register interest

Professor Simon Travis FRCP

Research Area: Drug Discovery
Technology Exchange: Drug discovery and In vivo imaging
Keywords: ulcerative colitis, Crohn's disease, outcomes research, clinical trials and novel drug therapy
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Ulcerative colitis and Crohn’s disease (‘IBD’) are one of the central clinical and scientific
problems in Gastroenterology, affecting the lives of over 2 million people in Europe and their families, costing over €4bn/yr. The causes are unknown, but the rapid rise in cases in the Gulf, Indian subcontinent, East Asia and Latin America mirror changes that happened in Western Europe and North America fifty years ago. Predicting the prognosis, reliable metrics for clinical trials and novel therapy are pivotal to progress in a condition that predominantly affects young people, has a definable mortality and cure is still impossible. Our clinical research into IBD includes:

  • Predictive indices for ulcerative colitis. After developing the Oxford predictive index for acute severe colitis in 1996, the index has been independently validated (2009), incorporated into practice (four UK National IBD Audits since 2008 and all international guidelines) and been the basis of the CONSTRUCT HTA-funded trial (2009-14). A new index for predicting the risk of acute severe colitis (2013) over the next 3 years from diagnosis, has now been independently replicated in Cambridge and Uppsala (2014)
  • Endoscopic assessment of ulcerative colitis. An international programme of the world's leading IBD specialists created the first validated endoscopic index for ulcerative colitis (UC), now (2015) being introduced into Phase 2 and 3 trials and clinical practice. It is (2015) under consideration as the endoscopic index of choice for central reading in clinical trials. This has reduced variance in endoscopic reporting from 73% to 14%.
  • Evaluation of novel therapies for inflammatory bowel disease (IBD): Global Chief Investigator of 8 clinical trials of therapy for IBD, some through to registration and UK CI or PI in 20 others, including a first in class small molecule for ulcerative colitis, stem cell transplantation for Crohn’s, anti-CD3 MAb for ulcerative colitis, post-operative prevention studies and devices (an adsorbent compound AST-120). As senior author on the first trial of an anti-IL17A MAb (secukinumab, Novartis), we were first to report that this exacerbated Crohn’s disease, in contrast to its therapeutic benefit in psoriasis and rheumatoid arthritis and that a SNP in the TLA1 gene might (in contrast) be associated with therapeutic benefit.
  • Measurement of outcomes for clinical trials and practice: An explicit recommendation for defining robust criteria for entry into clinical trials of ulcerative colitis and endpoints helped reduce the placebo response from 20-30% in past trials of UC to <5% for budesonide MMX (Cosmo), leading to drug registration by the FDA and EMA (Global Chief Investigator). Development of the Oxford IBD cohort for the Translational Gastroenterology Unit (Co PI with Uhlig, Powrie, Keshav) in the clinical description/ research database and genetic characterisation of >2000 patients with IBD.   
  • Gastrointestinal bleeding: The paradigm of liberal blood transfusion for acute gastrointestinal bleeding was challenged through the UK’s first cluster-randomised trial (Lancet 2015). Co-supervisor of the UK’s first prospective national audit of GI bleeding, transfusion practice and outcomes.
  • Quality of life and burden of IBD: Chair of a global group to develop patient outcome measures for IBD through the Oxford Academic Health Sciences Network (2015-). Also developing real-time data collection in ulcerative colitis (TrueColours in IBD) to relate fluctuations in disease activity with the biology of the disease

Simon Travis is the author of 6 books, 29 chapters and over 230 papers. He was President of the European Crohn’s and Colitis Organisation (ECCO), an elected Member of the International Organisation of Inflammatory Bowel Disease and author of 22 peer-reviewed international guidelines. Member of Council of the British Society of Gastroenterology (2004-2007) and Chair of the scientific committee of ECCO (2007-2010). He is on the Editorial Board of Gut (IF 14.8) and Journal of Crohn’s & Colitis (IF 6.2), among other journals.

Name Department Institution Country
Professor Satish Keshav Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Professor Jean-Frederic Colombel Mt Sinai Hospital, New York United States
Professor William Sanborn University of San Diego, California United States
Professor Bruce Sandt Mt Sinai Hospital, NY United States
Professor Philippe Marteau Hôpital Lariboisière, Paris France
Professor Chris Hawkey University of Nottingham United Kingdom
Professor John Williams University of Swansea, Wales United Kingdom
Prof Mike Murphy (RDM) Nuffield Division of Clinical Laboratory Sciences Oxford University, John Radcliffe Hospital United Kingdom
Professor Joseph Sung Chinese University of Hong Kong China
Dr Alissa Walsh St Vincent's Hospital Sydney Australia
Professor Vineet Ahuja Gastroenterology AIIMS, New Delhi India
Professor Haruhiko Ogata Keio University, Tokyo Japan
Associate Professor Siew Ng Chinese University of Hong Kong Hong Kong
Professor Jane Andrews Royal Adelaide Hospital Australia
Associate Professor Graham Radford-Smith Royal Brisbane Hospital Australia
Professor Ian Lawrance University of Western Australia Australia
Professor Daniel Hommes University of California, Los Angeles United States
Dr Saad Al Kaabi Hamad Medical Corporation, Doha Qatar
Professor Peter Gibson Monash University, Melbourne Australia
Bryant RV, Schultz CG, Ooi S, Goess C, Costello SP, Vincent AD, Schoeman S, Lim A, Bartholomeusz FD, Travis SPL, Andrews JM. 2018. Authors' reply: The Association Between Visceral Adipose Tissue and Stricturing Crohn's Disease Behavior, Fecal Calprotectin and Quality of Life. Inflamm Bowel Dis, | Read more

Irving P, Burisch J, Driscoll R, Olsson M, Fullarton JR, Rodgers-Gray BS, Travis SP. 2018. IBD2020 global forum: results of an international patient survey on quality of care. Intest Res, 16 (4), pp. 537-545. | Show Abstract | Read more

Background/Aims: IBD2020 is a global forum for standards of care in inflammatory bowel disease (IBD). The aim of the IBD2020 survey was to identify and describe variations in quality care of IBD. Methods: Patients with IBD from Finland, Italy, France, Canada, Germany, UK, Spain and Sweden were surveyed during 2013 to 2014, covering: disease characteristics; impact on life and work; organization and perceived quality of care. Results: Seven thousand five hundred and seven patients participated (median age, 39 years [range, 10-103 years]; 2,354 male [31.4%]), including 4,097 (54.6%) with Crohn's disease (CD) and 3,410 (45.4%) with ulcerative colitis (UC). Median time from symptom onset to diagnosis was 1 year for both CD (range, 0-47 years) and UC (range, 0-46 years), with no clear evidence of improvement in diagnostic delay over the preceding 24 years. Half of the patients (3,429; 50.0%) rated their care as "excellent" or "very good," with similar results for CD and UC across countries. Five factors were significantly (P<0.01) associated with perceived good quality of care: quality of specialist communication; review consultation being long enough; failure to share information; no access to a dietician; speed of advice. Conclusions: The IBD2020 survey has highlighted areas related to quality of care of IBD from the patients' perspective, with scope for improvement.

Lahiff C, Wang LM, Travis SPL, East JE. 2018. Polyp-adjacent biopsies no longer required in inflammatory bowel disease. Gastrointest Endosc, 88 (4), pp. 782-783. | Read more

Bryant RV, Schultz CG, Ooi S, Goess C, Costello SP, Vincent AD, Schoeman S, Lim A, Bartholomeusz FD, Travis SPL, Andrews JM. 2018. Visceral Adipose Tissue Is Associated With Stricturing Crohn's Disease Behavior, Fecal Calprotectin, and Quality of Life. Inflamm Bowel Dis, | Show Abstract | Read more

Background: Visceral adipose tissue (VAT) has been proposed to play a pathogenic role in Crohn's disease (CD); however, prospective clinical data are lacking. The aim was to evaluate whether VAT, beyond body mass index (BMI), is associated with CD behavior, disease activity, quality of life (QoL), or outcomes. Methods: Body composition data and clinical, anthropometric, disease activity (fecal calprotectin [FC]), and QoL scores were gathered prospectively on adults with CD at 0, 12, and 24 months. BMI and, VAT metrics (visceral adipose tissue volume [cm3]/height [m2] index and VAT:subcutaneous adipose tissue [SAT] ratio) were calculated. Inflammatory bowel disease-related surgery and hospitalization were recorded over extended follow-up (median, 51 months). Multivariable linear mixed effects and logistic regression analyses were performed. Results: Ninety-seven participants were assessed at baseline (55% male; median age, 31 years), 84 at 12 months, and 72 at 24 months. VAT:SAT was positively associated with stricturing disease behavior (log odds ratio [OR], 1.7; 95% confidence interval [CI], 0.32 to 3; P = 0.01) and elevated FC in patients with ileocolonic disease (β, 1.3; 95% CI, 0.32 to 2.3; P = 0.01). VAT:SAT was associated with lower QoL, particularly in those with ileal disease (β, -12; 95% CI, -19 to -4.5; P = 0.05). However, no prospective associations were observed between serial VAT measurements and time to surgery or hospitalization. No correlations were found between BMI and disease behavior, activity, or QoL. Conclusions: VAT:SAT, rather than BMI, is associated with stricturing CD behavior, elevated FC, and reduced QoL in a disease distribution-dependent manner. Further studies are required to substantiate the role of VAT as a useful biomarker in CD.

