in both Crohn's disease and ulcerative colitis—notably, interleukin (IL)-23 signalling6 and Th17 cell activation,7 other innate immune mechanisms appear to be implicated in Crohn's disease only (eg, autophagy, and NOD2 signalling). Similarly, aspects of the maintenance of epithelial barrier function are most strongly implicated in ulcerative colitis.8 Furthermore, it is clear that many of the genetic determinants involved in IBD are also implicated in other complex disorders, such as type I diabetes and coeliac disease ( in press ).9 Both expected and unexpected associations are evident, and have provided avenues for further research. Along with this exciting progress, however, new challenges have emerged for researchers in this complex field. Of the estimated heritability of IBD, which has been derived from concordance rates in twin pairs

Introduction Anti-TNF therapy use in paediatric IBD (PIBD) is increasing worldwide with evidence of short-term effectiveness and safety. Longer term outcomes are less clear due to lack of follow-up (FU) of young people after transition to adult services. We aimed to assess effectiveness and safety of anti-TNF therapy in PIBD post-transition to adult care. Method A retrospective case review of PIBD patients treated with anti-TNF (Infliximab (IFX) or Adalimumab (ADA)) in the SE Scotland regional PIBD unit at RHSC, Edinburgh and then transitioned to the regional adult specialist IBD centre at WGH, Edinburgh, during 01/01/00–30/09/13. Data (including outcome and duration of anti-TNF therapy, dose escalation, adverse events and discontinuation/re-start of therapy) were collected prior to, at the time of transition from PIBD services, and to study end point (transfer out of region, loss to FU, death or ongoing adult care at 31/07/2014), a minimum 10 months FU. Results 34 children (30 Crohn’s disease (CD), 4 ulcerative colitis (UC)) had anti-TNF exposure in PIBD services then a median (range) duration of FU post-transition of 2.9 (0.7–9.3) years. At transition, 19/34 were still on anti-TNF (12 IFX and 7 ADA). 10/12 IFX were in steroid-free remission (SFR) and 8/10 remained in SFR at last FU; 2 discontinued IFX due to loss of response (LoR), both then had ADA with 1 ADA LoR and 1 SFR on ADA at last FU. 1/12 IFX patient with moderate disease at transition then achieved remission, had planned drug withdrawal (PDW) then relapsed, restarted IFX and had mild disease at last FU. 1/12 IFX patients had response with mild disease post-induction IFX but transitioned and had primary non-response (PNR) by 6 doses IFX, and switched to ADA with moderate disease activity at last FU. 3/7 ADA patients at transition were in SFR; 1 stopped as PDW in prolonged remission but 2 stopped due to adverse events. 2/7 ADA patients with mild disease at transition then achieved sustained remission up to last FU. 2/7 ADA patients had moderate disease at transition; one had ADA LoR and moderate disease at last FU, the other gained remission so had PDW, relapsed but was in remission at last FU. There were no deaths or malignancies associated with anti-TNF use. Conclusion Anti-TNF therapy post-transition is effective at maintaining remission in those with remission prior to transition, although some may require a 2nd anti-TNF agent to maintain remission. Those previously not in remission can achieve sustained remission, usually if just starting anti-TNF maintenance at transition; others do not and have a more complicated disease course. Loss of response remains a key reason for stopping anti-TNF therapy. Disclosure of interest None Declared.

Introduction The recently published paediatric inflammatory bowel disease (PIBD) Paris classification highlights that patients diagnosed before their 10thbirthday (Paris A1a) have a different clinical phenotype at presentation than those diagnosed aged 10–16 years (A1b). However, data regarding accurate incidence rates, disease natural history, medication use and surgery in the A1a group is lacking. Method All A1a PIBD patients within our prospective, regional PIBD database from South-East Scotland (SES) diagnosed from 08/97–07/14 had data recorded regarding demographics, phenotype data, details of medical therapy and surgery; data at last paediatric follow-up (FU) was also collected. Accurate incidence data was generated using publicly available population data for SES. Statistics were performed in GraphPad Prism and R with Poisson regression analysis for incidence data. Results 121 A1a PIBD patients (77 Crohn’s disease [CD], 28 ulcerative colitis [UC] and 16 IBD-unclassified [IBDU]) were identified in the 17 yr period (31% of entire PIBD cohort); 52% were male. Median FU was 7.1yrs (IQR 3.6–9.6). The incidence of A1a PIBD during 2000–2013 was 4.4/100,000/yr (CD 2.8/100,000/yr; UC 1.0/100,000/yr; IBDU 0.6/100,000/yr); there was no significant increase in incidence between 2000–2006 and 2007–2013 (p = 0.577). At diagnosis 20% of CD patients diagnosed at 2–5 yrs had panenteric disease, 36% isolated colonic disease, and 16% had isolated oral and/or perianal disease; all had inflammatory behaviour. At prolonged FU phenotype was stable. In the older CD cohort (6–9 yrs) 41% had panenteric disease at diagnosis (45% at FU), 25% had isolated colonic disease, and 17% of this group progressed to penetrating/fistulising disease at follow-up. The older age-group were more likely to have panenteric disease at diagnosis (p = 0.002) or progress to penetrating disease (p Conclusion A third of patients are diagnosed with PIBD present before 10 years of age, with the incidence of very early-onset disease remaining stable in recent years. The requirement for immunosuppression, especially biological therapy, is significant and represents a high disease burden in these patients. Intriguingly, differences exist between those diagnosed at 6–9 years in that they are exposed to immunosuppressants and undergo surgery sooner after diagnosis and are more likely to have panenteric CD at diagnosis and to progress to penetrating disease. Disclosure of interest None Declared.

