Two-year real-world outcome data from a single tertiary centre shows reduced ustekinumab persistence in a non-bio-naïve Crohn's disease cohort with penetrating disease, -ostomies and sarcopenia.

Background: Ustekinumab was approved in 2016 for the treatment of moderate-severe Crohn's disease (CD). Clinical trials and real-world studies have suggested ustekinumab to be a safe and effective treatment; however, studies to date infrequently use imaging techniques to predict response to biologics in CD. Objectives: We assessed the 2-year real-world effectiveness and safety of ustekinumab in a tertiary CD cohort with the use of novel imaging techniques. Design: Retrospective cohort study. Methods: Retrospective data were collected between 2016 and 2021. Study end points included ustekinumab persistence, biological and/or clinical response and remission at 12, 18 and 24 months. Statistical analysis included demographic and inferential analyses. Results: In all, 131 CD patients [57.3% female, median age of 26.0 (21.0-37.0)] were included. Patients were non-bio naïve, and the majority received ustekinumab as third- or fourth-line treatment. At 24 months, 61.0% (80/131) persisted with ustekinumab [52.7% (69/131) steroid free]. Clinical response was reported in 55.2% (37/67), clinical remission in 85.7% (57/67), biological response in 46.8% (22/47) and biological remission in 31.9% (15/47) of patients at 24 months. The low outcome numbers were attributable to missing data. Improvements in routine disease markers, including C-reactive protein and Harvey-Bradshaw Index, were also reflected in magnetic resonance imaging-derived disease scores. The presence of penetrating CD, an -ostomy and sarcopenia were all predictors of poorer ustekinumab outcomes (p < 0.05). Conclusion: Ustekinumab is effective in non-bio-naïve CD patients with non-stricturing, non-penetrating disease with an unremarkable safety profile but may be less effective in those with penetrating disease, -ostomies and sarcopenia.

Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab.

Background: Sequential drug treatment with biological agents in ulcerative colitis (UC) is becoming increasingly complex. There are few studies comparing head-to-head outcomes in second-line treatments. The study assesses whether using anti-tumour necrosis factor (anti-TNF)-α therapy following the α4ß7 integrin blocker vedolizumab (VDZ) or VDZ after an anti-TNF has more favourable clinical outcomes in UC in a real-world outpatient setting. Methods: Patients with UC who were exposed to first-line anti-TNF (adalimumab or infliximab) or VDZ who subsequently switched to the alternate class between May 2013 and August 2020 were identified by reviewing patient databases at 10 hospitals. Data were collected retrospectively using patient records. Baseline demographics, disease activity indices, biochemical markers, endoscopic Mayo score, colectomy rates, treatment persistence and urgent hospital utilisation composite endpoint (UHUC) rates were examined over a 52-week period. Results: Second-line week 52 treatment persistence was higher in the VDZ group (71/81, 89%) versus the anti-TNF group (15/34, 44%; p=0.0001), as were week 52 colectomy-free survival (VDZ: 77/80, 96%, vs anti-TNF: 26/32, 81%; p=0.009), week 52 UHUC survival (VDZ: 68/84, 81%, vs anti-TNF: 20/34, 59%; p=0.002) and week 52 corticosteroid-free clinical remission (CFCR) rates (VDZ: 22/34, 65%, vs anti-TNF: 4/20, 20%; p=0.001). Conclusion: Compared with second-line anti TNF usage, the VDZ second-line cohort had significantly higher 52-week treatment persistence, UHUC survival, higher colectomy-free survival rates and higher week 52 CFCR. These data suggest that VDZ is an effective biologic in UC as a second-line therapy after anti-TNF exposure. It highlights the effect of biological order on clinically important outcomes.

Benefits of Structured Pediatric to Adult Transition in Inflammatory Bowel Disease: The TRANSIT Observational Study.

OBJECTIVE: To evaluate the impact of structured transition from pediatric to adult inflammatory bowel disease (IBD) services on objective patient outcomes, including disease flares, admission rates, and healthcare resource use. METHODS: A retrospective observational study in 11 United Kingdom gastroenterology centers. Transition patients attended ≥2 visits to the gastroenterology service with both pediatric and adult personnel jointly present; non-transition patients transferred to adult services without joint visits. Data were collected from medical records for the 12-month periods before and after the date of the first visit involving adult IBD services (index visit). RESULTS: A total of 129 patients were included: 95 transition patients and 34 non-transition patients. In the 12 months post-index visit, transition patients had fewer disease flares (P  = 0.05), were more likely to be steroid-free (71% vs 41%, P < 0.05), and were less likely to have an emergency department visit leading to hospital admission (5% vs 18%, P < 0.05). During this period, the mean estimated overall cost of care per patient was £1644.22 in the transition group and £1827.32 in the non-transition group (P = 0.21). CONCLUSION: Structured transition from pediatric to adult IBD care services was associated with positive and cost-neutral outcomes in patients with pediatric IBD.

