Fraser Cummings

Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

A genome-wide association scan in individuals with Crohns disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 × 10−4, combined P = 2.1 × 10−10) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohns disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohns disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07–3.26, P = 2 × 10−16). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01–HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Summary Background Up to 60% of patients with Crohns disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohns disease. Methods We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohns disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohns disease (Crohns Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). Findings Between June 6, 2008, and April 23, 2012, 240 patients with Crohns disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohns disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. Interpretation Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohns disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. Funding Medical Research Council.

Tuberculosis and TNF-inhibitors: history of exposure should outweigh investigations

A 39-year-old Indian man was diagnosed with ulcerative colitis on colonic biopsy and started on mesalazine, prednisolone and azathioprine. However, the colitis remained active and required antitumour necrosis factor (TNF) treatment with infliximab. Prior to starting infliximab, his chest X-ray was normal and QuantiFERON interferon γ release assay for tuberculosis (TB) was negative. However, his wife had been treated for pulmonary TB 11 years previously when they were cohabiting. On attending for his third dose of infliximab, he was feverish and tachycardic, and was admitted for investigation. Chest X-ray on admission showed changes consistent with miliary TB, and thoracic CT confirmed extensive miliary nodules with supraclavicular and mediastinal lymphadenopathy. Abdominal CT showed multiple mesenteric lymph nodes. Subsequent bronchoalveolar lavage, neck lymph node aspirate and colonic biopsies all cultured Mycobacterium tuberculosis. In retrospect, a clear history of close household TB exposure should have precipitated consideration of TB chemoprophylaxis prior to anti-TNF treatment.

Inflammatory bowel disease registries for collection of patient iron parameters in Europe

Iron deficiency without anemia and iron deficiency anemia are common and frequently overlooked complications of inflammatory bowel disease. Despite the frequency and impact of iron deficiency in inflammatory bowel disease, there are gaps in our understanding about its incidence, prevalence and natural history and, consequently, patients may be undertreated. Medical registries have a key role in collecting data on the disease’s natural history, the safety and effectiveness of drugs in routine clinical practice, and the quality of care delivered by healthcare services. Even though iron deficiency impacts inflammatory bowel disease patients and healthcare systems substantially, none of the established European inflammatory bowel disease registries systematically collects information on iron parameters and related outcomes. Collection of robust iron parameter data from patient registries is one way to heighten awareness about the importance of iron deficiency in this disease and to generate data to improve the quality of patient care, patient outcomes, and thus quality of life. This objective could be achieved through collection of specific laboratory, clinical, and patient-reported measurements that could be incorporated into existing registries. This review describes the status of current European inflammatory bowel disease registries and the data they generate, in order to highlight their potential role in collecting iron data, to discuss how such information gathering could contribute to our understanding of iron deficiency anemia, and to provide practical information in regard to the incorporation of accumulated iron parameter data into registries.

OTU-028 Benchmarking of activity, process and outcome of emergency admission for ulcerative colitis across english hospitals

Introduction The UK IBD Registry aims to make information work better for patients, clinical teams and the NHS. As part of the benchmarking reports provided to participating Trusts, we have developed organisational level metrics from routinely collected hospital episode statistics (HES) data – working with front-line teams to iteratively develop reports with feedback on content and local face-validity. We report national-level findings and institutional variation in activity, process and outcome of emergency care for UC. Methods Admitted patient care data for English hospitals were analysed, identifying all-cause admissions for patients with UC and constructing algorithms to identify emergency activity, track process and outcome for UC-specific emergency admissions (UC-Em-Ad), including in-hospital death (I-H-D) and emergency surgery (Em-Surg), all-cause 30 day readmission (30D-RA) and twelve month outcome. Reports containing 5 year national and local trends and cumulative 5 year performance were distributed to sites in Dec 2017. This analysis summarises selected data for 133 Trusts present in all fiscal years (11/12 to 15/16). Results Nationally, there were 31,371 UC-Em-Ad (2 65 799 bed days; median LoS 6 days; 22 809 patients; mean age 40 years; male 50%; additional coded co-morbidities in 23%) with 1451 Em-Surg (4.62%=crude surgery rate; mean age 44 years; male 56.1%), 324 I-H-D (1.03%=crude mortality rate; mean age 76 years; 67% had additional coded co-morbidities; only 16% of deaths were post-surgery), 4916 30D-RA (15.7%=crude readmission rate). At Trust level, mean (95% limits) for indirectly standardised rates were: I-H-D 1.03% (0.90%–1.15%), Em-Surg 4.79% (4.31%–5.27%), 30D-RA 15.55% (15.0%–16.1%). Few outliers were identified and none consistently over time, with no significant trends identified for volume-outcome relationships. Funnel plots and regression analyses will be presented. Conclusions These data provide real-world insights into processes and outcomes of emergency care for UC across England in the last five years, with a series of metrics to support both national and local quality improvement efforts. Linkages between HES and local Registry data offers potential to validate, refine and extend these benchmarking metrics. Funding Crohn’s and Colitis UK.