Introduction Epigenetic alterations including DNA methylation may provide important insights into gene-environment interaction in complex immune diseases such as inflammatory bowel disease (IBD). Whilst whole tissue methylation changes may provide clinically useful biomarkers, epigenetic changes are cell-type specific. This study aimed to characterise the circulating methylome in IBD, and relate changes seen in whole blood to the methylation profile in separated leucocytes, gene expression data, as well as our previous data in childhood-onset disease. 1 Method The Illumina 450k array was used to assess whole blood leucocyte DNA methylation at over 485,000 CpG sites across the genome in 240 patients (121 Crohn’s disease [CD], 119 ulcerative colitis [UC]) and 191 controls. Differentially methylated sites discovered in whole blood were investigated in immunomagnetically separated leucocytes (CD4 + and CD8 + lymphocytes, CD14 + monocytes). Results There were 439 differentially methylated positions (DMPs) meeting epigenome wide significance as defined as a Holm corrected p value of –7 ) in IBD cases versus control. No markers were significantly different between CD and UC. There were 55 differentially methylated regions (DMRs) with unidirectional methylation change in 3 or more adjacent markers each achieving False Discovery Rate significance of p There was significant enrichment of methylation alteration around known susceptibility loci. 2 Linear Discriminant analysis using two CpG sites discriminated IBD cases and controls with high accuracy (area under curve 0.87). Established as well as novel pathways pertinent to disease pathogenesis are strongly implicated. The most significantly DMP in whole blood (RPS6KA2 [corrected p = 1.2 × 10 –16 ] was also hypomethylated in monocytes in UC (uncorrected p = 3.5 × 10 –6 ). The most significant DMR,VMP1/miR21 (most significant probe corrected p = 2 × 10 –14 ) strongly replicates the same finding in our previous study. The gene encoding Beta-2 Integrin (ITGB2) was a hypermethylated DMR in IBD and more specifically CD (most significant probe corrected p = 3.3 × 10 –5 ) compared with controls. Conclusion This is the most detailed characterisation of the epigenome carried out in IBD to date and includes novel data exploring the circulating methylome in UC. The findings strongly validate this approach in complex disease, replicate and expand previous data, and provide clear translational opportunities. Disclosure of interest N. Ventham Grant/Research Support from: EC grant IBD-BIOM, Conflict with: Abbvie, MSD speakers fees, N. Kennedy Grant/Research Support from: Wellcome Trust, Conflict with: Abbvie, MSD, Warner Chilcott, Ferring speakers fees. Shire Travel bursay, A. Adams: None Declared, R. Kalla: None Declared, K. O’Leary: None Declared, IBD BIOM consortium: None Declared, D. Wilson Grant/ Research Support from: MRC, CICRA, and EC grant IBD-BIOM, Consultant for: Pfizer, Conflict with: MSD investigator grant, MSD speaker fee, and Ferring speaker fee, E. Nimmo Grant/ Research Support from: EC grant IBD-BIOM, CSO, J. Satsangi Grant/ Research Support from: EC grant IBD-BIOM, Wellcome, CSO, MRC, Consultant for: Takeda, Conflict with: MSD speaker fees. SHire travelling expenses. References Adams AT, et al . IBD 2014;20(10):1784–93 Jostins L, et al . Nature 2012; 491(7422):119–24

Introduction Although worldwide and Scottish 1 data has clearly shown a persistent rise in paediatric inflammatory bowel disease (PIBD), population-based trends in early-onset incident PIBD (i.e. diagnosed before their 10 th birthday; Paris A1a) are lacking. We aimed to evaluate the incidence of PIBD A1a between 1981–2013 using a complete national cohort study. Method National data from previously published incident cohorts of PIBD in Scotland during 1981–1995 and 2003–2008 were first examined; prospectively collected incident cases from 2009–2013 were also included. Patients were only included following thorough case-note review. As IBD-unclassified (IBDU) was not a recognised IBD type in the earlier cohorts, the classification of non-Crohn’s colitis (NCC; i.e. ulcerative colitis and IBDU combined) was introduced to allow comparisons. Incidence rates were calculated using publicly available population data and trends across cohorts calculated using Poisson regression. Results 402 A1a PIBD patients were identified with a slight (53%) male preponderance; approximately 60% were Crohn’s disease (CD) with the remainder NCC. There was a steady increase in incident cases with 39 patients diagnosed between 1981–1985 and 134 between 2008–2013. The adjusted incidence of A1a PIBD rose from 1.2/100,000/yr (95% CI 0.8–1.6) (1981–1985) to 4.1/100,000/yr (95% CI 3.5–4.7) (2008–2013) (p Conclusion Using population-based Scottish data from the previous four decades we have shown that early-onset PIBD (A1a) has shown a significant rise in incidence, with three-fold increases seen in both the very-early-onset (0–5 yr) and 6–9 yr age groups. However, incidence rates seem to have stabilised in the last decade, despite a sustained rise in overall PIBD. 1 Further examination of these young patients may provide clues to IBD aetiopathogenesis. Disclosure of interest None Declared. References Henderson P, et al . J Crohns Colitis . 2015; 9 (S1):S2 Benchimol, et al . Gastroenterology 2014;147(4):803–813

Introduction The worldwide incidence of paediatric-onset inflammatory bowel disease (PIBD) is rising, with Scotland having the highest rate in the UK. Scottish PIBD data over the last 40 years has shown a consistent increase, including a 76% rise over 13 years around the millennium. 1 The aim of this study was to calculate current PIBD incidence rates in Scotland and to determine if the temporal trend of significant increase has been maintained. Method Historical data from 2003–2008 (cohort 1) was compared to prospective, nationwide data of all incident cases diagnosed in paediatric services (under 16 years of age) from 2009–2013 (cohort 2). Age-sex adjusted incidence rates were calculated using population data from the General Registrar’s Office for Scotland. Cases were classified as Crohn’s disease (CD), ulcerative colitis (UC) or inflammatory bowel disease unclassified (IBDU) and diagnosed according to the Porto criteria. Statistical analysis was performed using Poisson regression. Results A total of 436 patients were diagnosed with PIBD over six years in cohort 1 (265 CD, 115 UC, 56 IBDU) compared to 478 children over five years in cohort 2 (286 CD, 126 UC, 66 IBDU). Median age at diagnosis in cohort 2 (60% males) was 12.3 years, similar to cohort 1 (58% males) at 11.9 years. The adjusted incidence rate increased from 7.8/100,000/year (95% CI 7.1–8.6) in cohort 1 (2003–2008) to 10.4/100,000/year (95% CI 9.6–11.5) in cohort 2 (2009–2013) (p Conclusion There continues to be an ongoing rise in incident PIBD (and both CD and UC) in 2009–13 in this national, population-based study compared to recent historical data, with a further significant rise of 33%. The reasons behind this continued increase remain unclear and further research is needed to elucidate potential factors in aetiopathogenesis. Disclosure of interest None Declared. References Henderson P, et al . Rising incidence of pediatric inflammatory bowel disease in Scotland. Inflamm Bowel Dis . 2012; 18 :999–1005