Prebiotic fructans have greater impact on luminal microbiology and CD3+ T cells in healthy siblings than patients with Crohn's disease: A pilot study investigating the potential for primary prevention of inflammatory bowel disease.

BACKGROUND & AIMS: Siblings of people with Crohn's disease (CD) share aspects of the disease phenotype (raised faecal calprotectin, altered microbiota), which are markers of risk for their own development of CD. The aim was to determine whether supplementation with prebiotic oligofructose/inulin induces a prebiotic response and impacts the risk phenotype in CD patients and siblings. METHODS: Patients with inactive CD (n = 19, CD activity index <150) and 12 of their unaffected siblings (with calprotectin >50 µg/g) ingested oligofructose/inulin (15 g/day) for three weeks. Faecal microbiota (qPCR), intestinal permeability (lactulose-rhamnose test), blood T cells (flow-cytometry) and calprotectin (ELISA) were measured at baseline and follow-up. RESULTS: Following oligofructose/inulin, calprotectin did not significantly change in patients (baseline mean 537 SD 535 µg/g; follow-up mean 974 SD 1318 µg/g, p = 0.08) or siblings (baseline mean 73 SD 90 µg/g: follow up mean 58 SD 72 µg/g, p = 0.62). Faecal Bifidobacteria and Bifidobacterium longum increased in patients and siblings; Bifidobacterium adolescentis and Roseburia spp. increased only in siblings. Compared with patients, siblings had a greater magnitude change in Bifidobacteria (+14.6% vs +0.4%, p = 0.028), B. adolescentis (+1.1% vs 0.0% p = 0.006) and Roseburia spp. (+1.5% vs -0.1% p = 0.004). Intestinal permeability decreased significantly in patients after oligofructose/inulin to a level that was similar to siblings. Blood T cell abundance reduced in siblings but not patients following oligofructose/inulin. CONCLUSIONS: Oligofructose/inulin supplementation did not significantly impact calprotectin, but the prebiotic effect was more marked in healthy siblings compared with patients with inactive CD and was associated with alterations in other CD risk markers. Future research should focus on dietary intervention, including with prebiotics, in the primary prevention of CD.

Ferric carboxymaltose treatment for iron deficiency anemia in children with inflammatory bowel disease: Efficacy and risk of hypophosphatemia.

BACKGROUND: Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS: We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS: All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS: 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS: FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.

A Qualitative Research for Defining Meaningful Attributes for the Treatment of Inflammatory Bowel Disease from the Patient Perspective.

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBD). Each class and type of medication available for the treatment of IBD has distinct characteristics and long-term effects that a patient may consider. We present the results of qualitative research that aimed to develop a descriptive framework that outlines the most relevant disease and/or treatment attributes for IBD treatment decisions and focuses on the patient perspective. METHODS: This research employed a three-step approach: a literature review to identify a broad list of attributes, a focus group meeting including patients and clinicians to assess the relevance of the attributes, and two rounds of voting to name and define each attribute. The literature review was used to develop the initial list of attributes. Although the same attributes were defined for both UC and CD, the relative importance of each attribute to UC or CD was considered. The list of attributes was discussed and evaluated in the focus group meeting, which included eight patient representatives and nine gastroenterologists. Using feedback elicited from the focus group meeting, the research team developed a draft of the descriptive framework that grouped the attributes into domain subsets. All members of the focus group participated in two subsequent rounds of structured, online voting, which was used to refine the wording to name and define each attribute. Additionally, participants ranked all the attributes included in the descriptive framework to suggest which attributes were less relevant and could be omitted. RESULTS: Among 574 publications retrieved from the databases and registries, we identified 32 eligible publications, and an initial list of attributes was developed. This list was refined during the focus group meeting, resulting in a draft descriptive framework of attributes within subsets of domains. The final descriptive framework was developed based on structured rounds of online voting to further refine attribute names and definitions. In the final descriptive framework, a total of ten attributes were identified: abdominal pain, other disease-related pain, bowel urgency, fatigue, risk of cancer and serious infections within the next 10 years, risk of mild to moderate complications, aesthetic complications related to treatment, emotional status, sexual life, and social life and relationships. These attributes were distributed across three domains: efficacy, complications and risk, and health-related quality of life. CONCLUSIONS: Through the identification of the ten most relevant attributes that influence patient decision making for IBD treatments, we developed a descriptive framework that should be considered by physicians when discussing IBD treatment options with their patients. The results of our qualitative research may also be helpful for the development of future IBD clinical studies and quantitative research.