Vleugels JLA, Rutter MD, Ragunath K, Rees CJ, Ponsioen CY, Lahiff C, Ket SN, Wanders LK, Samuel S, Butt F et al. 2018. Diagnostic accuracy of Endoscopic Trimodal Imaging and Chromoendoscopy for lesion characterisation in ulcerative colitis surveillance: ETMI or chromoendoscopy for lesion characterisation in colitis. J Crohns Colitis, | Show Abstract | Read more

Background: During surveillance colonoscopy of patients with longstanding ulcerative colitis (UC), a variety of dysplastic and non-dysplastic lesions are detected. The aim of this study was to address the diagnostic accuracy of endoscopic characterisation of Endoscopic Trimodal Imaging (ETMI) and chromoendoscopy (CE). ETMI includes the combination of autofluorescence imaging (AFI), narrow band imaging (NBI) and white light endoscopy (WLE). Methods: This is a pre-specified additional analysis of a multicentre randomised controlled trial that compared AFI with CE for dysplasia detection in 210 patients with longstanding UC (FIND-UC trial). In the AFI arm, endoscopists used the ETMI system to record AFI color, Kudo pit pattern using NBI and WLE for lesion characterisation. For AFI, purple colour and ambiguous colour combined with pit pattern type III-V on NBI was considered dysplastic. Kudo pit pattern was described in the CE arm. For pit pattern description using NBI and CE, type III-V was considered dysplastic. Histology was the reference standard. Results: In total, 52 dysplastic and 255 non-dysplastic lesions were detected. Overall sensitivity for real-time prediction of dysplasia was 76.9% (95% confidence interval (CI) 46.2-95.0) for ETMI, and 81.6% (95% CI 65.7-92.3) for CE. Overall negative predictive value (NPV) for ETMI was 96.9% (95% CI 92.0-98.8) and 94.7% (90.2-97.2) for CE. Interpretation: Sensitivity for endoscopic differentiation of dysplastic lesions detected during surveillance of patients with longstanding UC seems limited using ETMI and CE. Future research is warranted as the high NPV indicates that these techniques are valuable for the exclusion of dysplastic lesions (NTR4062).

Bryant RV, Schultz CG, Ooi S, Goess C, Costello SP, Vincent AD, Schoeman SN, Lim A, Bartholomeusz FD, Travis SPL, Andrews JM. 2018. Obesity in Inflammatory Bowel Disease: Gains in Adiposity despite High Prevalence of Myopenia and Osteopenia. Nutrients, 10 (9), | Show Abstract | Read more

BACKGROUND: Rising rates of obesity have been reported in patients with inflammatory bowel disease (IBD); however, prospective data is lacking. The aim of this study is to prospectively evaluate body composition in adults with IBD over 24 months. METHODS: Whole body dual energy X-ray absorptiometry (DXA) data was performed at 0 months, 12 months, and 24 months. Bone mineral density (BMD), fat mass index (FMI (kg)/height (m²)), appendicular skeletal muscle index (ASMI (kg)/height (m²)), visceral adipose tissue and the visceral adipose height index (VHI, VAT area (cm³)/height (m²)), and clinical and anthropometric assessments were performed at each time point. Multivariable linear mixed effects regression analyses were performed. RESULTS: Initially, 154 participants were assessed at baseline (70% Crohn's disease, 55% male, median age 31 years), of whom 129 underwent repeated DXA at 12 months, and 110 underwent repeated DXA at 24 months. Amongst those undergoing repeated DXA, their body mass index (BMI) significantly increased over time, such that by 24 months, 62% of patients were overweight or obese (annual change BMI β = 0.43, 95%CI = [0.18, 0.67], p = 0.0006). Gains in BMI related to increases in both FMI and VHI (β = 0.33, 95%CI = [0.14, 0.53], p = 0.0007; β = 0.08, 95%CI = [0.02, 0.13], p = 0.001; respectively), whereas ASMI decreased (β = -0.07, 95%CI = [-0.12, -0.01], p = 0.01) with a concordant rise in rates of myopenia (OR = 3.1 95%CI = [1.2, 7.7]; p = 0.01). Rates of osteopenia and osteoporosis were high (37%), but remained unchanged over time (p = 0.23). CONCLUSION: Increasing rates of obesity in patients with IBD coincide with decreases in lean muscle mass over time, while high rates of osteopenia remain stable. These previously undocumented issues warrant attention in routine care to prevent avoidable morbidity.

Probert F, Walsh A, Jagielowicz M, Yeo T, Claridge TDW, Simmons A, Travis S, Anthony DC. 2018. Plasma Nuclear Magnetic Resonance metabolomics discriminates between high and low endoscopic activity and predicts progression in a prospective cohort of patients with ulcerative colitis. J Crohns Colitis, | Show Abstract | Read more

Background & aims: Endoscopic assessment of ulcerative colitis (UC) is one of the most accurate measures of disease activity, but frequent endoscopic investigations are disliked by patients and expensive for the health care system. A minimally-invasive test that provides a surrogate measure of endoscopic activity is required. Methods: Plasma Nuclear Magnetic Resonance (NMR) spectra from 40 patients with UC followed prospectively over 6 months were analysed with multivariate statistics. NMR metabolite profiles were compared with endoscopic (Ulcerative Colitis Endoscopic Index of Severity: UCEIS), histological (Nancy Index), and clinical (Simple Clinical Colitis Activity Index: SCCAI) severity indices, along with routine blood measurements. Results: A blinded principal component analysis spontaneously separated metabolite profiles of patients with low (≤3) and high (>3) UCEIS. Orthogonal partial least squares discrimination analysis identified low and high UCEIS metabolite profiles with an accuracy of 77±5%. Plasma metabolites driving discrimination included decreases in lipoproteins and increases in isoleucine, valine, glucose, and myo-inositol in high compared to low UCEIS. This same metabolite profile distinguished between low (Nancy 0-1) and high histological activity (Nancy 3-4) with a modest though significant accuracy (65±6%) but was independent of SCCAI and all blood parameters measured. A different metabolite profile, dominated by changes in lysine, histidine, phenylalanine, and tyrosine, distinguished between improvement in UCEIS (decrease >1) and worsening (increase >1) over 6 months with an accuracy of 74±4%. Conclusion: Plasma NMR metabolite analysis has the potential to provide a low-cost, minimally invasive technique that may be a surrogate for endoscopic assessment, with predictive capacity.

Das B, Ghosh TS, Kedia S, Rampal R, Saxena S, Bag S, Mitra R, Dayal M, Mehta O, Surendranath A et al. 2018. Analysis of the Gut Microbiome of Rural and Urban Healthy Indians Living in Sea Level and High Altitude Areas. Sci Rep, 8 (1), pp. 10104. | Show Abstract | Read more

The diversity and basic functional attributes of the gut microbiome of healthy Indians is not well understood. This study investigated the gut microbiome of three Indian communities: individuals residing in rural and urban (n = 49) sea level Ballabhgarh areas and in rural high altitude areas of Leh, Ladakh in North India (n = 35). Our study revealed that the gut microbiome of Indian communities is dominated by Firmicutes followed by Bacteroidetes, Actinobateria and Proteobacteria. Although, 54 core bacterial genera were detected across the three distinct communities, the gut bacterial composition displayed specific signatures and was observed to be influenced by the topographical location and dietary intake of the individuals. The gut microbiome of individuals living in Leh was observed to be significantly similar with a high representation of Bacteroidetes and low abundance of Proteobacteria. In contrast, the gut microbiome of individuals living in Ballabhgarh areas harbored higher number of Firmicutes and Proteobacteria and is enriched with microbial xenobiotic degradation pathways. The rural community residing in sea level Ballabhgarh areas has unique microbiome characterized not only by a higher diversity, but also a higher degree of interindividual homogeneity.

