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ObjectiveLack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn’s disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD.DesignCandidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores.ResultsA total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion).ConclusionA fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.

Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved. IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

BACKGROUND: Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue. METHODS: We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed. FINDINGS: 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events. INTERPRETATION: Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly. FUNDING: National Institute of Health and Research Health Technology Assessment.

Background: Perianal Crohn’s fistula and their response to anti-tumour necrosis factor (TNF) therapies are best assessed with magnetic resonance imaging (MRI), but radiologist reporting is subjective and variable. This study investigates whether segmentation software could provide precise and reproducible objective measurements of fistula volume. Methods: Retrospective analysis of patients with perianal Crohn’s fistula at our institution between 2007 and 2013. Pre- and post-biologic MRI scans were used with varying time intervals. A total of two radiologists recorded fistula volumes, mean signal intensity and time taken to measure fistula volumes using validated Open Source segmentation software. A total of three radiologists assessed fistula response to treatment (improved, worse or unchanged) by comparing MRI scans. Results: A total of 18 cases were reviewed for this pilot study. Inter-observer variability was very good for volume and mean signal intensity; intra-class correlation (ICC) 0.95 [95% confidence interval (CI) 0.91–0.98] and 0.95 (95% CI 0.90–0.97) respectively. Intra-observer variability was very good for volume and mean signal intensity; ICC 0.99 (95% CI 0.97–0.99) and 0.98 (95% CI 0.95–0.99) respectively. Average time taken to measure fistula volume was 202 s and 250 s for readers 1 and 2. Agreement between three specialist radiologists was good [kappa 0.69 (95% CI 0.49–0.90)] for the subjective assessment of fistula response. Significant association was found between objective percentage volume change and subjective consensus agreement of response (p = 0.001). Median volume change for improved, stable or worsening fistula response was −67% [interquartile range (IQR): −78, −47], 0% (IQR: −16, +17), and +487% (IQR: +217, +559) respectively. Conclusion: Quantification of fistula volumes and signal intensities is feasible and reliable, providing an objective measure of perianal Crohn’s fistula and response to treatment.

Background Perianal Crohn’s fistula and their response to anti-TNF therapies are best assessed with MRI, but radiologist reporting is subjective and variable. This study investigates whether segmentation software could provide precise and reproducible objective measurements of fistula volume. Methods Retrospective analysis of patients with perianal Crohn’s fistula at our institution between 2007 and 2013. Pre- and post biologic MRI scans were used with varying time intervals. Two radiologists recorded fistula volumes, mean signal intensity and time taken to measure fistula volumes using validated open-source segmentation software. Three radiologists assessed fistula response to treatment (improved, worse or unchanged) by comparing MRI scans. Results Eighteen cases were reviewed for this pilot study. Inter-observer variability was very good for volume and mean signal intensity; ICC 0.95 (95%CI 0.91-0.98) and 0.95 (95%CI 0.90-0.97) respectively. Intra-observer variability was very good for volume and mean signal intensity; ICC 0.99 (95%CI 0.97-0.99) and 0.98 (95%CI 0.95-0.99) respectively. Average time taken to measure fistula volume was 202s and 250s for readers 1 and 2. Agreement between 3 specialist radiologists was good (kappa 0.69 [95%CI 0.49-0.90]) for the subjective assessment of fistula response. Significant association was found between objective percentage volume change and subjective consensus agreement of response (p=0.001). Median volume change for improved, stable or worsening fistula response was -67% (IQR:-78,-47), 0% (IQR:-16,+17), and +487% (IQR:+217,+559) respectively. Conclusion Quantification of fistula volumes and signal intensities is feasible and reliable, providing an objective measure of perianal Crohn’s fistula and response to treatment.

Background Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes. Results The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age. Methods Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties. Conclusions In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing.

© 2016 The Authors.Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/- subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon. Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. Results: Colonic DC identified were myeloid (mDC, CD11c+CD123-) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3-CCR2-. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

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