Magnetic resonance enterography compared with ultrasonography in newly diagnosed and relapsing Crohn's disease patients: the METRIC diagnostic accuracy study.

BACKGROUND: Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared. OBJECTIVE: To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease. DESIGN: Prospective multicentre cohort study. SETTING: Eight NHS hospitals. PARTICIPANTS: Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse. INTERVENTIONS: Magnetic resonance enterography and ultrasonography. MAIN OUTCOME MEASURES: The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness. RESULTS: Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests. LIMITATIONS: Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice. CONCLUSIONS: Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03982913. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 42. See the NIHR Journals Library website for further project information.

Crohn's disease is a waxing and waning lifelong inflammatory condition that affects the colon (large bowel) and small bowel. Treatment relies on accurately determining disease extent and underlying inflammation. Colonoscopy is very good for examining the colon, but it is invasive and, at best, can only visualise a few centimetres of the small bowel, so radiological imaging is very important. Magnetic resonance enterography (a type of magnetic resonance imaging scan) and ultrasonography are both radiological tests commonly performed in the NHS, and it is unclear which method is better. We performed a study to compare the accuracy of magnetic resonance enterography and ultrasonography for determining the extent of Crohn's disease in the bowel of participants newly diagnosed and in those participants with established Crohn's disease but with suspected deterioration. We also investigated how often radiologists agree with each other during test interpretation, the participant experience of undergoing the tests and their cost-effectiveness. We compared the tests in 284 participants (133 newly diagnosed and 151 with suspected deterioration). We found that both tests were accurate for detecting the presence (97% for magnetic resonance enterography and 92% for ultrasonography) and location (80% for magnetic resonance enterography and 70% for ultrasonography) of disease in the small bowel, but magnetic resonance enterography was better than ultrasonography for both (correctly classifying disease extent in 107 more participants for every 1000 participants with Crohn's disease). Magnetic resonance enterography was similarly better than ultrasonography at determining if the bowel was inflamed. The results were similar in newly diagnosed participants and those participants with suspected deterioration. Agreement between radiologists interpreting the same images was, at best, moderate for both tests. A total of 88% of participants tolerated magnetic resonance enterography well or fairly well, which was less than the percentage (99%) of participants who tolerated ultrasonography well or fairly well. Both tests had a similar effect on the treatment decisions made by doctors. Both tests were also similar in their value for money for the NHS.

Biologic therapies for Crohn's disease: optimising the old and maximising the new.

The era of biologic agents for the treatment of Crohn's disease has brought about significant benefits for patients, and since the introduction of infliximab at the turn of the century, the entire field has moved on rapidly. Clinicians now have multiple agents at their disposal and a choice between several different anti-inflammatory mechanisms of action. This has allowed unprecedented improvements not only in symptoms and quality of life for patients previously refractory to conventional treatments but also for demonstrated healing of the intestinal mucosa and resolution of perianal fistulation. However, despite the undisputed efficacy of these agents, there remains a significant proportion of patients who fail to gain a meaningful benefit. Through years of studying infliximab and its counterpart anti-tumour necrosis factor (anti-TNF) agent, adalimumab, we now understand that strategies such as combining use with a conventional immunomodulator or measuring serum levels can help to optimise outcomes and reduce the proportion of patients for whom treatment fails. Work is ongoing to understand whether these principles apply to newer biologics such as vedolizumab and ustekinumab. In addition, novel approaches are being investigated in an attempt to maximise the benefit that these agents could offer. In this article, we summarise these new understandings and consider ways in which they could be integrated into clinical practice for the benefit of patients.

Current Practices in Ileal Pouch Surveillance for Patients With Ulcerative Colitis: A Multinational, Retrospective Cohort Study.