Walsh A, Travis S. 2018. What's app? Electronic health technology in inflammatory bowel disease. Intest Res, 16 (3), pp. 366-373. | Show Abstract | Read more

Electronic health (eHealth) data collection is increasingly used in many chronic illnesses, to track pattern of disease. eHealth systems have the potential to revolutionize care. Inflammatory bowel disease (IBD) is a paradigm for such an approach: this is a chronic disease that usually affects young and technologically literate patient population, who are motivated to be involved in their own care. A range of eHealth technologies are available for IBD. This review considers the strengths and weaknesses of 7 platforms that focus on patient-provider interaction. These have been developed in Denmark, United States, the Netherlands, and the United Kingdom, demonstrating an international interest in this form of technology and interaction. Not only do these technologies aim to improve care but they also have the potential to collect large amounts of information. Information includes demographics and patient reported outcomes (symptoms, quality of life), quality of care (steroid use, among other metrics) and outcomes such as hospitalization. These data could inform quality improvement programmes to improve their focus. eHealth technology is also open to machine learning to analyze large data sets, through which personalized algorithms may be developed.

Irani NR, Wang LM, Collins GS, Keshav S, Travis SPL. 2018. Correlation between Endoscopic and Histological Activity in Ulcerative Colitis using Validated Indices. J Crohns Colitis, | Show Abstract | Read more

Background and Aims: Endoscopy and histopathology are pivotal for evaluating disease activity in ulcerative colitis (UC); correlation between validated endoscopic and histological indices has not been examined. We aim to correlate the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) with two new validated histological indices in patients with established UC. Methods: A single centre cohort of patients with established UC who underwent flexible sigmoidoscopy or colonoscopy by a single endoscopist. The UCEIS was scored at the worst affected area in the distal colon, which was biopsied; histological disease activity using Nancy (NI) and Robarts' Histological (RHI) indices was scored by a pathologist blinded to the endoscopy. Spearman correlation between the UCEIS, NI and RHI, and between NI and RHI were performed. Results: 125 patients, median age 37 years (range 16-81 years), with UCEIS scores (scale 0-8) 0=21; 1-3=48; 4-6=51; 7-8=5. Correlation coefficients between UCEIS and NI (scale 0-4) were r=0.84 (95% CI 0.76-0.89, p<0.001) and between UCEIS and RHI (scale 0-33) r=0.86 (95% CI 0.80-0.90, p<0.001). The difference in correlation was not significant (p=0.57). There was excellent correlation between the two histological indices (r=0.92, 95% CI 0.87-0.95, p<0.001). Quiescent disease activity defined as the absence of neutrophils (Nancy 0-1, Robarts 0-3) was most closely correlated with UCEIS=0. Conclusions: The UCEIS strongly correlates with both NI and RHI. Complete mucosal healing is best defined as a UCEIS=0/8, since this correlates with the absence of microscopic disease activity.

Quaranta M, Wilson R, Gonçalves Serra E, Pandey S, Schwerd T, Gilmour K, Klenerman P, Powrie F, Keshav S, Travis SPL et al. 2018. Consequences of Identifying XIAP Deficiency in an Adult Patient With Inflammatory Bowel Disease. Gastroenterology, 155 (1), pp. 231-234. | Read more

Kedia S, Jain S, Goyal S, Bopanna S, Yadav DP, Sachdev V, Sahni P, Pal S, Dash NR, Makharia G et al. 2018. Potential of Fecal Calprotectin as an Objective Marker to Discriminate Hospitalized Patients with Acute Severe Colitis from Outpatients with Less Severe Disease. Dig Dis Sci, 63 (10), pp. 2747-2753. | Show Abstract | Read more

BACKGROUND: Acute severe colitis (ASC) is conventionally diagnosed by Truelove and Witts' criteria which are non-specific and can be affected by other pathologic conditions. Fecal calprotectin (FCP) is a gut-specific marker of inflammation which can predict short-term outcomes in patients with ASC. We aimed to define the role of FCP in the diagnosis of ASC. METHODS: This prospective observational cohort study included adult patients (> 18 years) with ulcerative colitis (UC) for whom FCP was measured and was under follow-up from April 2015 to December 2016. Patients were divided into two cohorts: (1) all consecutive hospitalized patients with ASC as defined by Truelove and Witts' criteria; (2) outpatients with active UC (defined by Mayo score) who did not fulfill Truelove and Witts' criteria. FCP levels were compared between the two cohorts, and a cutoff for FCP to diagnose ASC was determined. RESULTS: Of 97 patients, 49 were diagnosed with ASC (mean age: 36.1 ± 11.9 years, 36 males) and 48 with active UC (mean age: 37.9 ± 12.4 years, 25 males). Median FCP levels were significantly higher in patients with ASC [1776(952-3123) vs 282(43-568) µg/g, p < 0.001] than mild to moderately active UC (n = 48) or moderately active UC [n = 35, 1776(952-3123) vs 332(106-700) µg/g, p < 0.001]. A FCP cutoff of 782 μg/g of stool had excellent diagnostic accuracy, with an area under the curve of 0.92(95% CI 0.87-0.97), sensitivity of 84% and specificity of 88% to differentiate ASC from active UC. CONCLUSION: FCP could differentiate ASC from mild to moderate patients with UC, but requires validation before clinical use.

Brierley CK, Castilla-Llorente C, Labopin M, Badoglio M, Rovira M, Ricart E, Dierickx D, Vermeire S, Hasselblatt P, Finke J et al. 2018. Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes from the European Society for Blood and Marrow Transplantation. J Crohns Colitis, 12 (9), pp. 1097-1103. | Show Abstract | Read more

Background/Aims: Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe, treatment-refractory Crohn's disease (CD). The evidence base for AHSCT for CD is limited, with one randomised trial (ASTIC) suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe outside the ASTIC trial. Methods: We identified 99 patients in the European Society for Blood and Marrow Transplantation (EBMT) registry who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in 7 countries. Results: Median patient age was 30 years (range 20-65). Patients had failed or been intolerant to a median of 6 lines of drug therapy. 61/82 (74%) had had surgery. Following AHSCT, 53/78 (68%) experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months (range 6-174). 22/82 (27%) required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at last follow-up, 57% (24/42) achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at one year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% CI 1.14-4.83, p=0.02). One patient died due to infectious complications (CMV disease) at day +56. Conclusions: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.

Feagan BG, Bhayat F, Khalid M, Blake A, Travis SPL. 2018. Respiratory Tract Infections in Patients With Inflammatory Bowel Disease: Safety Analyses From Vedolizumab Clinical Trials. J Crohns Colitis, 12 (8), pp. 905-919. | Show Abstract | Read more

Background and Aims: Vedolizumab, a humanised monoclonal antibody for the treatment of inflammatory bowel disease, selectively blocks gut lymphocyte trafficking. This may reduce the risk of respiratory tract infections [RTIs] compared with systemic immunosuppressive therapies. To assess this possibility, we evaluated the rates of RTIs in clinical trials of vedolizumab. Methods: Patient-level data from Phase 3 randomised controlled trials [RCTs] of vedolizumab in ulcerative colitis [UC; GEMINI 1] and Crohn's disease [CD; GEMINI 2], and a long-term safety study [UC and CD] were pooled. Cox proportional hazards models were used to estimate the incidence of upper RTIs [URTIs] and lower RTIs [LRTIs] with adjustment for significant covariates. Results: In the RCTs [n = 1731 patients], the incidence of URTIs was numerically higher in patients receiving vedolizumab compared with those receiving placebo, although this difference was not statistically significant (38.7 vs 33.0 patients per 100 patient-years; hazard ratio [HR] 1.12; 95% confidence interval [CI]: 0.83-1.51; p = 0.463). The rate of LRTIs, including pneumonia, was numerically lower in the vedolizumab versus the placebo group: this difference was not statistically significant (7.7 vs 8.5 per 100 patient-years [HR 0.85; 95% CI: 0.48-1.52; p = 0.585]). Both URTIs and LRTIs were more frequent in patients with CD compared with UC. Most RTIs in patients receiving vedolizumab were not serious and did not require treatment discontinuation. Conclusions: Vedolizumab therapy was not associated with an increased incidence of respiratory tract infection compared with placebo.