Introduction Barium meal enteroclysis (BM) is the recommended imaging technique for small bowel inaccessable by ileocolonoscopy when diagnosing paediatric inflammatory bowel disease (IBD) (1). However it is subject to poor sensitivity and involves ionising radiation. MRI enterography (MRE) has recently been reported as an alternative methodology. We aimed to critically appraise the published evidence on use of MRE in diagnosis of paediatric IBD by systematic review. Methods Review of all English language data reporting MRE for the investigation of patients

Introduction Growth failure is well-recognised in paediatric IBD (PIBD; Methods Retrospective review of all children receiving anti-TNF (infliximab (IFX) and adalimumab (ADA)) from 2000–2012 in paediatric services in Scotland. Height (Ht), weight and Tanner stage were collected at 3 times: 12 months before anti-TNF (T-12), start of anti-TNF (T0) and 12 (T+12) months after anti-TNF. Ht and growth were converted into standard deviation scores (SDS) and height velocity (HV, cm/ year) were calculated. Results 97/201 PIBD cases (3ADA, 94 IFX) had 12 month growth data, 58 (59%) males and 90 (93%) Crohn’s disease (CD); 84 (87%) received immunomodulators and 47 (48%) corticosteroids at T0. Median age at diagnosis was 10.3 years. In IFX treated, mean Ht SDS T-12 was -0.67 +/-1.1; improvement was then seen from T0 -0.82 +/-1.1 to T+12 -0.74 +/-1.1 (p = 0.031). Mean ΔHtSDS improved from -0.16 +/-0.38 at T0 to 0.08 +/- 0.36 at T+12 (p 44/94 IFX (48%) were Tanner stage 1–3; 40 CD. Mean HtSDS decreased from -1.0 (+/- 1.1) at T-12 to -1.2 (+/-1.3) at T+12 but, HV 3.6 cm/yr (+/-2.1) at T0 improved to 5.5cm/yr (+/-2.7) at T12 (p 61 (65%) had disease for ≥2 years at start of IFX, HtSDS improved from -0.77+/-1.2 at T0 to -0.65+/-1.2 at T+12 (p = 0.007) whilst disease 0.05). Conclusion Improvements in HtSDS and height velocity at 12 months were seen in the whole cohort. In Tanner 1–3 improvement was only seen in HV after 12 months with no improvement in Ht sSDS. No improvement in height noted in UC. Further follow up will determine if growth improvement is maintained or further improves. Disclosure of Interest None Declared.

Introduction Infliximab and adalimumab have established roles in IBD therapy. NICE and SMC guidelines mandate reassessment of disease activity after 12 months. Therapy should ordinarily be discontinued where clinical remission and mucosal healing has been achieved. However, there are presently few data about outcomes of anti-TNF withdrawal. Methods We conducted a retrospective clinical audit of outcomes following withdrawal of anti-TNF therapy. Inclusion criteria were confirmed diagnosis of IBD; ≥12 m continuous anti-TNF therapy; primary withdrawal reason sustained clinical remission (no corticosteroids for 6 m); ≥12 m follow-up post-withdrawal. Relapse was defined as moderate (oral steroids, immunomodulators, recommencement of anti-TNF agent) or severe (hospitalisation, iv steroids, surgical resection). All UK centres were invited to participate. Demographic and phenotypic data plus clinical, laboratory and endoscopic parameters were recorded. Results 80 cases (62 infliximab; 18 adalimumab) with a median follow-up time of 26 m post drug withdrawal were included in this analysis (59% female; median age at drug withdrawal 32y). All were in clinical remission at withdrawal; 47/80 had normal laboratory parameters (Hb, WCC, plts, Albumin, CRP, FC) prior to withdrawal. 49/80 had endoscopic re-evaluation with mild disease noted on 9/50 and moderate on 1. 23/70 (33%; 2/23 severe) of patients with Crohn’s disease relapsed by 12 months and 49% relapse (3/35 severe) by 24 months (Fig 1, median time to relapse 10.4 m). Younger age at diagnosis (p = 0.017) and elevated WCC (p = 0.025), but not CRP or faecal calprotectin, were predictive of relapse. 4/10 (none severe) with UC/IBDU had relapsed by 12 and 24 months. Anti-TNF therapy was re-introduced in 30 patients following relapse and was successful in 93%. Conclusion Planned withdrawal of anti-TNF therapy for sustained clinical remission is associated with a moderate relapse of Crohn’s disease in up to half of patients by 2 years. Data collection of an expanded cohort is ongoing around the UK to improve power to dissect predictive factors at time of drug withdrawal. Disclosure of Interest None Declared.

Introduction DNA methylation influences transcriptional activity and marks sites of active transcription. Technological developments allow the rapid assessment of methylation state at 450,000 sites across the genome. The aim of this study was to identify genes with a possible role in Crohn’s disease pathogenesis, and candidate genes for methylation based diagnostic biomarkers. Methods Using the Illumina 450k platform we analysed genome-wide DNA methylation in symptomatic children who underwent diagnostic colonoscopy, half of whom were diagnosed with CD and half had no pathology. Replication was performed in children with established CD vs. symptomatic non-disease controls. Further targeted replication by pyrosequencing was performed in adults with CD vs. healthy controls, with qPCR and microarray data to analyse expression. Results Meta-analysis of the combined paediatric datasets (n = 66) identified 165 individual CpGs with epigenome-wide significance (Bonferroni correction) and 138 differentially methylated regions (DMR). Methylation changes were significantly enriched (p The strongest result by each approach was MicroRNA 21, within the autophagy gene VMP1 (p = 1.2 × 10 –14 ), 48 kb from GWAS SNP rs1292053. In adults with CD we replicated MIR21 hypomethylation (p = 6.6 × 10 –5 , n = 172), and showed increased expression in blood (p –6 , n = 99) but not controls (n = 73). Linear discriminant analysis of methylation in the paediatric discovery cohort accurately predicted disease state in the paediatric replication cohort (94% sensitivity, 100% specificity) based on methylation at two CpG sites. Conclusion MIR21 emerges as a target for further investigation based on methylation and expression, further strengthened by other positive findings – notably dysregulation in dysplasia and colorectal cancer in IBD, an established role in T-cell differentiation, and protection from DSS-induced fatal colitis by MIR21 knockout. These data demonstrate a novel approach for identifying biological variations associated with germ-line variants identified by GWAS, and demonstrate translational potential for biomarker development and therapeutic target discovery. Disclosure of Interest None Declared.