BACKGROUND AND AIMS: There are no universally accepted guidelines regarding surveillance of ulcerative colitis [UC] patients after restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA]. There also exists a lack of validated quality assurance standards for performing pouchoscopy. To better understand IPAA surveillance practices in the face of this clinical equipoise, we carried out a retrospective cohort study at five inflammatory bowel disease [IBD] referral centres. METHODS: Records of patients who underwent IPAA for UC or IBD unclassified [IBDU] were reviewed, and patients with <1-year follow-up after restoration of intestinal continuity were excluded. Criteria for determining the risk of pouch dysplasia formation were collected as well as the use of pouchoscopy, biopsies, and completeness of reports. RESULTS: We included 272 patients. Median duration of pouch follow-up was 10.5 [3.3-23.6] years; 95/272 [35%] had never undergone pouchoscopy for any indication; 191/272 [70%] had never undergone pouchoscopy with surveillance as the specific indication; and 3/26 [12%] high-risk patients had never undergone pouchoscopy. Two cases of adenocarcinoma were identified, occurring in the rectal cuff of low-risk patients. Patients under the care of surgeons appeared more likely to undergo surveillance, but rates of incomplete reporting were higher among surgeons [78%] than gastroenterologists [54%, p = 0.002]. CONCLUSIONS: We observed wide variation in surveillance of UC/IBDU-IPAA patients. In addition, the rate of neoplasia formation among 'low-risk' patients was higher than may have been expected. We therefore concur with previous recommendations that pouchoscopy be performed at 1 year postoperatively, to refine risk-stratification based on clinical factors alone. Reports should document findings in all regions of the pouch and biopsies should be taken.

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease. METHODS: A total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed. RESULTS: The 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn's disease. CONCLUSIONS: This study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.

Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn's disease (METRIC): a multicentre trial.

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.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care.

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition2. Risks of failing transition or poor transition3. Models of AYP transition4. Patient and carer/parent perspective in AYP transition5. Surgical perspective.

Siblings of patients with Crohn's disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities.

OBJECTIVE: To determine the existence of mucosal dysbiosis in siblings of patients with Crohn's disease (CD) using 454 pyrosequencing and to comprehensively characterise and determine the influence of genotypical and phenotypical factors, on that dysbiosis. Siblings of patients with CD have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. Whether the mucosal microbiota is disrupted in these at-risk individuals is unknown. DESIGN: Rectal biopsy DNA was extracted from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated healthy controls. Mucosal microbiota was analysed by 16S rRNA gene pyrosequencing and were classified into core and rare species. Genotypical risk was determined using Illumina Immuno BeadChip, faecal calprotectin by ELISA and blood T-cell phenotype by flow cytometry. RESULTS: Core microbiota of both patients with CD and healthy siblings was significantly less diverse than controls. Metacommunity profiling (Bray-Curtis (SBC) index) showed the sibling core microbial composition to be more similar to CD (SBC=0.70) than to healthy controls, whereas the sibling rare microbiota was more similar to healthy controls (SBC=0.42). Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity both between siblings and controls, and between patients and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. CONCLUSIONS: Individuals with elevated CD-risk display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. This dysbiosis in healthy people at risk of CD implicates microbiological processes in CD pathogenesis.

Incidence and Severity of Prepouch Ileitis: A Distinct Disease Entity or a Manifestation of Refractory Pouchitis?

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the operation of choice for patients with treatment-refractory ulcerative colitis. However, after this intervention, up to 50% of patients develop pouchitis. Moreover, a subgroup will also develop inflammation in the afferent ileum proximal to the pouch, a condition named prepouch ileitis (PI). METHODS: Data on 546 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were retrospectively collected from 3 tertiary inflammatory bowel disease referral centers in the Netherlands, Belgium, and England. PI was considered present if there was endoscopic and histological inflammation in the afferent limb proximal to the pouch. Crohn's disease was excluded by reviewing the histology of colectomy resection specimens. RESULTS: PI was present in 33/546 (6%) patients and all of these had concurrent pouchitis. One hundred forty-four (26%) patients had pouchitis without PI and 369 (68%) patients did not have inflammatory pouch disease. Of the 33 patients with PI, 6 (18%) received no specific treatment, 9 (27%) responded to antibiotics, and 18 (54%) required escalation in therapy to steroids/immunomodulators or anti-tumor necrosis factor agents. Potent immunosuppressive treatment was required more frequently in patients with PI than those with pouchitis alone. CONCLUSIONS: PI is less common and more treatment refractory than pouchitis alone. Once PI is diagnosed, clinicians should be aware that response to antibiotic therapy is less likely than in pouchitis alone. Immunomodulatory therapy and escalation to anti-tumor necrosis factor agents should be considered early in cases of nonresponse. The suggestion that PI represents misdiagnosed Crohn's disease could not be substantiated in our cohort.

Lymphoid nodular hyperplasia of the terminal ileum can mimic active crohn disease on MR enterography.