Samaan MA, Shen B, Mosli MH, Zou G, Sandborn WJ, Shackelton LM, Nelson S, Stitt L, Bloom S, Pardi DS et al. 2018. Reliability among central readers in the evaluation of endoscopic disease activity in pouchitis. Gastrointest Endosc, 88 (2), pp. 360-369.e2. | Show Abstract | Read more

BACKGROUND AND AIMS: Pouchitis is a common adverse event after proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis. Evaluation of pouchitis disease activity and response to treatment requires use of validated indices. We assessed the reliability of items evaluating endoscopic pouchitis disease activity. METHODS: Twelve panelists used a modified RAND appropriateness methodology to rate the appropriateness of items evaluating endoscopic pouchitis disease activity derived from a systematic review and also identified additional potential endoscopic items based on expert opinion. Four central readers then evaluated 50 pouchoscopy videos in triplicate, in random order. Intra- and inter-rater reliability for each item was assessed by calculating and comparing intraclass correlation coefficients (ICCs). A Delphi process identified common sources of disagreement among the readers. RESULTS: Ten existing endoscopic items were identified from the systematic review and an additional 7 exploratory items from the panelists. ICCs for inter-rater reliability were highest for the existing item of pouch ulceration (.72; 95% confidence interval [CI], .60-.82) and for the exploratory item of ulcerated surface in the pouch body (.67; 95% CI, .53-.75). Inter-rater reliability for all other existing and exploratory items was "moderate" (ICC < .60). The item "ulcerated surface in the pouch body" demonstrated the best correlation with a global evaluation of lesion severity (r = .80; 95% CI, .73-.85). CONCLUSION: Substantial reliability was observed only for the endoscopic items of ulceration and ulcerated surface in the pouch body. Future studies should assess responsiveness to treatment in the next stage toward development of an endoscopic pouchitis disease activity index.

Kurioka A, Cosgrove C, Simoni Y, van Wilgenburg B, Geremia A, Björkander S, Sverremark-Ekström E, Thurnheer C, Günthard HF, Khanna N et al. 2018. CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells. Front Immunol, 9 (APR), pp. 486. | Show Abstract | Read more

CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.

Fairhurst NG, Travis SPL. 2018. Why is it so difficult to evaluate faecal microbiota transplantation as a treatment for ulcerative colitis? Intest Res, 16 (2), pp. 209-215. | Show Abstract | Read more

Faecal microbiota transplantation (FMT) has recently re-emerged as a viable therapeutic option for colonic disorders. Its efficacy has been proved in the treatment of Clostridium difficile infection which has encouraged research into the use of FMT for other disorders involving gut dysbiosis, such as ulcerative colitis (UC), a chronic inflammatory disease characterized by relapsing and remitting colonic inflammation. Although the FMT protocol for C. difficile treatment is well established, there are numerous additional factors to consider when applying FMT to treat inflammatory diseases. Various studies have attempted to address these factors but technical inconsistency between reports has resulted in a failure to achieve clinically significant findings. Case reports of FMT in UC have shown favorable outcomes yet demonstrating these effects on a larger scale has proved difficult. The following review aims to explore these issues and to analyze why they may be hindering the progression of FMT therapy in UC.

Vleugels JLA, Rutter MD, Ragunath K, Rees CJ, Ponsioen CY, Lahiff C, Ket SN, Wanders LK, Samuel S, Butt F et al. 2018. Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol, 3 (5), pp. 305-316. | Show Abstract | Read more

BACKGROUND: Patients with longstanding ulcerative colitis undergo regular dysplasia surveillance because they have an increased colorectal cancer risk. Autofluorescence imaging and chromoendoscopy improve dysplasia detection. The aim of this study was to determine whether autofluorescence imaging should be further studied as an alternative method for dysplasia surveillance in patients with longstanding ulcerative colitis. METHODS: This prospective, international, randomised controlled trial included patients from an ulcerative colitis-dysplasia surveillance cohort from five centres in the Netherlands and the UK. Eligible patients were aged 18 years or older who were undergoing dysplasia surveillance after being diagnosed with extensive colitis (Montreal E3) at least 8 years before study start or with left-sided colitis (Montreal E2) at least 15 years before study start. Randomisation (1:1) was minimised for a previous personal history of histologically proven dysplasia and concomitant primary sclerosing cholangitis. The coprimary outcomes were the proportion of patients in whom at least one dysplastic lesion was detected and the mean number of dysplastic lesions per patient. The relative dysplasia detection rate, calculated as the ratio of the detection rates by autofluorescence imaging and chromoendoscopy, needed to be more than 0·67 (using an 80% CI) for both primary outcomes to support a subsequent large non-inferiority trial. Outcomes were analysed on a per-protocol basis. The trial is registered at the Netherlands Trial Register, number NTR4062. FINDINGS: Between Aug 1, 2013, and March 10, 2017, 210 patients undergoing colonoscopy surveillance for longstanding ulcerative colitis were randomised for inspection with either autofluorescence imaging (n=105) or chromoendoscopy (n=105). Dysplasia was detected in 13 (12%) patients by autofluorescence imaging and in 20 patients (19%) by chromoendoscopy. The relative dysplasia detection rate of autofluorescence imaging versus chromoendoscopy for the proportion of patients with ulcerative colitis with at least one dysplastic lesion was 0·65 (80% CI 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 (SD 0·37) for autofluorescence imaging and 0·37 (1·02) for chromoendoscopy (relative dysplasia detection rate 0·36, 80% CI 0·21-0·61). Adverse events were reported for two patients in the autofluorescence imaging group (one patient had intraprocedural mild bleeding, and one patient had abdominal pain) and for three patients in the chromoendoscopy group (two patients had intraprocedural mild bleeding, and one patient had perforation). INTERPRETATION: Autofluorescence imaging did not meet criteria for proceeding to a large non-inferiority trial. Therefore, existing autofluorescence imaging technology should not be further investigated as an alternative dysplasia surveillance method. FUNDING: Olympus Europe and Olympus Keymed.

Jairath V, Levesque BG, Vande Casteele N, Khanna R, Mosli M, Hindryckx P, Travis S, Duijvestein M, Rimola J, Panes J et al. 2018. Corrigendum: Evolving Concepts in Phases I and II Drug Development for Crohn's Disease. J Crohns Colitis, 12 (5), pp. 631. | Show Abstract | Read more

© 2018 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. In the original article, author Marjolijn Duijvestein's first and surnames were incorrectly spelt. This has now been corrected.

Lahiff C, Mun Wang L, Travis SPL, East JE. 2018. Diagnostic Yield of Dysplasia in Polyp-adjacent Biopsies for Patients with Inflammatory Bowel Disease: A Cross-sectional Study. J Crohns Colitis, 12 (6), pp. 670-676. | Show Abstract | Read more

Introduction: Patients with inflammatory bowel disease (IBD) undergoing polypectomy are recommended by current guidelines to have biopsies taken from adjacent mucosa to determine whether there is dysplasia present. With improvements in endoscopic imaging, it is now possible to characterize colonic lesions with higher levels of confidence than previously. We have reviewed the diagnostic yield of polyp-adjacent biopsies in IBD. Materials and Methods: A systematic search of our histopathology database revealed cases in which polyps had been endoscopically resected or biopsied in patients with IBD. Endoscopy reports and medical records were reviewed, and patient demographic and disease-specific details were recorded, along with details of polyp characteristics and histopathology outcomes. Results: Three hundred and two polyps were biopsied or resected in 131 patients undergoing 178 colonoscopies. The median polyp size was 4 mm (range 1-45), and the predominant morphology was Paris 0-Is (n = 98, 32%). The histology was tubular adenoma in 76 (25%), tubulovillous adenoma in 14 (5%), hyperplastic in 112 (37%), post-inflammatory in 32 (11%), sessile serrated polyp in 31 (10%), traditional serrated adenoma in 2 (0.7%), flat high-grade dysplasia or cancer in 2 (0.7%) and other in 33 (11%). Dysplasia in adjacent biopsies was detected in 2 patients (0.7%), and was endoscopically visible in both cases. The proportion of endoscopically unsuspected dysplasia was 0/300 (0%, 95% CI 0-1.6%). Conclusion: The diagnostic yield for polyp-adjacent biopsies in patients with IBD is negligible. With high-definition technology and chromoendoscopy, it may no longer be necessary to biopsy endoscopically normal adjacent tissue to detect invisible dysplasia.

Taylor SA, Mallett S, Bhatnagar G, Baldwin-Cleland R, Bloom S, Gupta A, Hamlin PJ, Hart AL, Higginson A, Jacobs I et al. 2018. 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. Lancet Gastroenterol Hepatol, 3 (8), pp. 548-558. | Show Abstract | Read more

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.

