Gareth Walker

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

HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy

Background Anti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits. Methods The PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development. Findings The Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58). Interpretation HLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

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

PTU-055 Anti-TNF Patient Treatment Preferences: Data from the Pants Study

Introduction Personalised ANti-TNF Study (PANTS) is a prospective observational study of anti-TNF (aTNF) use in patients with Crohn’s disease. Patients receive either 8 weekly intravenous infliximab (IFX) or fortnightly adalimumab (ADA) subcutaneously. Whether patients are given a choice of aTNF agent by their clinician and what factors influence patient’s decision making, is unknown. Methods A voluntary anonymous questionnaire was given to all adult patients upon enrolment into PANTS. 9 point Lickert scales and unprompted free-text entries were used to evaluate 3 domains: a) patient perceptions of aTNF choice, b) the methods used by healthcare teams to impart information regarding aTNF therapies, c) how drug-related factors influenced aTNF choice. Ethics approval ref:12/SW/0323. Results The questionnaire response rate was 40% (534/1339). 57% (305/534) of patients were given a choice of aTNF. A: Patient perception(n = 283). For 73% (206) the ability to choose aTNF treatment was important, and choosing between ADA and IFX was easy (195;69%). About a third (106;37%), however, were either ambivalent, or would rather their healthcare team made the choice for them. 15% (42) of patients felt their healthcare team tried to influence their choice. B: Imparting information(n = 266). Information on aTNF therapies was delivered equally by consultants (221;83%) and IBD nurses (209;79%). Of patients who saw both (n = 123), it was nurses (76;62%) rather than doctors (47;38%) who had the greatest influence over the final decision (p = 0.0089). 53% of all patients (n = 140) conducted their own research; most commonly using patient organisation(45%) and drug company websites (23%). C: Drug factors(n = 287). The most important drug factor which influenced choice of aTNF was place of administration (154; 54%) with 79% (121/154) favouring home rather than hospital treatment. In the free text comments (n = 90), 30% (27) patients stated they preferred ADA as it required them to take “less time off work” and “avoided hospitals”. Conclusion Physicians and nurses need to ascertain if their patients feel strongly about which aTNF treatment they receive, and try to facilitate these preferences where appropriate. Clearly some patients would rather their team made this decision for them. IBD nurses play a crucial role in this process and have significant influence over patient decisions. Patients value the ability to receive their treatment at home, although home IFX infusions may provide a cost effective alternative.1Online resources are commonly used by patients - healthcare teams need to be aware of their content and guide patients towards reliable sources. Reference 1 Kuin S, et al. Remicade infusions at home: an alternative setting of infliximab therapy for patients with Crohn’s. Eur J Gastroenterol Hepatol 2016;28(2);222–5. doi:10.1097/MEG.0000000000000530 Disclosure of Interest G. Walker Consultant for: AbbVie SpR advisory board, Speaker bureau with: Dr Falk Pharma, Conflict with: Educational meeting,travel, accommodation MSD, G. Heap Grant/research support from: AbbVie, Dr Falk Pharma, and Tillotts Pharma UK, Consultant for: AbbVie SpR advisory board, C. Bewshea Grant/research support from: AbbVie, MSD, T. Ahmad Grant/research support from: Unrestricted educational grant/consultancy fees for AbbVie, Merck, Takeda, NAPP, and Celltrion, P. Irving Grant/research support from: AbbVie, MSD., Consultant for: AbbVie, MSD, Vifor, Genentech Inc., Takeda, Warner Chilcott, Falk and Pharmacosmos, Speaker bureau with: AbbVie, MSD, Ferring, Warner Chilcott, Shire and Johnson and Johnson, J. Goodhand: None Declared