OBJECTIVE: The purpose of this article is to describe the MRI findings associated with lymphoid nodular hyperplasia at MR enterography and test the ability of radiologists to differentiate healthy control subjects from patients with Crohn disease (CD). MATERIALS AND METHODS: Ethical approval was granted for this retrospective study. Thirty-five subjects (nine with lymphoid nodular hyperplasia, 13 with CD, and 13 control subjects) who had undergone MR enterography and ileocolonoscopy were identified from the hospital database. Two abdominal radiologists, working in consensus and blinded to diagnosis, scored enteric MR images for T2 signal, contrast enhancement, mural thickness, and diffusion-weighted imaging (DWI) signal and measured the apparent diffusion coefficient (ADC) in all three groups. Scores were compared using the Kruskal-Wallis test. RESULTS: T2 signal and contrast enhancement were judged subjectively to be greater in patients with lymphoid nodular hyperplasia and CD than control subjects (p < 0.001). Mural thickness was greater for patients with lymphoid nodular hyperplasia (median, 6.0 mm) and CD (median, 7.3 mm) than control subjects (median, 2.3 mm) (p < 0.001). Lymphoid nodular hyperplasia and CD increased subjective DWI signal and reduced ADC in comparison with normal control subjects; median ADC was 1.34 × 10(-3) mm(2)/s for lymphoid nodular hyperplasia, 1.36 × 10(-3) mm(2)/s for CD, and 1.86 × 10(-3) mm(2)/s for control subjects (p < 0.001). None of T2 signal, contrast enhancement, wall thickness, DWI signal, or ADC value significantly differed between lymphoid nodular hyperplasia and CD. Lymphoid nodular hyperplasia was erroneously diagnosed as CD in blinded assessment in four of nine cases (44%), whereas all cases of CD and healthy control subjects were correctly classified. CONCLUSION: Lymphoid nodular hyperplasia alters both subjective and quantitative MRI parameters, including T2 signal, contrast enhancement, mural thickness, and ADC. In a subset of patients, lymphoid nodular hyperplasia may be indistinguishable from CD on MR enterography.

METRIC (MREnterography or ulTRasound in Crohn's disease): a study protocol for a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in those aged 16 and over.

BACKGROUND: Crohn's disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. METHODS: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. DISCUSSION: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. TRIAL REGISTRATION: METRIC - ISRCTN03982913 - 05.11.13.

Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings.

OBJECTIVE: Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. DESIGN: Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip. RESULTS: Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell ß7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 µg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. CONCLUSIONS: Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.

Evaluation of Crohn's disease activity: initial validation of a magnetic resonance enterography global score (MEGS) against faecal calprotectin.

OBJECTIVES: To develop an MRI enterography global score (MEGS) of Crohn's disease (CD) activity compared with a reference standard of faecal calprotectin (fC), C-reactive protein (CRP) and Harvey-Bradshaw index (HBI). METHODS: Calprotectin, CRP and HBI were prospectively recorded for 71 patients (median age 33, male 35) with known/suspected CD undergoing MRI enterography. Two observers in consensus scored activity for nine bowel segments, grading mural thickness, T2 signal, mesenteric oedema, T1 enhancement and pattern, and haustral loss. Segmental scores were multiplied according to disease length. Five points each were added for lymphadenopathy, comb sign, fistulae and abscesses to derive the MEGS. A previously validated MRI CD activity score (CDAS) was also calculated. MRI scores were correlated with clinical references using Spearman's rank. A logistic regression diagnostic model was built to discriminate active (fC > 100 µg/g) from inactive disease. RESULTS: MEGS and CDAS were significantly correlated with fC (r = 0.46, P < 0.001) and (r = 0.39, P = 0.001) respectively. MEGS correlated with CRP (r = 0.39, P = 0.002). The model for discriminating active from inactive disease achieved an area under the receiver-operating curve of 0.75 and 0.66 after leave-one-out analysis. CONCLUSION: A magnetic resonance enterography global score (MEGS) of CD activity correlated significantly with fC levels. KEY POINTS: • Magnetic resonance imaging is now widely used to assess Crohn's disease. • Existing MRI activity scores depend on local segmental endoscopic/histological reference standards. • Scores including assessment of disease extent/complications better demonstrate full disease burden. • This new global Crohn's disease burden score correlates with calprotectin and CRP. • The MRI enterography score of disease activity can complement existing clinical markers.

Azathioprine-associated myelodysplastic syndrome in two patients with ulcerative colitis.

Azathioprine is a commonly used immunosuppressive agent in post-transplantation regimens and autoimmune diseases. An increased risk of lymphoma with thiopurine therapy in patients with inflammatory bowel disease has been described previously; however, there are few reported cases of azathioprine therapy-related myelodysplastic syndrome and acute myeloid leukaemia. We report two patients with ulcerative colitis who subsequently developed azathioprine-related myelodysplastic syndrome. It is imperative that gastroenterologists remain vigilant for this rare complication as this subset of patients has a particularly poor prognosis. These cases are also important in considering the risk of open-ended thiopurine therapy.