Jain S, Kedia S, Bopanna S, Yadav DP, Goyal S, Sahni P, Pal S, Dash NR, Makharia G, Travis SPL, Ahuja V. 2018. Are Truelove and Witts criteria for diagnosing acute severe colitis relevant for the Indian population? A prospective study. Intest Res, 16 (1), pp. 69-74. | Show Abstract | Read more

Background/Aims: Truelove and Witts criteria have been used to define acute severe colitis since the 1950s. However, hemoglobin (an additional criterion of the definition) levels in the general population in developing countries are lower than in the population of developed countries. We aimed to determine the relevance of Truelove and Witts criteria in the Indian population. Methods: Consecutive patients with acute severe colitis satisfying the Truelove and Witts criteria, hospitalized at a single center between April 2015 and December 2016 were included. All patients received intravenous corticosteroids and 16 required colectomy. The hemoglobin levels at admission were subsequently excluded from the classification criteria, and the effect this had on the criteria for diagnosis was determined. Results: Out of 61 patients of acute severe colitis diagnosed according to the original Truelove and Witts criteria, 12 patients (20%) had 1 additional criterion, 33 (54%) had 2 additional criteria and 16 (26%) had 3 or more additional criteria in addition to 6 or more blood stained stools on admission. On excluding hemoglobin as an additional criterion from the Truelove and Witts definition, all patients still met the criteria for acute severe colitis. Conclusions: Truelove and Witts criteria can be used to define acute severe colitis in India, despite lower mean hemoglobin in the native population.

Kim AH, Roberts C, Feagan BG, Banerjee R, Bemelman W, Bodger K, Derieppe M, Dignass A, Driscoll R, Fitzpatrick R et al. 2018. Developing a Standard Set of Patient-Centred Outcomes for Inflammatory Bowel Disease-an International, Cross-disciplinary Consensus. J Crohns Colitis, 12 (4), pp. 408-418. | Show Abstract | Read more

Background and Aims: Success in delivering value-based healthcare involves measuring outcomes that matter most to patients. Our aim was to develop a minimum Standard Set of patient-centred outcome measures for inflammatory bowel disease [IBD], for use in different healthcare settings. Methods: An international working group [n = 25] representing patients, patient associations, gastroenterologists, surgeons, specialist nurses, IBD registries and patient-reported outcome measure [PROM] methodologists participated in a series of teleconferences incorporating a modified Delphi process. Systematic review of existing literature, registry data, patient focus groups and open review periods were used to reach consensus on a minimum set of standard outcome measures and risk adjustment variables. Similar methodology has been used in 21 other disease areas [www.ichom.org]. Results: A minimum Standard Set of outcomes was developed for patients [aged ≥16] with IBD. Outcome domains included survival and disease control [survival, disease activity/remission, colorectal cancer, anaemia], disutility of care [treatment-related complications], healthcare utilization [IBD-related admissions, emergency room visits] and patient-reported outcomes [including quality of life, nutritional status and impact of fistulae] measured at baseline and at 6 or 12 month intervals. A single PROM [IBD-Control questionnaire] was recommended in the Standard Set and minimum risk adjustment data collected at baseline and annually were included: demographics, basic clinical information and treatment factors. Conclusions: A Standard Set of outcome measures for IBD has been developed based on evidence, patient input and specialist consensus. It provides an international template for meaningful, comparable and easy-to-interpret measures as a step towards achieving value-based healthcare in IBD.

Travis S, Feagan BG, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson AM, Petersson J, Pappalardo BL, Bereswill M et al. 2017. Effect of Adalimumab on Clinical Outcomes and Health-related Quality of Life Among Patients With Ulcerative Colitis in a Clinical Practice Setting: Results From InspirADA JOURNAL OF CROHNS & COLITIS, 11 (11), pp. 1317-1325. | Read more

Schwerd T, Bryant RV, Pandey S, Capitani M, Meran L, Cazier J-B, Jung J, Mondal K, Parkes M, Mathew CG et al. 2018. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol, 11 (2), pp. 562-574. | Show Abstract | Read more

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Colombel J-F, Panaccione R, Bossuyt P, Lukas M, Baert F, Vaňásek T, Danalioglu A, Novacek G, Armuzzi A, Hébuterne X et al. 2018. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet, 390 (10114), pp. 2779-2789. | Show Abstract | Read more

BACKGROUND: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING: AbbVie.

Jain S, Kedia S, Bopanna S, Sachdev V, Sahni P, Dash NR, Pal S, Vishnubhatla S, Makharia G, Travis SPL, Ahuja V. 2017. Faecal Calprotectin and UCEIS Predict Short-term Outcomes in Acute Severe Colitis: Prospective Cohort Study. J Crohns Colitis, 11 (11), pp. 1309-1316. | Show Abstract | Read more

Background and Aims: Early objective markers for failure of intravenous[iv] corticosteroid for acute severe colitis [ASC] can avoid delay in rescue therapy or colectomy. We investigated faecal calprotectin [FC], C-reactive protein [CRP], and endoscopy using the ulcerative colitis endoscopic index of severity [UCEIS] as predictors of steroid failure following intensive therapy of ASC. Methods: Consecutive patients with ASC satisfying Truelove and Witts' criteria, hospitalised at a single centre from May 2015 to November 2016, were included; all received iv corticosteroids. The primary outcome measure was steroid failure defined as colectomy and/or rescue therapy with ciclosporin or infliximab during admission. FC levels were measured at admission and on Day 3 of intensive therapy. UCEIS was scored at admission, and CRP on Day 3 of intensive therapy. Results: Of 49 patients, 21 [43%] failed iv corticosteroids and 15 [31%] underwent surgery. FC levels were significantly higher in steroid failures (2522 [590-9654] µg/g) compared with steroid responders (1530 [352-10278] µg/g) at admission [p = 0.04], as well as on Day 3 of iv corticosteroid therapy (2718 [222-9175] µg/g vs 727 [218-4062] µg/g, p = 0.001). Steroid failures had a higher median [range] UCEIS score than responders (6 [4-8] vs 5 [4-7] [p = 0.001]). CRP level did not differ significantly between steroid failures and responders. A UCEIS > 6 at admission and FC > 1000 µg/g on Day 3 were independent predictors of steroid failure and need for rescue therapy/colectomy. Conclusions: All patients with UCEIS > 6 and Day 3 FC > 1000 µg/g failed iv corticosteroids. The UCEIS score on admission and Day 3 FC are early predictors of failure of ivcorticosteroid therapy.

Hibi T, Panaccione R, Katafuchi M, Yokoyama K, Watanabe K, Matsui T, Matsumoto T, Travis S, Suzuki Y. 2017. The 5C Concept and 5S Principles in Inflammatory Bowel Disease Management. J Crohns Colitis, 11 (11), pp. 1302-1308. | Show Abstract | Read more

Background and Aims: The international Inflammatory Bowel Disease [IBD] Expert Alliance initiative [2012-2015] served as a platform to define and support areas of best practice in IBD management to help improve outcomes for all patients with IBD. Methods: During the programme, IBD specialists from around the world established by consensus two best practice charters: the 5S Principles and the 5C Concept. Results: The 5S Principles were conceived to provide health care providers with key guidance for improving clinical practice based on best management approaches. They comprise the following categories: Stage the disease; Stratify patients; Set treatment goals; Select appropriate treatment; and Supervise therapy. Optimised management of patients with IBD based on the 5S Principles can be achieved most effectively within an optimised clinical care environment. Guidance on optimising the clinical care setting in IBD management is provided through the 5C Concept, which encompasses: Comprehensive IBD care; Collaboration; Communication; Clinical nurse specialists; and Care pathways. Together, the 5C Concept and 5S Principles provide structured recommendations on organising the clinical care setting and developing best-practice approaches in IBD management. Conclusions: Consideration and application of these two dimensions could help health care providers optimise their IBD centres and collaborate more effectively with their multidisciplinary team colleagues and patients, to provide improved IBD care in daily clinical practice. Ultimately, this could lead to improved outcomes for patients with IBD.

