Association between body mass index and age of disease onset with clinical outcomes in paediatric-onset Crohn's Disease (CD): a UK nation-wide analyses using the NIHR-IBD BioResource.

BACKGROUND: The evidence on the relationship between adiposity and disease outcomes in paediatric Crohn's disease (CD) is limited and lacks consensus. AIM: To investigate the relationship between (a) body mass index (BMI) and clinical CD outcomes (hospitalisation, surgery, disease behaviour, biologic use, extra-intestinal manifestations (EIMs)) and (b) the age of CD onset with clinical outcomes. DESIGN: Clinical outcomes were examined in CD patients diagnosed at age <17 years and enroled in the National Institute for Health Research IBD-UK BioResource at a median age of 24 years. All outcomes and BMI were recorded at the time of enrolment. Participants were categorised into normal (<25 kg/m2) and high (≥25 kg/m2) BMI. Age at disease diagnosis was categorised into pre-puberty/early puberty (<11 years), puberty (11-14 years) and post-puberty (15-17 years). Spearman rank correlation was used to test the associations between continuous variables and chi-square test to compare categorical variables. RESULTS: 848 participants with CD were included (51.8% males) and median age at diagnosis was 14 years. Participants with high BMI experienced a greater frequency of EIMs (P = 0.05) than those with low BMI (1 type of EIM: 18.5% vs. 13.2%, respectively; ≥2 types of EIMs: 7.8% vs. 5.6%, respectively). Age at diagnosis and BMI showed weak correlations with corticosteroid use (ρ = 0.08, P = 0.03 and ρ = -0.09, P = 0.01; respectively). An early diagnosis (<11 years) was associated with higher occurrence of stenosing and penetrating disease behaviour (P = 0.01) and hospitalisations (P < 0.001). CONCLUSIONS: A higher BMI and an earlier age of disease onset are associated with worse CD clinical presentation.

Substantial cost savings of ultrasound-based management over magnetic resonance imaging-based management in an inflammatory bowel disease service.

BACKGROUND: Imaging is used to monitor disease activity in small bowel Crohn's disease (CD). Magnetic Resonance Enterography is often employed as a first modality in the United Kingdom for assessment and monitoring; however, waiting times, cost, patient burden and limited access are significant. It is as yet uncertain if small bowel intestinal ultrasound (IUS) may be a quicker, more acceptable, and cheaper alternative for monitoring patients with CD. METHODS: A clinical service evaluation of imaging pathways was undertaken at a single NHS site in England, United Kingdom. Data were collected about patients who were referred and underwent an imaging analysis for their IBD. Only patients who underwent a therapy change were included in the analysis. Data were collected from care episodes between 01 January 2021-30 March 2022. RESULTS: A combined total of 193 patient care episodes were reviewed, 107 from the IUS pathway and 86 from the MRE pathway. Estimated costs per patient in the IUS pathway was £78.86, and £375.35 per patient in the MRE pathway. The MRE pathway had an average time from referral to treatment initiation of 91 days (SD= ±61) with patients in the IUS pathway waiting an average of 46 days (SD= ±17). CONCLUSIONS: Findings from this work indicate that IUS is a potential cost-saving option when compared to MRE when used in the management of CD. This is in addition to the cost difference of the radiological modalities. A large, multicentre, prospective study is needed to validate these initial findings.

What is already known on this topic ­ Ultrasound is a quick and accurate imaging investigation for patients living with Crohn's disease. Its effect on the cost utility of an Inflammatory Bowel Disease service is unknown.What this study adds ­ This work provides initial data suggesting that an ultrasound-based service may provide significant cost savings when compared to a magnetic resonance imaging-based service.How this study might affect research, practice, or policy ­ This work is part of a larger programme of work to investigate the barriers to wider ultrasound implementation in UK IBD services. This work will contribute to the design of an implementation and training package for intestinal ultrasound in the UK.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Systematic review: Sarcopenia in paediatric inflammatory bowel disease.