PTH-090 Monitoring unplanned care and surgical events for crohn’s disease patients treated with biologics in england: linkage of routine administrative data and uk ibd registry

Introduction The UK IBD Registry (UK-IBD-R) is developing analyses of Hospital Episode Statistics (HES) with linkage to locally-recorded registry data to generate aggregated reports and indicators to support IBD services. We have created methods to categorise relevant hospital events and track outcomes in HES. For this project, we produced metrics of unplanned care and surgical events before and after initiation of biologics, generating a national scale analysis from HES alone and a proof-of-concept study with linkage to UK-IBD-R. Method Datasets: HES for England (04/05 to 13/14); UK-IBD-R dataset (to June 2016). Patient cohorts: (1) HES cohort identified using HES only. We flagged all admissions (incl. daycases) with a diagnosis of CD and procedure code X921 (biologic infusion; assumed to be infliximab), locating 1 st infusion for each case; (2) Registry cohort was based on anonymized linkage (undertaken by NHS Digital), identifying cases with a registry-recorded diagnosis of CD, a medication entry for anti-TNF drug (infliximab, inflectra or adalimumab) and a valid start date. Hospital events in HES: All-cause episodes were extracted for 1 year before (Yr-Pre) and after (Yr-Post) start of treatment, categorising each inpatient and daycase event based on admission method, diagnoses (IBD-specific, IBD-related and Other) and procedures. Abstract PTH-090 Figure 1 Results HES cohort: n=15 399 (Age: 35 [16]; 47% male); Registry cohort: n=217 (Age: 26 [13.5]; 56% male). Unplanned care activity for Yr-Pre versus Yr-Post are shown in Abstract PTH090 Figure 1, confirming substantial reductions in all-cause and CD-specific emergency care following initiation of biologics in routine UK practice (p<0.05). Of HES cohort, 10 877 (71%) continued infusion visits beyond induction phase (’Maintenance’), and 4522 (29%) did not (’Stopped’). Surgical resections at 1 year: Total, 944 (6.2%); Maintenance versus Stopped: 395 (3.6%) v. 549 (12%), p<0.05. Emergency admissions with ‘infections’ at 1 year: Total, 222 (1.4%); Maintenance versus Stopped: 146 (1.3%) v. 76 (1.7%), p=0.11. Conclusion These national scale data provide new insights into activity, costs and outcomes associated with routine use of biologics for CD in England. Linkage between UK-IBD-R and HES provides a potentially powerful tool for monitoring of activity, process and outcome of IBD care. The use of existing datasets reduces the burden of local point-of-care data collection, allowing focus on collecting items to enhance accuracy and clinical depth of analyses. [Funding: Crohn’s and Colitis UK] Disclosure of Interest None Declared

PTH-096 Improved outcomes of emergency admission for ulcerative colitis (uc) in england over the last decade: a ten year analysis of routine nhs data

