Neel Heerasing

Exclusive enteral nutrition provides an effective bridge to safer interval elective surgery for adults with Crohn's disease

Few studies have reported the systematic use of exclusive enteral nutrition in the perioperative setting.

Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study

Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms.

PTH-092 Clinical validity and utility of faecal calprotectin in primary care

Introduction Faecal Calprotectin (FC) is recommended in primary care (1°care) to help differentiate inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS), although data to justify this practice are limited.1,2 In 2014 we introduced FC to 1°care and in parallel conducted a large prospective observational study to assess the clinical validity and utility of FC in this setting, and develop an integrated decision tool. Method GPs from 57 local practices were recommended to submit an FC test for patients with suspected or possible IBD. Criteria for testing included age <46 years and a low suspicion of colorectal cancer (CRC). A request form captured patient symptoms and referral intentions. We used the following cut-offs: negative <50 µg/g, indeterminate 50–99 µg/g, positive ≥100 µg/g. We advised referral of patients with elevated FC and GP management for negative tests. Indeterminate tests were repeated. All patients were followed-up for ≥12 months and clinical data captured from 1° and 2°care records. We assessed the impact of FC on referral practice, time to diagnosis and endoscopic activity. Results 1143 FC tests were submitted (Jan’14-Mar’16), with 761 used in this interim analysis. 458 (59%) were female and median age was 30 years. 50 (7%) patients were diagnosed with IBD, one (0.2%) with an adenoma ≥1 cm and none with CRC. FC≥100 µg/g had a sensitivity=0.92, specificity=0.75, PPV=0.21, NPV=0.99 (AUROC=0.83 [95%CI 0.79–0.87]) for IBD. False negative FC tests occurred in 4 patients later diagnosed with IBD. Red-flag symptoms were reported in 411 (54%) of all patients, 194 (47%) of whom were not referred to 2°care. FC was negative in 520 (68%), and yet 169 (33%) of this group were sill referred to GI services. Multivariable logistic regression demonstrated FC (log10FC=OR 48.2, p<0.01), family history (FHx) of IBD (OR 2.8, p=0.05), and rectal bleeding (OR 3.0, p<0.01) as the best predictors of IBD (R2 0.50). Based on pre-test referral intentions FC saved 252 referrals. The median time from GP referral to IBD diagnosis was 45 days (IQR 25–98). Conclusion FC is a sensitive and specific test in the primary care setting to distinguish IBD from IBS. It reduces referrals and subsequent endoscopic investigations in patients<46 years including those with red-flag symptoms, but deemed at low risk of CRC. However, a third of patients with a normal FC are still referred. This may reflect lack of confidence in FC and the challenges of managing some IBS patients. We propose a future clinical decision tool integrating FC with rectal bleeding and FHx IBD to facilitate rapid patient identification for secondary care referral. References . Waugh N, et al. doi:10.3310/hta17550(2013) . NICE DG11 (2013). Disclosure of Interest None Declared

472 - NUDT15 Variants Contribute to Thiopurine-Induced Myelosuppression in European Populations

Introduction Thiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1 Thiopurine S-methyltransferase (TPMT) variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2 We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing. Method We recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses. Results We first confirmed an association of TIM with TPMT in an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15 (5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15 coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15 genotype (OR 21.7,p=2.0×10-8) and TPMT genotype (OR 2.2,p=2.6×10-4 for MUT/WT and OR 51.2,p=1.8×10-4 for MUT/MUT) were independently associated with TIM. Conclusion These are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15 coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPT genotype and thiopurine dose. Although NUDT15 variants are less common than TPMT variants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15 coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15 heterozygotes is 59%. A future clinical decision tool incorporating NUDT15 and TPMT genotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity. Reference . Gisbert JP & Gomollon F.doi10.1111/j.1572-0241.2008.01848.x (2008) . Yang SK et al. doi10.1038/ng.3060 (2014) Disclosure of Interest None Declared

Interaction Between NOD2 and Smoking in the Pathogenesis of Crohn's Disease

http://dx.doi.org/10.1016/j.ebiom.2017.06.016 2352-3964/© 2017 The Authors. Published by Elsevier B.V Crohns disease (CD) is a common form of chronic inflammatory bowel disease (IBD) affecting 21–294 per 100,000 in European populations (Cosnes et al., 2011). It arises most likely from an interaction between genetic and environmental factors leading to an aberrant immune response to the gut microbiota. Previous genome-wide association studies have describedmore than 200 genetic loci that are associated with IBD (Liu et al., 2015).NOD2 (nucleotide-binding oligomerisation domain containing 2), an intracellular sensor of bacteria-derived muramyl dipeptide, was the first genetic association discovered in CD and remains one of the strongest associations (Knights et al., 2013). The mechanisms whereby NOD2mutations result in intestinal inflammation in CD remain incompletely understood. Evidence suggests that NOD2mutations are associatedwith a loss of innate immune protectivemechanisms in both circulating antigen presenting cells and in the intestine (Van Heel et al., 2006). The three main reported disease-associated polymorphisms (R702W, G908R, and 1007fs) all contribute to disease pathogenesis through interference with bacterial recognition (Van Heel et al., 2006). Several environmental factors have been postulated in CD, but the most consistent epidemiological evidence points to a clear risk associated with cigarette smoking. Two meta-analyses reveal that current smokers are up to twice as likely to develop CD as non-smokers (OR = 1.8–2.0) (Mahid et al., 2006). Cigarette smoking can impair both innate and adaptive immune responses, thereby increasing susceptibility tomicrobial infectionswhichwould support its role in the pathogenesis of CD (Sopori, 2002). The role of genetics and environmental contribution to the aetiology of CD has been the subject of much research over the past decade. It has been reported that cigarette smoke extract can delay NOD2 mRNA expression leading to the impairment of NOD2 functioning in intestinal epithelial cells (Helbig et al., 2012). Given the established roles of NOD2 and cigarette smoking on innate immunity, it is conceivable that cigarette smoking might modulate the functional consequences of CD-associated polymorphism in NOD2 (Helbig et al., 2012). Kuenzig et al. (2017)) describe a study of the interaction of smoking and one of three loss-of-function risk variants in the NOD2 gene (1007fs). This is the first comprehensive systematic review and metaanalysis of the interaction between NOD2 and cigarette smoking in CD.