Introduction Genome wide association studies and functional experiments in inflammatory bowel disease (IBD) have delineated the importance of autophagy in IBD pathogenesis. We aimed to determine the effect of commonly utilised IBD drugs on autophagy induction and the pathways involved in vitro . Methods Cells naturally expressing (HCT116) and not expressing (HEK293) NOD2, both stably expressing green fluorescent protein-labelled light chain 3 (LC3), were treated with varying concentrations of 6-thioguanine, azathioprine, methotrexate or infliximab at different time points; rapamycin, serum-starvation and bafilomycin A1 served as positive controls. Cells were also treated with ERK (U0126) and autophagy (3-methyladenine) inhibitors where appropriate. For immunofluorescent microscopy images were captured using an Axioskop 2 fluorescent microscope and ImageJ software used to identify cells with >5 punctate foci indicating autophagy induction. For western blot analysis cell lysates were immunoblotted with antibodies to LC3, p62, phospho-rpS6 or total rpS6. All statistical analyses were performed using GraphPad Prism. Results All four drugs induced significant autophagy in HCT116 cells, with only azathioprine inducing autophagy robustly in both cell lines. Azathioprine induced autophagy in a dose-dependent manner in HEK293 cells with significant autophagy induction at all concentrations (30–90 μM) in HCT116 cells. HCT116 cells treated with 6-thioguanine, azathioprine and methotrexate showed strong LC3-I to LC3-II conversion and a reduction in p62, with 6-thioguanine and azathioprine showing loss of phospho-S6K suggesting autophagy induction through the mTORC1 pathway. Use of U0126 and 3-methyladenine in HCT116 cells treated with azathioprine demonstrated that azathioprine may exert its autophagic effect via mTORC1 through the class I PI3K/Akt pathway. Conclusion Common IBD drugs effect autophagy induction in vitro suggesting that manipulation of the autophagy pathway may be partly involved in the mechanism of action of many of these drugs, most convincingly azathioprine. Further work is now required to replicate these findings and further delineate the pathways in vivo . Disclosure of Interest None Declared.

Introduction Inflammatory Bowel Disease Unclassified (IBDU) accounts for ~10% of paediatric IBD (PIBD). The natural history of IBDU includes potential evolution to Crohn’s disease (CD) or ulcerative colitis (UC). Few epidemiologically robust studies of IBDU exist so we aimed to describe the incidence and the natural history of paediatric IBDU in a population-based cohort. Methods Incidence of IBDU was collected over a 10-year period (01/03–12/12) from the two largest Scottish paediatric gastroenterology networks (serving 74.4% of Scottish population Results 65 patients were IBDU (57% male) at diagnosis with a median age of 11.3yrs (range 2.6–15.9). The age adjusted incidence of IBDU was 0.65/100,000/yr (95% CI 0.42–0.97) in the 5-year epoch 2003–2007 and 1.14/100,000/yr (95% CI 0.81–1.56) for 2008–2012, a non-significant increase (p = 0.068). All patients had colonoscopy (74% ileal intubation), 62 (95%) had an upper GI endoscopy; remaining 3 had small bowel imaging. 61 (94%) had radiological imaging, 44 (68%) had a barium meal and follow through with 15 (23%) having MR enterography. At diagnosis, 53 (82%) had a pancolitis, 4 (6%) had disease distal to the hepatic flexure, 5 (8%) had disease distal to the splenic flexure and 3 (4%) had proctitis. 37 (57%) had mild disease (defined as mild infrequent relapses) while 7 (11%) had severe chronically active disease with 5 (8%) requiring Infliximab. Median follow-up was 3.1 yrs (range 0.4–6.8). 16 (25%) had their diagnosis changed (all after endoscopic re-evaluation) after a median of 1.6yrs (range 0.6–5.7), to CD in 11 and UC in 5; 10 (15%) remained IBDU. 3 (4%) required surgery and had colectomy and end ileostomy, 2 (66%) had diagnosis changed to UC prior to surgery whilst the other remained IBDU and reclassified to CD later. Conclusion In the first ever UK population-based epidemiological study of IBDU, the incidence of IBDU demonstrated a non-significant trend to rise during the 10 year study period. 25% of patients had their diagnosis changed after endoscopic re-evaluation, more than previously reported by systematic review (Prenzel and Uhlig JCC 2009) after median follow up of 1.6 years. Most cases had inactive/mild disease activity; a minority remained IBDU despite re-assessment. Disclosure of Interest None Declared.

The aetiology of Crohn's disease is unknown. Any hypothesis must take into account the continuing increase in incidence in some countries, including the UK. The increase affects the population from early teens, and specific comprehensive epidemiological studies in children and adolescents show a continuing rise in the rate of age and sex standardised incidence in Scotland.1 This suggests an environmental trigger, which may interact with underlying genetic susceptibility. A number of such environmental triggers have been proposed, including persistent infections, transient infections in a host with abnormal mucosal immunity, particulate materials, or dietary changes. Persistent infection with the measles virus after wild-type virus infections or immunisation with live attenuated measles vaccine have been proposed as important environmental triggers based on epidemiological observations.2 3 Measles is a single stranded RNA virus which can induce immune suppression. Measles infection is generally self limited and results in long term immunity, but rarely, persistent infection may occur after wild-type virus infection. The virus has special affinity for epithelial cells of the respiratory tract and cells of the immune system, such as lymphocytes and macrophages.4 A number of chronic diseases have been linked with persistent measles virus infection. These include multiple sclerosis, Paget's disease, a variety of autoimmune diseases, and autism, although definite evidence is lacking in each. Inflammatory bowel disease (IBD), especially Crohn's disease, has been linked to persistent measles virus infection. Ekbom et al proposed perinatal exposure to wild-type measles virus may lead to development of Crohn's disease later in life.2 3 Such case control epidemiological studies are of course prone to a variety of confounding factors, especially selection and recall biases. Epidemiologically robust data from a large controlled prospective study showed absence of a link between intrauterine exposure to measles and Crohn's disease.5 However, epidemiological studies linking …