Jairath V, Zou GY, Parker CE, MacDonald JK, AlAmeel T, Al Beshir M, Almadi MA, Al-Taweel T, Atkinson NS, Biswas S et al. 2017. Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis. Cochrane Database Syst Rev, 9 (9), pp. CD011572. | Show Abstract | Read more

BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

Bryant RV, Costello SP, Schoeman S, Sathananthan D, Knight E, Lau S-Y, Schoeman MN, Mountifield R, Tee D, Travis SPL, Andrews JM. 2018. Limited uptake of ulcerative colitis "treat-to-target" recommendations in real-world practice. J Gastroenterol Hepatol, 33 (3), pp. 599-607. | Show Abstract | Read more

BACKGROUND AND AIMS: A "treat-to-target" approach has been proposed for ulcerative colitis (UC), with a target of combined clinical and endoscopic remission. The aim of the study was to evaluate the extent to which proposed targets are achieved in real-world care, along with clinician perceptions and potential challenges. METHODS: A multicentre, retrospective, cross-sectional review of patients with UC attending outpatient services in South Australia was conducted. Clinical and objective assessment of disease activity (endoscopy, histology, and/or biomarkers) was recorded. A survey evaluated gastroenterologists' perceptions of treat to target in UC. Statistical analysis included logistic regression and Fisher's exact tests. RESULTS: Of 246 patients with UC, 61% were in clinical remission (normal bowel habit and no rectal bleeding), 35% in clinical and endoscopic remission (Mayo endoscopic sub-score ≤ 1), and 16% in concordant clinical, endoscopic, and histological (Truelove and Richards' Index) remission. Rather than disease-related factors (extent/activity), clinician-related factors dominated outcome. Hospital location and the choice of therapy predicted combined clinical and endoscopic remission (OR 3.6, 95% CI 1.6-8.7, P < 0.001; OR 3.3, 95% CI 1.1-12.5, P = 0.04, respectively). Clinicians used C-reactive protein more often than endoscopy as a biomarker for disease activity (75% vs 47%, P < 0.001). In the survey, 45/61 gastroenterologists responded, with significant disparity between clinician estimates of targets achieved in practice and real-world data (P < 0.001 for clinical and endoscopic remission). CONCLUSIONS: Most patients with UC do not achieve composite clinical and endoscopic remission in "real-world" practice. Clinician uptake of proposed treat-to-target guidelines is a challenge to their implementation.

Jain S, Kedia S, Sethi T, Bopanna S, Yadav DP, Goyal S, Padhan R, Venigalla PM, Sahni P, Dash NR et al. 2018. Predictors of long-term outcomes in patients with acute severe colitis: A northern Indian cohort study. J Gastroenterol Hepatol, 33 (3), pp. 615-622. | Show Abstract | Read more

BACKGROUND AND AIM: Knowledge of long-term outcomes following an index episode of acute severe colitis (ASC) can help informed decision making at a time of acute exacerbation especially when colectomy is an option. We aimed to identify long-term outcomes and their predictors after a first episode of ASC in a large North Indian cohort. METHODS: Hospitalized patients satisfying Truelove and Witts' criteria under follow-up at a single center from January 2003 to December 2013 were included. Patients avoiding colectomy at index admission were categorized as complete (≤ 3 non bloody stool per day) or incomplete responders, based upon response to corticosteroids at day 7. Random Forest-based machine learning models were constructed to predict the long-term risk of colectomy or steroid dependence following an index episode of ASC. RESULTS: Of 1731 patients with ulcerative colitis, 179 (10%) had an index episode of ASC. Nineteen (11%) patients underwent colectomy at index admission and 42 (26%) over a median follow-up of 56 (1-159) months. Hazard ratio for colectomy for incomplete responder was 3.6 (1.7-7.5, P = 0.001) compared with complete responder. Modeling based on four variables, response at day 7 of hospitalization, steroid use during the first year of diagnosis, longer disease duration before ASC, and number of extra-intestinal manifestations, was able to predict colectomy with an accuracy of 77%. CONCLUSIONS: Disease behavior of ASC in India is similar to the West, with a third undergoing colectomy at 10 years. Clinical features, especially response at day 7 hospitalization for index ASC, can predict both colectomy and steroid dependence with reasonable accuracy.

Bye WA, Jairath V, Travis SPL. 2017. Editorial: gut selective immunosuppression-is it a double edged sword? Authors' reply. Aliment Pharmacol Ther, 46 (3), pp. 374. | Read more

Travis S, Feagan BG, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson AM, Petersson J, Pappalardo BL, Bereswill M et al. 2017. Effect of Adalimumab on Clinical Outcomes and Health-related Quality of Life Among Patients With Ulcerative Colitis in a Clinical Practice Setting: Results From InspirADA. J Crohns Colitis, 11 (11), pp. 1317-1325. | Show Abstract | Read more

Background and Aims: Randomised trials have described the benefits of adalimumab [ADA] for ulcerative colitis [UC]; however, few data are available on health-related quality of life [HRQL] and health care costs in clinical practice. Methods: InspirADA, a multicentre, prospective study, evaluated the effect of ADA in patients with moderate to severe UC treated according to usual clinical practice. Outcomes assessed were: Simple Clinical Colitis Activity Index [SCCAI] response/remission rates; changes in HRQL; all-cause direct costs; and UC-related direct and indirect costs from baseline to Week 26. Results: Data from 463 patients were analysed. At Week 26, 67% (95% confidence interval [CI]: 62%, 71%) of patients achieved response; 48% [95% CI: 44%, 53%] were in remission. For the overall population, significant [all p < 0.001] improvements from baseline to Week 26 were observed for the Short Inflammatory Bowel Disease Questionnaire [SIBDQ] (mean change ± standard deviation [SD]: 17.4 ± 14.5) and the European Quality of Life-5 Dimensions-5 Level [EQ-5D-5L] (index: 0.1 ± 0.2; visual analogue scale [VAS]: 19.5 ± 25.8). Parallel improvements were seen in work productivity [11% absolute decrease in absenteeism; 25% absolute decrease in impairment while working; and 27% absolute decrease in impairment of ability to perform daily activities, all p < 0.001]. Among study completers, cumulative all-cause medical costs and UC-related medical costs were significantly [both p < 0.001] reduced by 59% and 77%, respectively, 6 months after initiation of therapy compared with the preceding 6 months. The safety profile of ADA was consistent with that observed in previous clinical trials. Conclusions: ADA therapy in usual clinical practice is effective at improving and maintaining symptomatic control, improving HRQL, and decreasing costs of medical care among patients with UC.

Bye WA, Jairath V, Travis SPL. 2017. Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther, 46 (1), pp. 3-15. | Show Abstract | Read more

BACKGROUND: Vedolizumab specifically recognises the α4β7 integrin and selectively blocks gut lymphocyte trafficking: potentially, it offers gut-specific immunosuppression. AIM: To review the safety of vedolizumab and summarise post-marketing data to assess if any safety concerns that differ from registration trials have emerged. METHOD: A systematic bibliographic search identified six registration trials and nine cohort studies. RESULTS: Integrated data from registration trials included 2830 vedolizumab-exposed patients (4811 person-years exposure [PYs]) and 513 placebo patients. This reported lower exposure-adjusted incidence rates of infection (63.5/100 PYs; 95% CI: 59.6-67.3) and serious adverse events (20.0/100 PYs; 95% CI: 18.5-21.5) compared to placebo (82.9/100 PYs; 95% CI: 68.3-97.5) and (28.3/100 PYs 95% CI: 20.6-35.9) respectively. Higher, but statistically insignificant rates of enteric infections occurred in vedolizumab-exposed patients (7.4/100 PYs; 95% CI: 6.6-8.3) compared to placebo (6.7 PYs; 95% CI: 3.2-10.1). Six post-marketing cohort studies (1049 patients, 403 PYs) demonstrated rates of infection of 8% (82/1049); enteric infection of 2% (21/1049) and adverse events of 16% (166/1049). Multivariate analysis in one cohort study suggested increased risk of surgical site infection with perioperative VDZ. Human experience in pregnancy is limited. CONCLUSIONS: Post-marketing data confirm the excellent safety of vedolizumab observed in registration trials. The signal of post-operative complications should be interpreted with caution, but warrants further study. Although comparative studies are needed, Vedolizumab may be a safe alternative in patients who best avoid systematic immunosuppression, including those pre-disposed to infection, malignancy or the elderly.