BACKGROUND: Low skeletal muscle mass (MM) and deteriorated function (sarcopenia) can be a frequent complication in paediatric inflammatory bowel disease (IBD). AIM: To conduct a systematic review of the paediatric IBD literature on skeletal muscle function and mass and identify interventions that could affect them. METHODS: Systematic searches (EMBASE, Medline, Cochrane library central for registered control trials and Web of Science) were conducted using the terms 'lean body mass' (LM), 'fat free mass' (FFM) or 'MM' and 'IBD'. RESULTS: Fourteenth studies were included, presenting data from 439 Crohn's disease (CD), 139 ulcerative colitis (UC) and 2 IBD-unclassified participants compared with healthy matched or unmatched groups or reference populations. Six out of 14 studies reported lower LM, whilst 7 studies observed lower MM and FFM in CD patients compared to healthy controls. Research in UC patients reported lower LM in 3 studies, lower MM in 3 studies and lower FFM in 4 studies. Three prospective studies measured the impact of enteral feeding and showed improvement on disease activity and LM or FFM, while one retrospective study did not show any impact on LM. CONCLUSION: Despite the variety of experimental approaches and methods used to assess sarcopenia, most studies showed reduction in MM, LM and FFM in IBD. Nutritional intervention may have a positive effect on LM and FFM. Future research should focus on standardizing the terminology and methodologies used in assessing body composition and investigating sarcopenia in diseased and matched healthy control cohorts in adequately powered studies with a longitudinal design.

In Vitro and in Vivo Assays for Testing Retinoids Effect on Intestinal Progenitors' Lineage Commitments.

The intestine consists of epithelial cells surrounded by a complex environment as mesenchymal cells and the gut microbiota. With its impressive stem cell regeneration capability, the intestine is able to constantly replenish cells lost through apoptosis or abrasion by food passing through. Over the past decade, researchers have identified signaling pathways involved in stem cell homeostasis such as retinoids pathway. Retinoids are also involved in cell differentiation of healthy and cancer cells. In this study, we describe several approaches in vitro and in vivo to further investigate the effect of retinoids on stem cells, progenitors, and differentiated intestinal cells.

BSG 2024 IBD guidelines protocol (standard operating procedures).

INTRODUCTION: In the past 5 years, there have been several advances in the management of inflammatory bowel disease (IBD). We aim for a new guideline to update the most recent guideline published in 2019. We present the prospective operating procedure and technical summary protocol in the manuscript. METHODS: 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) will be followed in the development of the guideline, approach as laid out in the GRADE handbook, supported by the WHO. The guideline development group is formed by a variety of disciplines, across both primary and secondary care that took part in an online Delphi process and split into key areas. A final consensus list of thematic questions within a 'patient, intervention, comparison, outcome' format has been produced and agreed in the final phase of the Delphi process.There will be a detailed technical evidence review with source data including systematic reviews appraised with AMSATAR 2 tool (Assessment of multiple systematic reviews), randomised controlled trial data that will be judged for risk of bias with the Cochrane tool and observational studies for safety concerns assessed through the Robins-I tool. Based on the available evidence, some of the recommendations will be based on GRADE while others will be best practice statements.A full Delphi process will be used to make recommendations using online response systems.This set of procedures has been approved by the Clinical Services and Standards Committee, the British Society of Gastroenterology executive board and aligned with IBD UK standards.

Skeletal muscle anabolic and insulin sensitivity responses to a mixed meal in adult patients with active Crohn's disease.

BACKGROUND AND AIMS: We have previously shown reduced protein balance in response to nutrition in paediatric Crohn's disease (CD) in remission, associated with reduced lean mass (sarcopenia) and reduced protein intake in males. We aim to compare skeletal muscle metabolic response to feeding in adult active CD and healthy volunteers. METHODS: Eight CD participants with active disease (41.3 ± 4.5 yrs; BMI 26.9 ± 1.5 kg/m2) and eight matched healthy volunteers (Con) (41.2 ± 4.3 yrs; BMI 25.1 ± 1.1 kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialized hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20mins for 2hrs after the ingestion of a standardized mixed liquid meal. Net balance of branched chain amino acids (BCAA), glucose and free fatty acids across the forearm were derived. RESULTS: No differences in muscle BCAA, glucose or FFA net balance were found between CD and Con. Neither were differences in muscle mass and function, physical activity or diet found. CD did not differ from Con in whole body insulin and lipid responses, or in energy expenditure and fuel oxidation. CONCLUSIONS: Skeletal muscle mass, function, dietary protein intake and response to a test meal in an adult CD cohort with active disease is similar to that seen in healthy volunteers. Combining these results with our previous findings in paediatric patients suggests that age of onset and/or disease burden over time, as well as daily protein intake, may be significant in the development of sarcopenia in CD. Longitudinal studies investigating these factors are required.