Introduction Hypothesis: Over the last decade, therapy advances and a national audit programme should have improved outcomes for UC patients admitted as emergencies (Em). Method To support IBD Registry analytics, we have developed metrics from routine NHS data to allow reporting of trends in national-level indicators of IBD care. Design: Retrospective analysis of 10 years of HES data for England. Target population: 54,533 Em. admissions with UC as primary diagnosis (April ‘05 to March ‘13; n=37 170 patients). Binary Outcome Measures: Surgery (colectomy) during index admission (Sx-Index) or within 1 year (Sx-1-Year); Em. readmission within 30 days of discharge (Readmit-30d); Inpatient death during index admission (Death-Index). Case-mix Variables: Age, Gender, Co-morbidities (0, 1 or 2+, Charlson), Deprivation Status (IMD Quintiles), Any Cancer, Em. bed bays (all-cause) in preceding year (EmBedDaysLastYr). Predictor Variable: Year of Admission (Yr-Adm). Analyses: Uni- and multivariable logistic regression (stepwise), reporting adjusted odds ratios (OR) for retained variables. Adjusted for repeat admissions in same patient (clustered standard errors). Results Multivariable Models: OR for Sx-Index was reduced with increased age (0.98 per yr), 2+ co-morbidities (0.81 vs. none), females (0.74 vs. male) and for >28 EmBedDaysLastYr. OR for Death-Index was increased with increased age (1.10 per yr), co-morbidities (1.87 for one, 3.2 for two or more, vs none) and colectomy during admission (6.99 vs. no surgery) but reduced for >28 EmBedDaysLastYr (0.88 vs. none). Models for Sx-1-Year showed a similar pattern with respect to reduced OR for age, co-morbidity and females. For Readmit-30d, the most significant factor associated with reduced OR was colectomy during admission (0.43), whereas >28 EmBedDaysLastYr was associated with increased OR (2.0 vs. none). Deprivation status was not independently associated with any outcome. After adjusting for these co-variates, Yr-Adm was associated with a significant reduction in OR for both Sx-Index and Death-Index, with OR of 0.98 (0.976–0.998) and 0.91 (0.88, 0.94) per yr relative to base year. Models for all-cause admissions did not show these trends, suggesting condition-specific findings. Conclusion Risk of colectomy and inpatient death for UC patients admitted as emergencies to English hospitals has reduced over the last 10 years. Many factors may explain these trends, but cycles of UK-wide IBD audit are likely contributors. We found no signal for social inequality, but a reduced odds of surgery for females requires further study. Funding: Crohn’s and Colitis UK Disclosure of Interest M. Shawihdi: None Declared, S Dodd: None Declared, R Grainger: None Declared, S Bloom: None Declared, F Cummings: None Declared, R Driscoll: None Declared, M Pearson: None Declared, P Williamson: None Declared, K Bodger Conflict with: AbbVie, Conflict with: Boston Scientific | Takeda

Transcriptomic Profiling of Intestinal Macrophages Isolated from Patients Reveals a Profound Gene Expression Reprogramming Underlying IBD Pathogenesis

Introduction Macrophages play a major role as effector cells of the innate immune system and are vital for intestinal tissue homeostasis. An altered function of intestinal macrophages may contribute to the development and propagation of intestinal inflammation in IBD. However, all data available come from mouse models, human whole tissue or in vitro derived macrophages from blood monocytes. We have isolated intestinal macrophages from patients and healthy subjects and analysed their transcriptome in order to study the intrinsic role that macrophages play in the pathogenesis of IBD. Method Fresh colonic mucosal tissue biopsies from 10 CD patients, 10 UC patients and 10 healthy controls were disaggregated to cell suspensions and sorted using fluorescence-activated cell sorting. RNA from intestinal macrophages, identified as CD163+CD14+CD3- population, was extracted and subjected to RNA sequencing. Differential Gene Expression analysis and pathway analysis were performed between the groups. Results The transcriptomic analysis revealed that the gene expression profile of the intestinal macrophages from IBD is dramatically reprogrammed. Differential Gene Expression analysis revealed 1287 DEGs between macrophages from UC patients and healthy controls; 840 DEGs between macrophages from CD patients and healthy controls and 20 DEGs between macrophages from UC and CD patients (1.5 fold change and FDR Conclusion This is the first study to describe the transcriptome of intestinal macrophages from active lesions of patients with IBD by high throughput RNAseq. We show that the transcriptome of these macrophages is profoundly different from those taken from healthy subjects. These results suggest that macrophages play an important role in the propagation of inflammation and we have identified a number of molecules that should be investigated as potential therapeutic targets. Disclosure of Interest None Declared