Buchs NC, Bloemendaal ALA, Wood CPJ, Travis S, Mortensen NJ, Guy RJ, George BD. 2017. Subtotal colectomy for ulcerative colitis: lessons learned from a tertiary centre. Colorectal Dis, 19 (5), pp. O153-O161. | Show Abstract | Read more

AIM: Subtotal colectomy (STC) is a well-established treatment for complicated and refractory ulcerative colitis (UC). A laparoscopic approach offers potentially improved outcomes. The aim of the study was to report our experience with STC for UC in a single large centre. METHOD: From January 2007 to May 2015, all consecutive patients undergoing STC for UC were retrospectively analysed from a prospectively managed database. Patients with known Crohn's disease or those undergoing one-stage procedures were excluded. Demographics, perioperative outcomes and second-stage procedures were analysed. RESULTS: During the study period, 151 STCs were performed for UC [100 emergency (66%) and 51 elective (34%)]. Acute severe colitis refractory to therapy was the most common indication (62%). Overall, 117 laparoscopic (78%) and 34 open STCs were performed, with a conversion rate of 14.5%. Mortality and morbidity rates were 0.7% and 38%, respectively. Whilst operative time was shorter for open STC (by 75 min; P = 0.001), there were fewer complications (32% vs 62%; P = 0.002) and a shorter hospital stay (by 6.9 days; P = 0.0002) following laparoscopic STC. Fewer complications and shorter hospital stay were also observed after elective STC. Patients undergoing laparoscopic STC were more likely to undergo a restorative second-stage procedure than those having open STC (75% vs 50%; P = 0.03). CONCLUSION: Laparoscopic STC for UC is feasible and safe, even in the emergency situation. A laparoscopic approach may offer advantages in terms of lower morbidity and reduced length of stay. Elective resection may offer similar advantages and is best performed whenever possible.

Gwela A, Siddhanathi P, Chapman RW, Travis S, Powrie F, Arancibia-Cárcamo CV, Geremia A. 2017. Th1 and Innate Lymphoid Cells Accumulate in Primary Sclerosing Cholangitis-associated Inflammatory Bowel Disease. J Crohns Colitis, 11 (9), pp. 1124-1134. | Show Abstract | Read more

Background and Aims: Primary sclerosing cholangitis [PSC] is an idiopathic chronic disorder of the hepatobiliary system associated with inflammatory bowel disease [IBD], mainly ulcerative colitis [UC]. Colitis in patients with PSC and UC [PSC-UC] exhibits characteristic features and is linked to increased colon cancer risk. Genetic studies have identified immune-related susceptibility genes that only partially overlap with those involved in IBD. These observations suggest that PSC-UC may represent a distinct form of IBD. It remains to be elucidated whether different immune mechanisms are involved in colitis in these patients. We aimed to evaluate systemic and intestinal T cell and innate lymphoid cell [ILC] responses, previously associated with IBD, in patients with PSC-UC compared with patients with UC and healthy controls. Methods: Blood samples and colorectal biopsies were collected from patients with PSC-UC, patients with UC, and healthy controls. T cell and ILC phenotypes were analysed by multicolour flow cytometry. Results: Chemokine receptor [CCR] profiling of circulating T cells showed decreased CCR6-CXCR3+ Th1 cells in PSC-UC, but increased CCR6-CCR4+ Th2 cells only in UC, whereas increased CCR6+CCR4+ Th17 cells were found in both patient groups compared with healthy controls. Increased frequencies of IFN-γ secreting T cells were found in the colon of patients with PSC-UC compared with UC. Interestingly, we observed accumulation of ILC in the colon in PSC-UC. Conclusions: Our study suggests that PSC-UC represents a different immunological disorder from UC, characterised by increased intestinal Th1 and ILC responses. These results provide further evidence that PSC-UC may represent a distinct form of IBD.

West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B, Buonocore S, Coccia M, Görtz D, This S, Stockenhuber K et al. 2017. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med, 23 (5), pp. 579-589. | Show Abstract | Read more

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.

Vuitton L, Peyrin-Biroulet L, Colombel JF, Pariente B, Pineton de Chambrun G, Walsh AJ, Panes J, Travis SPL, Mary JY, Marteau P. 2017. Defining endoscopic response and remission in ulcerative colitis clinical trials: an international consensus. Aliment Pharmacol Ther, 45 (6), pp. 801-813. | Show Abstract | Read more

BACKGROUND: Recently, endpoints for clinical trials have been changing from measuring clinical response to mucosal healing in ulcerative colitis. Endoscopic evaluation is the current gold standard to assess mucosal lesions and has become a major measure of therapeutic efficacy in addition to patients reported outcomes. AIM: To achieve consensus on endoscopic definitions of remission and response for clinical trials in patients with ulcerative colitis. METHODS: In reaching the current international recommendations on an International Organization For the Study of Inflammatory Bowel Disease (IOIBD) initiative, we first performed a systematic review of technical aspects of endoscopic scoring systems. Then, to achieve consensus on endoscopic definitions of remission and response for clinical trials, we conducted a two-round vote using a Delphi-style process among fifteen specialists in the field of inflammatory bowel diseases. RESULTS: The literature review showed that many endoscopic indices have been proposed to evaluate disease activity in ulcerative colitis; most are unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response or remission. At the end of the voting process, the investigators ranked initially the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 0 for the definition of endoscopic remission, and a decrease in Mayo endoscopic score ≥1 grade or a decrease in UCEIS ≥2 points for the definition of endoscopic response in ulcerative colitis. CONCLUSIONS: These international recommendations represent the first consensus on measurement indices for endoscopic outcomes in ulcerative colitis. They should be subject to prospective testing in clinical trials of ulcerative colitis.

Bojic D, Bodger K, Travis S. 2017. Patient Reported Outcome Measures (PROMs) in Inflammatory Bowel Disease: New Data. J Crohns Colitis, 11 (suppl_2), pp. S576-S585. | Show Abstract | Read more

Patient reported outcome measures [PROMs] are standardized, validated questionnaires intended for completion by patients in order to measure their perceptions of their own health condition or its treatment without interpretation of the patient's response by a clinician or anyone else. Mayo Clinic Score [MCS] or Crohn's Disease Activity Index [CDAI], most frequently used as end points in conventional clinical trials, are composite instruments that are not fully objective nor capture the impact of disease from the patient's perspective. They are difficult to apply to routine clinical practice because they are complex and time consuming. The European Medicines Agency and Food and Drug Administration are re-evaluating composite indices in clinical trials and product development guidelines. The ultimate goal is to support labelling claims to improve safety and effectiveness of medical products through PROMs allied to an objective measure of inflammation, as happens informally in clinical practice. PROMs, developed and validated according to rigorous criteria, are set to become a co-primary end point for clinical trials of therapy, together with objective measure[s] of inflammation. This will affect future trials' design and their results. To find a place in routine care, PROMs should be easy to use, acceptable to patients and healthcare teams, and able to demonstrate added value to normal practice, supporting decision-making at the level of individual patients. Ideally, the same PROMs should be used in clinical trials and practice, to avoid the current disconnect when interpreting the results of clinical trials and translating them into routine clinical practice.

Bryant R, Costello S, Schoeman S, Sathananthan D, Lau S, Schoeman M, Mountifield R, Tee D, Travis S, Andrews J. 2017. "Treat to target" recommendations in ulcerative colitis in practice: clinician perceptions and potential barriers JOURNAL OF CROHNS & COLITIS, 11 pp. S374-S375.

Taylor M, Duggal A, Rowley A, Foster M, Sirohi S, Solanke Y, Walshe C, Webber S, Travis S, Irving P. 2017. A first clinical trial of a novel narrow spectrum kinase inhibitor TOP1288 in patients with ulcerative colitis JOURNAL OF CROHNS & COLITIS, 11 (suppl_1), pp. S429-S430. | Read more

Kim A, Roberts C, Feagan B, Banerjee R, Bemelman W, Bodger K, Derieppe M, Dignass A, Driscoll R, Fitzpatrick R et al. 2017. Defining patient-centered outcomes for IBD - an international, cross-disciplinary consensus JOURNAL OF CROHNS & COLITIS, 11 (suppl_1), pp. S200-S200. | Read more

Travis S, Feagan B, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson A, Thakkar R, Pappalardo B, Petersson J et al. 2017. Effect of adalimumab dose escalation on clinical, health-related quality of life, treatment satisfaction and work productivity outcomes among patients with ulcerative colitis in a clinical practice setting: results from INSPIRADA JOURNAL OF CROHNS & COLITIS, 11 pp. S244-S245.

Travis S, Feagan B, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson A, Thakkar R, Pappalardo B, Petersson J et al. 2017. Effect of adalimumab on extraintestinal manifestations among patients with ulcerative colitis in a clinical practice setting: results from INSPIRADA JOURNAL OF CROHNS & COLITIS, 11 pp. S36-S36.

Feagan B, Bhayat F, Khalid JM, Palo W, Blake A, Shetzline M, Travis S. 2017. Incidence of pneumonia and other respiratory tract infections with vedolizumab treatment for inflammatory bowel disease: clinical trial experience JOURNAL OF CROHNS & COLITIS, 11 (suppl_1), pp. S301-S302. | Read more

Bhayat F, Blake A, Travis S. 2017. Post-marketing experience of vedolizumab in inflammatory bowel disease: analysis of pneumonia and other respiratory tract infections JOURNAL OF CROHNS & COLITIS, 11 pp. S421-S422.