Genetic association of the autophagy genes, autophagy-related 16-like 1 (ATG16L1) and immunity-related GTPase family, M (IRGM), has been confirmed by meta-analysis of three index genome-wide association studies (GWASs), and in other independent studies in adult-onset Crohn’s disease, but not ulcerative colitis.1–5 While the meta-analysis implicated a single nucleotide polymorphism (SNP; rs11747270) based on imputed data from the constituent GWAS with odds ratio (OR) 1.33, other studies have replicated the IRGM signal based on rs13361189 and rs4958847. Recently, rs13361189, upstream of IRGM, was shown to be in perfect linkage disequilibrium with a 20 kb deletion polymorphism affecting the expression of IRGM (and cellular autophagy) in a tissue-specific manner.5 We read with interest the letter by Peterson et al ( Gut 2008; 57 :1336–7) which suggested association of IRGM with childhood-onset Crohn’s disease in a North American cohort. Only one of the two IRGM variants studied (rs13361189) was weakly associated with Crohn’s disease in their study …

Introduction Paediatric intestinal failure (PIF) patients are often dependent on home parental nutrition (HPN) nd rely upon a central venous catheter (CVC) for its administration. There is a significant risk of catheter-related blood stream infections (CRBSI) with associated morbidity and mortality. Studies have suggested that the use of specialist line locks with ethanol or taurolidine may significantly reduce CRSBI for PIF. Our aim was systematically review the evidence for effectiveness of ethanol and taurolidine line locks in the prevention or treatment of CRBSI in PIF. Methods Systematic retrieval of data from studies of PIF (PN > 28 days, age Results The search strategy yielded 3142967 hits. Combination searches using ‘IF’ and ‘Child’ reduced this to 2993. 14 studies were read in detail; 5 were excluded due to containing purely adult data or where data on PIF could not be analysed seperately. Nine studies were included in our review, 5 of CRBSI prevention and 4 of CRSBI treatment. 8 studies used ethanol alone and 1 reported taurolidine use (Table). 4 studies reported success in prevention of recurrent line sepsis. 2 thrombotic episodes were reported. Conclusion The data for the use of ethanol line locks are limited of poor methodoligical quality and of lower EL (there are no RCT’s or well designed cohort studies). However ethanol locks appear to be an effective therapy in CRBSI prevention and treatment. With only 1 study of taurolidine locks no comparison can be made with ethanol locks. Future well designed studies are warranted to compare these two treatments. Disclosure of Interest None Declared.

Introduction Within nutrition support (NS) there is a spectrum of complexity ranging from oral supplements via enteral tube feeding (ETF) to parenteral nutrition (PN) for intestinal failure (IF). Nutrition support teams (NST) are involved with those children with chronic or complex nutrition needs on home ETF (HETF) and home PN (HPN). There is no current robust data available on the prevalence of children on each level of what we newly describe as the nutrition support pyramid (NSP). Aims To introduce the concept of the NSP and to describe the composition and temporal trends in the NSP in a UK regional paediatric cohort. Methods We performed a retrospective cohort study (database/clinical note review) of all children ( Results There were a total of 780 NS episodes in 702 children (51% male); 69 (10%) had multiple episodes of NS. Median (IQR) age at commencing NS was 1.0 (0.2–4.7) yrs. There was a significant increase in the period prevalence of children requiring NS between the two epochs (p=0.004). However, although the number of children requiring HETF (level 1) rose from 372 to 422 between the two epochs, there was a non-significant change in the shape of the NSP (determined by the relative size of each level) between the two epochs (p=0.736). During the entire study period a total of 715 NS episodes were located on the base level (HETF); 31 on the second level (jejunal HETF); 21 on the penultimate level (type II IF); and 14 on the top level (type III IF), with four children requiring Tx to achieve enteral autonomy. Conclusion We have introduced the concept of a NSP, not previously described, and shown that the NSP has significantly increased in size (number of children requiring NS) without a significant change in the shape (relative distribution of complexity). The NSP is a simple tool which allows us to show a significant increase in NST workload without any decrease in complexity over just 7 years. Competing interests None declared.

Introduction Home enteral tube feeding (HETF) is increasingly being used to provide nutrition support (NS) for children to promote growth and development. It is unclear if there are differences in the extent of use and temporal usage trends between neonatal and paediatric clinical practice. Aims To determine: Absolute numbers of children and neonates discharged on HETF from the regional (SE Scotland) tertiary paediatric and neonatal units, the temporal trends in both paediatric and neonatal HETF over an extended period, and the comparison of these trends. The numbers of neonates transferred on enteral tube feeding (ETF) from the regional neonatal to the regional paediatric unit over the last 2 years of the time period and their outcome in terms of need for HETF. Methods A retrospective cohort study (database and clinical note review) to compare numbers of children within the population of 838 573 in Lothian discharged on HETF from the single SE Scottish regional neonatal unit and the single SE Scottish regional paediatric unit, and their inter-relationships. All children and neonates discharged on HETF over the study period 1 July 2000–30 June 2011 were included. The fate of neonatal transfers requiring ETF to the paediatric centre was studied over the period of 1 July 2009–30 June 2011. Results 485 Lothian children were discharged on HETF from the regional paediatric hospital (paediatric HETF) compared with 114 from the neonatal unit (neonatal HETF) over the same time period. Over the study period a rise in numbers requiring paediatric HETF was observed (average of 34 per year in 2000–2005 increasing to 55 per year in 2006–2011), however there was a decreasing number requiring neonatal HETF (average of 16 per year in 2000–2005 decreasing to 8 per year in 2006–2011). HETF was primarily used short term in the neonatal group for immaturity alone. During the 2-year period of the study 7/2009–6/2011, 20 neonates were transferred to the regional paediatric unit on ETF; 11 (55%) were subsequently discharged on HETF from the paediatric unit, but these neonatal transfers only accounted for 10% of the total of 103 paediatric HETF discharges. Conclusion These novel data firstly demonstrate that the incidence of HETF usage on discharge from a UK paediatric regional centre continues to increase while that from the neonatal unit serving the same region is falling, and secondly that sick neonates transferred on ETF make up only a small number of incident paediatric HETF cases. Competing interests None declared.