Experiences of using vedolizumab in the treatment of inflammatory bowel disease in the East Midlands UK - a retrospective observational study.

PURPOSE: Clinical trials have demonstrated efficacy of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD). Further real-world data is needed to inform clinical practice. The primary outcome was to assess corticosteroid-free and clinical remission after vedolizumab initiation. Secondary outcomes included effect on disease activity scores, biochemical markers, concomitant drug use, endoscopic remission, surgical intervention, hospital admissions and adverse events. MATERIALS AND METHODS: A multi-centre retrospective observational study was conducted with patients initiated on vedolizumab across seven UK hospitals 1/11/14-30/11/16. Clinical disease activity was assessed using the partial Mayo Scores (pMS) and Harvey Bradshaw Index (HBI). Clinical remission was defined as HBI ≤4 or pMS <2 with a combined stool frequency and rectal bleeding sub score of ≤1. Clinical response was defined as ≥2-point decrease from baseline in pMS and ≥3-point decrease from baseline in HBI. RESULTS: One hundred ninety-two patients were included in the final analysis. 45% of UC and 10% of CD patients were anti-TNF naive. Over the observation period corticosteroid-free remission rates for UC and CD were 46% and 45%, while clinical remission rates were 52% and 44%, respectively. Time to corticosteroid free remission for UC and CD was 17.6 [IQR: 8.7-29.6] and 14.1 [QR: 6.0-21.7] weeks, respectively. Time to clinical response for UC was 9.4 [IQR: 5.7-15.4] and CD was 9.5 [IQR: 6.1-18.2] weeks. There was a substantial decrease in the concomitant use of immunomodulators and a similar decrease in concomitant corticosteroid use over the study period. CONCLUSIONS: Results in this predominately anti-TNF experienced population mirror other published real-world data, demonstrating good clinical effectiveness and a comparable safety profile.

Gastrointestinal peptides and small-bowel hypomotility are possible causes for fasting and postprandial symptoms in active Crohn's disease.

BACKGROUND: Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role. OBJECTIVES: This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI. METHODS: We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs. RESULTS: HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05). CONCLUSIONS: The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.

Reduced skeletal muscle protein balance in paediatric Crohn's disease.

BACKGROUND & AIMS: An inability to respond to nutrition could be implicated in low muscle mass in Crohn's disease. We aim to determine skeletal muscle metabolic response to feeding in Crohn's disease and healthy volunteers. METHODS: Twenty asymptomatic Crohn's disease participants (15.6 ± 0.5 yrs; BMI 20.6 ± 0.9 kg/m2); 9 with active disease (faecal calprotectin, 808 ± 225 ug/g and C-reactive protein, 2.2 ± 1.2 mg/dl), 11 in deep remission (faecal calprotectin, 61 ± 12 ug/g and C-reactive protein, 0.3 ± 0.2 mg/dl) and 9 matched healthy volunteers (16.0 ± 0.6 yrs; BMI 20.7 ± 0.6 kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialised hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20 min for 2 hrs after the ingestion of a standardised liquid meal. Net balance of branched chain amino acids (BCAA) and glucose were derived. RESULTS: Controls had a positive mean BCAA balance. CD participants had an initial anabolic response to the meal, with increasing BCAA balance between t = 0 & t = 20, but returned to negative by t = 60. This was associated with reduced FFM z-scores in CD but not with insulin resistance or disease activity. Exploratory analyses suggest that negative postprandial BCAA response seen in CD is predominant in males (p = 0.049), with associated lower appendicular muscle mass (p = 0.034), higher muscle fatigue (p = 0.014) and reduced protein intake (p = 0.026). CONCLUSIONS: The inability to sustain a positive protein balance postprandially could provide an explanation for the reduced muscle mass seen in CD. Further mechanistic studies will be needed to confirm these findings.

Evolution of treatment targets in Crohn's disease.

Crohn's disease is a chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract, associated with significantly morbidity due to both symptoms and complications that have a considerable detrimental impact on a patient's quality of life. An early treat to target approach with disease modifying agents has been shown to significantly improve long term outcomes, demonstrated by a number of therapeutic targets in a number of modalities. This review will outline the current treatment targets and measures of disease burden in Crohn's disease.

Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease.

BACKGROUND: Biological therapy is currently widely used to treat IBD. Infliximab, adalimumab and golimumab are currently licensed anti-TNF therapies. Biosimilar anti-TNF monoclonal antibodies are increasingly used. Anti-TNF therapies are widely used and their adverse effects are well characterised, and may cause significant morbidity and mortality in a small proportion of exposed patients. Gastroenterologists need to understand the mechanisms for these effects, recognise these swiftly and manage such events appropriately. AIM: To cover the range of potential adverse reactions as a result of biologic therapy and specifically management of these events. METHODS: A Medline and Pubmed search was undertaken. Search terms included were "anti-TNF," "infliximab" or "adalimumab" or "golimumab" combined with the keywords "ulcerative colitis" or "Crohn's disease" or "inflammatory bowel disease" and then narrowed to articles containing the keywords "complications," "side effects" or "adverse events" or "safety profile." International guidelines were also reviewed where relevant. RESULTS: Adverse events discussed in this review include infusion reactions, blood disorders and infections (including bacterial, viral, fungal and opportunistic infections) as well as autoimmune, dermatological disorders, cardiac and neurological conditions. Malignancies including solid organ, haematological and those linked to viral disease are discussed. CONCLUSIONS: Anti-TNF therapy has wide-ranging effects on the immune system resulting in a spectrum of potential adverse events in a small proportion of patients. Research advances are improving the understanding, recognition and management of these adverse events.

Acetarsol in the management of mesalazine-refractory ulcerative proctitis: a tertiary-level care experience.

BACKGROUND: Mesalazine-refractory ulcerative proctitis is common, with a significant proportion of the patients requiring escalation to immunomodulators or biological therapy. Three small preliminary cohort studies suggested good clinical efficacy for the organic arsenic derivative acetarsol in the management of proctitis. Our aim was to describe our experience on the use of acetarsol in proctitis and to review all existing evidence on its safety and efficacy. PATIENTS AND METHODS: We retrospectively reviewed clinical records of all ulcerative colitis patients exposed to acetarsol at Nottingham University Hospitals since 2012. Clinical response was determined basing on physicians' global assessments and patients' improvement over the baseline (reduction in stool frequency and rectal bleeding). Clinical remission was defined as total resolution of symptoms including bleeding cessation. Serum arsenic, C-reactive protein and faecal calprotectin levels reviewed when available. Nonparametric analysis performed. RESULTS: Twenty-eight (16 males) patients with median (range) age 39 (35) and 9 (19) years disease duration received acetarsol suppositories for proctitis. All had failed mesalazine or corticosteroid topical therapy, with 50% having additionally failed immunomodulators. Median treatment duration was 70 (64) days. 16/28 were prescribed acetarsol more than once. 67.9% achieved clinical response and 46.4% clinical remission. 32.1% required treatment escalation to steroids, thiopurines or antitumour necrosis factor agents. 6/28 patients stopped acetarsol due to side effects. CONCLUSION: Acetarsol could be an effective and safe option in the management of refractory proctitis. A definitive trial with long-term safety follow-up is required to investigate the efficacy and safety of this promising drug.

An Examination of Appetite and Disordered Eating in Active Crohn's Disease.

BACKGROUND: Crohn's disease [CD] patients suffer from nutritional deficiencies when in active disease. We aim to examine calorific intake, macronutrient choice, and disordered eating behaviour in patients with active CD. METHODS: CD patients with matched healthy volunteers [HV] were recruited. Active disease was defined by faecal calprotectin >250 µg/g, C-reactive protein 83.8 ± 47.1 mg/dL, or active disease seen on endoscopy or imaging. Symptoms were quantified by Harvey­Bradshaw Index [HBI]. Calorific intake was assessed by 24-h dietary recall. Disordered eating was assessed using validated questionnaires: Binge Eating Scale [BES]; Power of Food Scale [PFS]; Control of Eating Questionnaire [CoEQ]; Dutch Eating Behaviour Questionnaire [DEBQ]; and Three Factor Eating Questionnaire [TFEQ]. RESULTS: Totals of 30 CD (18 male[M]:12 female [F], age 32.3 ± 2.19 years, body mass index [BMI] 24.9 ± 0.8) and 31 matched HV [19 M:12 F, age 32.8 ± 2.0 years, BMI 24.7 ± 0.5] were recruited. Mean faecal calprotectin was 1032.5 ± 176 µg/g, C-reactive protein 8.38 ± 4.71 mg/dL, and HBI 4.8 ± 1. There were no significant differences in calorific intake between groups. Protein intake was lower in the CD cohort [p = 0.03]. Hospital Anxiety and Depression score was higher [p = 0.01] and CoEQ-Positive Mood [p = 0.001] lower in CD. CD patients were characterised by higher BES [p = 0.01] and lower CoEQ Craving Control [p = 0.027], with greater craving for Sweet [p = 0.043] and Savoury [p = 0.021] foods. PFS food Present [p = 0.005], DEBQ Emotional [p =< 0.001], and External Eating [p = 0.022] were significantly higher than among HV. CONCLUSIONS: Reduced protein consumption and more prevalent disordered eating behaviour traits were present in CD. Greater binge eating and decreased control of cravings may be attributed to lower mood and higher anxiety observed. Patients may benefit from stronger psychological support with firm dietetic advice for healthy eating.

Orbital Inflammatory Complications of Crohn's Disease: A Rare Case Series.

Orbital inflammatory disease is a rare ophthalmic manifestation of Crohn's disease. Inflammation is characteristically nonspecific, involving one or multiple structures of the orbit. Mechanisms of disease and optimal methods of treatment are poorly understood. The aim of this report is to present 3 cases of orbital involvement in Crohn's disease. A retrospective case note review of patients with orbital inflammatory disease and Crohn's disease was performed at our academic center to determine the clinical, imaging, and histopathologic features of this condition and its relationship to intestinal Crohn's disease. Three patients were identified with orbital inflammatory manifestations complicating Crohn's disease. All patients described were women with active intestinal disease and had a history of treatment with immunosuppressive therapies. Similarities were observed in clinical presentations with variance noted in radiologic and histopathologic findings. In all cases, symptoms improved with oral corticosteroids or nonsteroidal drugs in combination with anti-tumor necrosis factor agents. Inflammatory bowel disease-related orbital complications are rare but potentially vision-threatening. It is important to consider mimics of orbital inflammatory disease such as systemic inflammatory disease, malignancy, congenital malformations, infection, and trauma when formulating a comprehensive differential diagnosis. Therapeutic intervention is directed toward preservation of vision and orbital function and reducing the acute inflammatory process. Corticosteroids are typically the initial treatment of choice for moderate-to-severe disease, although several classes of immunomodulatory agents have been variably useful in treating this condition. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are mandatory.

Surgical Rates for Crohn's Disease are Decreasing: A Population-Based Time Trend Analysis and Validation Study.

OBJECTIVES: Temporal changes for intestinal resections for Crohn's disease (CD) are controversial. We validated administrative database codes for CD diagnosis and surgery in hospitalized patients and then evaluated temporal trends in CD surgical resection rates. METHODS: First, we validated International Classification of Disease (ICD)-10-CM coding for CD diagnosis in hospitalized patients and Canadian Classification of Health Intervention coding for surgical resections. Second, we used these validated codes to conduct population-based surveillance between fiscal years 2002 and 2010 to identify adult CD patients undergoing intestinal resection (n=981). Annual surgical rate was calculated by dividing incident surgeries by estimated CD prevalence. Time trend analysis was performed and annual percent change (APC) with 95% confidence intervals (CI) in surgical resection rates were calculated using a generalized linear model assuming a Poisson distribution. RESULTS: In the validation cohort, 101/104 (97.1%) patients undergoing surgery and 191/200 (95.5%) patients admitted without surgery were confirmed to have CD on chart review. Among the 116 administrative database codes for surgical resection, 97.4% were confirmed intestinal resections on chart review. From 2002 to 2010, the overall CD surgical resection rate was 3.8 resections per 100 person-years. During the study period, rate of surgery decreased by 3.5% per year (95% CI: -1.1%, -5.8%), driven by decreasing emergent operations (-10.1% per year (95% CI: -13.4%, -6.7%)) whereas elective surgeries increased by 3.7% per year (95% CI: 0.1%, 7.3%). CONCLUSIONS: Overall surgical resection rates in CD are decreasing, but a paradigm shift has occurred whereby elective operations are now more commonly performed than emergent surgeries.