Introduction Paediatric UC care is variable in the UK and appropriate clinical guidelines are very recent. Acute severe UC is rare with only a few cases presenting annually to each tertiary hospital. Methods UC patients aged Results 176 patients (98 males) of median age 13 years (IQR 10–13) were included in the audit; 22 were elective surgical admissions, 47 new diagnoses and 107 needed acute medical care for known UC. Median length of stay was 6 days (IQR 3–10); there were no deaths. 73% of patients with established disease had a pancolitis and 10% had co-existent liver disease. 88 (70%) of 126 patients with active disease had standard stool cultures performed (2% were positive) and 57 (45%) had C difficile toxin tested (none positive). Stool sample collection rates had improved significantly compared to the 2008 audit (70% vs 52%, p=0.001). 38% of emergency admissions had a plain abdominal XR taken on admission, but only 19% had a specific disease activity index (PUCAI score) recorded. There were three cases of toxic megacolon and 3 of thromboses. Rates of heparinisation were low but higher than in the 2008 audit (11% vs 2%, p=0.002). 71% of patients treated with steroids responded to treatment. 20 patients received 2nd line (rescue) therapy, of whom eight received infliximab, 11 Cyclosporin and one both, with an overall response rate of 90%; nine went to surgery without 2nd line medical therapy. Rescue therapy usage was significantly higher than in the 2008 audit (52% vs 26%, p=0.03). Overall, 71% of non-elective UC admissions were seen by an IBD nurse. Conclusion There were signs of improving UC care from 2008 to 2011 with significantly increased rates of stool culture sampling and use of rescue therapy, but the majority of sites did not use PUCAI scores to assess patients on emergency admission. Competing interests None declared.

Introduction The contribution of HETF issues to PED workload is poorly understood. We aimed to evaluate PED attendance records of children receiving HETF (rates, presenting complaints and outcomes). We also aimed to assess possible trends between timing of attendances and hours of service provided by our Children9s Community Nursing (CCN) team. Methods We searched 114 606 attendances to PED from April 2008 to March 2011, reviewed all those involving cases on HETF, and correlated with our regional paediatric nutrition support team (NST) records. Day, time and month of attendance plus the presenting triage complaint and outcome were noted. Descriptive results are presented with day of week attendance analysed by the z-test. Results There were 364 attendances of 183 patients with a mean (SD) annual point prevalence of HETF patients attending the PED of 23(3.1)%. Mean (SD) attendance rates were 121.3 (23.9) per year representing 61.0(5.2) patients. Presenting complaints included gastrostomy tube (GT) removal (29%), nasogastric tube (NGT) removal (27%), jejunal tube (JT) removal (5%) hardware fault (6%), tube blockage (12%), infection (9%), leakage (4%), malposition (5%) or other (3%). 324 (89%) patients were discharged home and 36 (11%) admitted, mostly for surgical reinsertion. More patients attended on Sundays than any other day of the week (p=0.045); December and January were the busiest months. Peak attendance time was 17:00–18:00; 43% attended out with CCN service hours (08:00–18:00). Most NGT and GT (64%) were reinserted in PED by medical, surgical or nursing staff. Imaging (fluoroscopy; chest x-ray) was required in 29 patients. Topical or enteral antibiotics were prescribed for 22 patients. No action or a simple flush was required in 24 and eight returned the following morning for placement. 20 repair kits for hardware problems were used. Conclusion Over 20% of HETF attend PED annually with feeding tube-related problems; 43% attend out with CCN service hours. Significantly higher attendance rates on the day without CCN service cover highlights a flaw in this service design, given the simple problems that occur usually do not need PED expertise and resources. Competing interests None declared. References 1. Saavedra H , et al. Gastrostomy tube related complaints in the pediatric emergency department. Pediatr Emerg Care 2009; 25 :728–32.

Introduction Current diagnostic practice for paediatric CD in the UK includes increased screening of family members and at- risk groups for example, diabetes mellitus. Aims To identify all incident cases of CD in SE Scotland over the 20-year period of 1990–2009 to assess trends in incidence, symptomatology, age at diagnosis and the impact of active screening of at-risk groups. Utility of routine laboratory tests at diagnosis was also evaluated (2005–2009 diagnoses only). Methods A retrospective review of case notes, pathology databases, endoscopy and patient records was performed for all children diagnosed with CD Results 266 biopsy positive children were diagnosed from 1990 to 2009 with an increase in incidence from 1.8 (95% CI 1.1 to 2.7) to 11.7 (95% CI 9.8 to 13.9) per 100 000 children aged Conclusion The incidence of paediatric CD has increased 6.5-fold over the last 20 years in SE Scotland. Children are older at diagnosis, presenting with fewer classical and more varied symptoms, and with iron deficiency anaemia the commonest laboratory abnormality. We show that both increased screening of at-risk groups and a lower threshold for serological screening (as a result of greater clinician awareness of the condition9s heterogeneic nature) do not fully explain the overall rise in incidence. Competing interests None declared.

Introduction The use of home enteral tube feeding (HETF) in children with chronic illness is increasing. 6-monthly nutritional blood test monitoring (NBTM) while on HETF is recommended by BAPEN for adults; there is minimal evidence to inform guidelines regarding the biochemical monitoring of children on long-term HETF. Aim To provide evidence for or against the practice of 6-monthly NBTM in children receiving HETF. Methods We performed a retrospective review of all children age 12 , fat-soluble vitamins and trace elements (Se, Cu, Zn). Results 42 children were included in the study; none developed refeeding syndrome. 37 (88%) had NBTM performed within 6 months of commencing HETF, 19 (45%) at 6 months after commencing HETF, and 21 (50%) at 1 year after commencing HETF. Significant abnormal parameters identified prior to commencing HETF included low Hb levels (32%), low ferritin levels (31%) and low folate levels (25%). Small groups of between 8% and 10% had low levels of trace elements (Se and Cu) and vitamin D levels. At 6 months and 1 year after start of HETF, there was a small increase of children with low Hb levels (40%) but an improvement in those with low ferritin (14%) and low folate levels (6%). 4% of the study had low vitamin D, and/or trace element (Zn, Cu, Se) levels. There were no toxic levels of vitamins or trace elements within 12 months of start of HETF. Trend comparison was performed in 25 children who had NBTM both before and within a year of commencing HETF. None of the children developed toxic levels of trace elements, one child developed high trace element levels (Se) and another continued to have high Se levels after starting HETF. None of the children developed toxic or high levels of fat soluble vitamins. There were no worryingly low micronutrient levels in any of the 25 children after the start of HETF. Conclusion Children on HETF in our study maintain and had improvement of their micronutrient status after start of HETF. Six monthly blood test monitoring may only be necessary in special circumstances (refeeding syndrome, frankly deficient or toxic micronutrient levels at start of HETF) and may not significantly enhance the overall nutritional monitoring and management of all children on HETF. Competing interests None declared.

Introduction The four tertiary centres in Scotland providing paediatric ( Methods The prospective cohort of HPN cases managed in all 4 tertiary paediatric HPN centres in Scotland (Aberdeen, Dundee, Edinburgh and Glasgow) has been ongoing from 01/2003. We reviewed prevalence and incidence of paediatric HPN for each year from 2003 to 2010 (10 months only for 2010), with point prevalence on the 31 st of each October. Outcomes of interest included fate - continuing HPN or leaving paediatric network, and reason why. Results There were 39 HPN cases in this period, with 6 prevalent cases on 01.01.03. There were 33 incident HPN, and 28 of 39 stopped HPN (14 adapted, 2 withdrew, 1 transitioned, 1 left Scotland, and 10 died). Prevalence and incidence data are shown in table 1. * 01.01.03-31.10.10 only. Conclusion We report nationwide data on the incidence and prevalence of paediatric HPN in Scotland, managed in the 4 HPN centres. Extrapolation of our Scottish nationwide data (collected within a national MCN) to the UK ((nx100/8.6)/12 years) suggests that there are annual minimum paediatric incidences and period prevalences of 48 and 126 cases respectively needing HPN in the UK, with an increasing trend in the last 8 years. These data are important for counselling families and for planning regional and national paediatric HPN specialist services in the UK.

Introduction C reactive protein (CRP) is an acute phase reactant which may possibly link innate and adaptive immunity by binding proteins such as complement factor H. IBD patients with an elevated serum CRP have demonstrated a superior response to biological therapies suggesting that CRP may also play a role in IBD pathogenesis. In addition, a proportion of IBD patients do not have a raised CRP even in the presence of severe inflammatory disease. We aimed to assess the gene-wide association signal of the CRP gene to IBD and Crohn9s disease (CD) susceptibility by means of a detailed haplotype-tagging investigation. Methods 1215 subjects consisting of 465 robustly phenotyped patients diagnosed with inflammatory bowel disease (IBD) 0.1): rs1417938, rs1205, rs1130864, rs1935193 and rs11265263. Two additional SNPs, previously shown to influence serum CRP levels (rs3091244 and rs1800947) were also genotyped. Detailed phenotypic characteristics of this cohort were previously described. Detailed single marker and haplotype analysis by transmission disequilibrium testing (ParenTDT) was carried out using Haploview (with permutation analysis, n=100 000). Results After stringent permutation analysis the rs1417938 A allele, located in the first 59 intron of the CRP gene, showed significant over transmission to affected IBD patients (p=0.0446). The 7-marker haplotype ACACATC also showed significant distortion of transmission (p=0.0068) This same 7-marker haplotype was also significantly associated with Crohn9s disease (p=0.0165). Using a sliding-haplotype analysis to assess the extent of the IBD and CD-associated signal from the 59 end to the 39UTR of the CRP coding sequence demonstrated that the strongest signal (p=0.0013 for IBD, p=0.0050 for CD) was achieved with a haplotype spanning the entire CRP gene. Conclusion We have demonstrated that in a well defined population, using analysis that eliminates the need for population stratification, that inherited variation of the haplotype containing CRP is associated with IBD and CD susceptibility. Our analysis indicates that it is now warranted to submit the CRP gene to further deep sequencing and to re-evaluate the contribution of CRP to IBD pathogenesis beyond its usefulness as an inflammatory marker.

Introduction Inducible T cell costimulator ligand (ICOSLG) is intimately involved in the proliferation and differentiation of T lymphocytes. A locus on Chr. 21q22 harbouring the ICOSLG gene has been shown to influence susceptibility to adult and paediatric Crohn9s disease (CD) and ulcerative colitis (UC). Our aim was to perform a detailed analysis of ICOSLG using a genewide haplotype-tagging approach and to delineate the region of strongest association. Methods 416 patients diagnosed with inflammatory bowel disease (IBD) ICOSLG as well as the region extending to rs762421 which achieved recent genomewide significance. Detailed phenotypic characteristics of this cohort were previously described. SNPs were selected using HapMap data (based on solid spine of LD, MAF > 0.1). Detailed single marker and haplotype analysis by transmission disequilibrium testing (ParenTDT) was carried out using Haploview (permutation analysis, n=100 000). Results The two-marker haplotypes rs762421A/G – rs8126734A/G and rs283529G/C – rs4818890C/A (both located within the 39 UTR of ICOSLG ) showed weak associations with overall IBD susceptibility (p 2 with rs762421 was 0.78 and 0.21, respectively). The two-marker haplotype consisting of rs762421A and rs8126734G also showed significant distortion of transmission (p=0.03). Using a sliding-2 marker haplotype analysis to assess the extent of the CD-association signal from the 39UTR to the 59 end of the ICOSLG coding sequence we found that association signals did not extend upstream from rs8126734, thus implicating the 39 interval between rs762421 and rs8126734 as a target region for deep sequencing. Conclusion We have applied the first family-based association analysis of ICOSLG in childhood onset CD (thus minimising the effect of population stratification) to demonstrate that the signal at the 21q22 locus is due to germline variation at the 39 end of ICOSLG . Our analysis makes it less likely for non-synonymous ICOSLG SNPs or for other genes in the region to contribute significantly to inherited CD susceptibility. Deep sequencing of the 39 UTR of the ICOSLG gene is now warranted to identify causative variants, potentially affecting mRNA stability.

Introduction Biological agents are increasingly used as treatment for paediatric inflammatory bowel disease (IBD) in the UK, yet the evidence base is very limited and safety concerns are rising. We aimed to evaluate pattern of usage, effectiveness and safety in the clinical setting using a Scottish national framework. Methods Usage of the biological agents infliximab (IFX), adalimumab (ADA) and natalizumab (NAT) for treatment of paediatric IBD (aged Results 112 children had 1 or more biological agent administered from a median (range) age of 14.3 (6.6–17.9) years; 50 (45%) were female and 102 (91%) had Crohn9s disease (CD), 8 (7%) had ulcerative colitis (UC) and 2 (2%) had inflammatory bowel disease unspecified (IBDU). Twenty-two (20%) had trials of 2 biological agents. 104 children (98 CD) had IFX, with a median (range) of 4 (1–25) infusions and almost all with moderate-severe IBD. 38 entered remission, 34 responded and 32 had no response. 11 of the 46 (24%) proceeding to maintenance IFX required escalation of therapy. 14 (13%) had infusion events with 3 having anaphylaxis and 7 reactions led to discontinuation. 1 child developed a lupus-like reaction requiring prolonged hospitalisation and 1 had severe infection, with no deaths. 19 (18%) proceeded to ADA. 23 children (all CD) had ADA therapy (including 19 after IFX, 2 as first biological and 2 with inflammatory arthritis in whom CD developed while on etanercept), with a median of 20 doses and nearly all with moderate-severe IBD. 11 entered remission, 6 responded and 6 had no response. All proceeded to maintenance and 11 (50%) required escalation of therapy. 13 had pain at injection site and none had reactions leading to discontinuation. 1 child developed leucopaenia and 1 had a severe viral infection, with no deaths. 2 children with CD had NAT, both in a trial, and both proceeded to IFX after the agent was withdrawn. Conclusion Our nationwide ‘real-life’ experience shows that biological agents are effective in moderate-severe paediatric IBD in the clinical setting, but there are significant financial issues (need for dose escalation or multiple biological usage), as well as safety issues.

Recent genome-wide association studies have identified more than 70 loci which confer susceptibility to Crohn's disease (CD).1 However, the critical coding regions within most of these loci are largely unidentified and it is therefore important that further work is carried out to robustly identify the candidate genes to guide future deep sequencing studies. A locus on chromosome 21q22 harbouring several genes including inducible T cell costimulator ( ICOSLG ), autoimmune regulator ( AIRE ) and periodic tryptophan protein 2 homologue ( PWP2 ) has been shown to influence susceptibility to both adult and paediatric CD and ulcerative colitis (UC).1 2 The protein encoded by ICOSLG is intimately involved in the proliferation and differentiation of T lymphocytes (through binding with inducible T-cell costimulator (ICOS)), especially with regard to the balance between regulatory and Th17 subsets. We read with interest the …

Introduction The incidence of early-onset inflammatory bowel disease (IBD) is high in Europe and North America with numbers rising in recent decades. An accurate indication of the current incidence and temporal trends experienced by a whole population is useful in understanding possible aetiological factors and is essential for the planning of future specialist healthcare provision. Methods This study reports the incidence of early-onset IBD within the Scottish population over a 6-year period (2003–2008), comparing the incidence and demographic attributes to previous figures. Three paediatric gastroenterology networks provide care for all paediatric IBD patients in Scotland. Retrospective data regarding incident cases of IBD diagnosed Results During the study period 430 patients Conclusion The number of Scottish children diagnosed with IBD continues to rise with the rates of IBD and CD rising significantly by 70% and 61%, respectively. Although UC has risen by 25%, this was not significant. This continuing rise has clear implications for the health of Scotland9s children and the local provision of specialist healthcare. A greater understanding of the changing demographic of early-onset IBD may give us clues as to the aetiology of this chronic condition and aid future disease prevention measures.

Introduction A significant proportion of inflammatory bowel disease (IBD) presents in childhood and adolescence, a critical time for growth and development, so timely diagnosis is desirable to ensure patients achieve their growth potential. Our aim was to delineate factors including referral pathway and endoscopic investigation that may delay diagnosis in paediatric-onset IBD (PIBD). Methods We performed a retrospective case note review in a tertiary PIBD centre from 1996–09. Symptom onset was defined as the length of history of presenting complaint; date of presentation was defined as the first presentation, often to primary care. Date of each referral, to whom, and the investigations carried out by each discipline before either diagnosis or onward referral were recorded. Date of diagnosis is defined as the date of the endoscopy providing definitive histological diagnosis. Statistical analysis was performed with Excel. Result 166 PIBD patients with a median (range) age at diagnosis of 11.5 (2–17) years: 58% had Crohn9s disease, 24% had ulcerative colitis and 18% had indeterminate colitis. Median time from first symptoms to diagnosis was 27.5 weeks (2–445) and from first referral to diagnosis was 14 (0–439) weeks. Median (range) time to diagnosis from referral was faster when first referral was made to medical paediatrics in contrast to surgical services at 11 (0–341) vs 33 (0–439) weeks (p=0.001). 23% of patients underwent sigmoidoscopy prior to diagnosis, 12% colonoscopy alone and 67% colonoscopy+upper GI endoscopy (UGIE). 76% of sigmoidoscopies, performed in isolation, were performed by surgeons, whereas 97% of colonoscopy+UGIE were performed by paediatric GI services; sigmoidoscopy diagnosed IBD on 55% of occasions whereas colonoscopy+UGIE diagnosed IBD on 99% of occasions (p=0.0001). Colonoscopy alone was diagnostic on 80% of occasions, inferior to colonoscopy and UGIE (p=0.002). Median time to PIBD diagnosis when sigmoidoscopy was performed prior to diagnosis was significantly longer than for patients who had no sigmoidoscopy performed, at 29.5 (1–402) vs 12 (0–439) weeks (p=0.005). Conclusion Use of sigmoidoscopy as opposed to colonoscopy+UGIE was associated with delayed PIBD diagnosis. We suggest that sigmoidoscopy should be abandoned in the diagnosis of PIBD, and Colonoscopy and UGIE is the endoscopic investigation of choice, supporting the “Porto criteria” for PIBD diagnosis. 1