Lahiff C, Wang LM, Travis SPL, East JE. 2017. Zero diagnostic yield of dysplasia in polyp adjacent biopsies for patients with inflammatory bowel disease JOURNAL OF CROHNS & COLITIS, 11 pp. S16-S16.

Mowat C, Arnott I, Cahill A, Smith M, Ahmad T, Subramanian S, Travis S, Morris J, Hamlin J, Dhar A et al. 2016. Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial. Lancet Gastroenterol Hepatol, 1 (4), pp. 273-282. | Show Abstract | Read more

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

Martí-Gallostra M, Myrelid P, Mortensen N, Keshav S, Travis SPL, George B. 2017. The role of a defunctioning stoma for colonic and perianal Crohn's disease in the biological era. Scand J Gastroenterol, 52 (3), pp. 251-256. | Show Abstract | Read more

OBJECTIVE: A defunctioning stoma is a therapeutic option for colonic or perianal Crohn's disease. In the pre-biologic era the response rate to defunctioning in our unit was high (86%), but intestinal continuity was only restored in 11-20%. Few data exist on the outcome of defunctioning since the widespread introduction of biologicals. MATERIAL AND METHODS: All patients undergoing a defunctioning stoma for colonic/perianal Crohn's disease since 2003-2011 were identified from a prospective database. Indications for surgery, medical therapy, response to defunctioning and long-term clinical outcome were recorded. Successful restoration of continuity was defined as no stoma at last follow up. RESULTS: Seventy-six patients were defunctioned (57 with biologicals) and at last follow up, 20 (27%) had continuity restored. Early clinical response rate (<3 months) was 15/76 (20%) and overall response 31/76 (41%). Complex anal fistulae/stenosis were associated with a very low chance of restoring continuity (10% and 0%, respectively), while colitis was associated with a higher chance of restoring continuity (48%). Endoscopic or histological improvement in colitis after defunctioning was associated with a higher rate of restoring continuity (10/16, 63%) compared to no such improvement (4/15, 27%, p = 0.05). Those failing biologics had similar chance of restoration as those not receiving biologics, 15/57 (26%) and 5/19 (26%), respectively. CONCLUSION: Overall response to colonic defunctioning was 41%. Successful restoration of continuity occurred in 27%, but 48% in the absence of perianal disease. Response is appreciably less in the pre-biologic era, so patient and physician expectations need to be managed appropriately.

Guirgis M, Wendt E, Wang LM, Walsh A, Burger D, Bryant RV, Kent A, Adamson R, Brain O, Travis SPL, Keshav S. 2017. Beyond Histological Remission: Intramucosal Calprotectin as a Potential Predictor of Outcomes in Ulcerative Colitis. J Crohns Colitis, 11 (4), pp. 460-467. | Show Abstract | Read more

Background and Aims: Histological remission and low faecal calprotectin are positive prognostic factors in ulcerative colitis [UC]. Intramucosal calprotectin [iMC], which can be readily determined by immunohistochemistry, has not so far been evaluated as a predictor of outcome in UC. We aimed to investigate the relationship between iMC and clinical, endoscopic, and histological measures of remission in UC, and the independent prognostic value of iMC. Methods: Ambulant patients with UC were recruited for a study comparing clinical activity indices. Sigmoidoscopy and biopsy were performed at the index visit. Clinical, endoscopic, and histological activity were scored and iMC semi-quantitatively measured using immunohistochemistry for the S100A8/9 heterodimer on colonic biopsies, scored as the mean number of positive cells in five high-power fields [HPF]. At the end of follow-up [6 years], data on steroid use, hospitalisation, and colectomy ['adverse outcomes'] were collected. Results: iMC was determined in 83 patients and 20 controls, and correlated with clinical, endoscopic, and histological activity [r = 0.51, 0.65, 0.53, p > 0.001, respectively]. iMC was lowest (median 2.4, interquartile range [IQR]: 5.2-5, p < 0.001) in patients with concordance between clinical, endoscopic, and histological remission. Median iMC > 5/HPF was associated with adverse outcome (hazard ratio [HR] 3.36, confidence interval [CI] 1.58, 7.15, p < 0.001). Only 53%, 33%, and 25% of patients in histological remission with iMC > 5 cells/HPF avoided an adverse outcome after 1, 3, and 6 years, respectively. Conclusions: iMC was lowest in patients with concordant clinical, endoscopic, and histological remission. Median iMC > 5/HPF was associated with adverse outcomes despite histological remission. Therefore iMC is a potentially useful independent marker of activity.

Siegel CA, Whitman CB, Spiegel BMR, Feagan B, Sands B, Loftus EV, Panaccione R, D'Haens G, Bernstein CN, Gearry R et al. 2018. Development of an index to define overall disease severity in IBD. Gut, 67 (2), pp. 244-254. | Show Abstract | Read more

BACKGROUND AND AIM: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. METHODS: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. RESULTS: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. CONCLUSIONS: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.

Walsh AJ, Bryant RV, Travis SPL. 2016. Current best practice for disease activity assessment in IBD. Nat Rev Gastroenterol Hepatol, 13 (10), pp. 567-579. | Show Abstract | Read more

Therapeutic advances in the management of IBD have led to a paradigm shift in the assessment of IBD disease activity. Beyond clinical remission, objective assessment of inflammation is now critical to guiding subsequent therapy as part of a 'treat to target' strategy. Multiple domains of disease activity assessment in IBD exist, each of which has its merits, although none are perfect. The aim of this Review is to comprehensively evaluate measures of disease activity in both ulcerative colitis and Crohn's disease, including clinical, endoscopic, histological and radiological assessment tools, as well as the use of biomarkers and quality of life evaluation. A subjective appraisal of the best indices for use in clinical practice is provided, based on index validation, responsiveness and experience in clinical trials, international specialist opinion, and practicality and suitability for use in clinical practice. This Review aims to enable the reader to gain confidence in IBD disease activity assessment and to give ready access to the necessary tools.

Cesarini M, Collins GS, Rönnblom A, Santos A, Wang LM, Sjöberg D, Parkes M, Keshav S, Travis SPL. 2017. Predicting the Individual Risk of Acute Severe Colitis at Diagnosis. J Crohns Colitis, 11 (3), pp. 335-341. | Show Abstract | Read more

Background and Aims : Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. Methods: The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. Results: The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. Conclusions: An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy.

Panés J, Feagan BG, Hussain F, Levesque BG, Travis SP. 2016. Central Endoscopy Reading in Inflammatory Bowel Diseases. J Crohns Colitis, 10 Suppl 2 (suppl 2), pp. S542-S547. | Show Abstract | Read more

Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for both patient eligibility and outcome measures. Variability in lesion interpretation between and within observers and the potential bias of local investigators in patient assessment have long been recognized. This variability can be reduced, although not completely removed, by independent evaluation of the examinations by experienced off-site (central) readers, properly trained in regard to lesion definition and identification, that should be removed from direct patient contact and blinded to any other clinical or study data. Adding endoscopic demonstration of active disease to eligibility criteria has the potential to reduce placebo response rates, whereas in outcome assessment it has the potential to provide a more precise estimation of the treatment effect, increasing the efficiency of the study. Central endoscopy reading is still at the beginning of its development, and the paradigms of central reading need refinement in terms of the number of readers, the process by which a final score is assigned, the selection and sequence of central readers, and the endoscopic indices of choice.

Williams JG, Alam MF, Alrubaiy L, Arnott I, Clement C, Cohen D, Gordon JN, Hawthorne AB, Hilton M, Hutchings HA et al. 2016. Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial. Lancet Gastroenterol Hepatol, 1 (1), pp. 15-24. | Show Abstract | Read more

BACKGROUND: Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness. METHODS: In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival-ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589. FINDINGS: Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI -22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707-912] days in the infliximab group vs 744 [638-850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group). INTERPRETATION: There was no significant difference between ciclosporin and infliximab in clinical effectiveness. FUNDING: NIHR Health Technology Assessment programme.

Jairath V, Levesque BG, Vande Casteele N, Khanna R, Mosli M, Hindryckx P, Travis S, Duijvenstein M, Rimola J, Panes J et al. 2017. Evolving Concepts in Phases I and II Drug Development for Crohn's Disease. J Crohns Colitis, 11 (2), pp. 246-255. | Show Abstract | Read more

The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn's disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn's disease.

Jairath V, Zou GY, Parker CE, Macdonald JK, Mosli MH, Alameel T, Al Beshir M, Almadi MA, Al-Taweel T, Atkinson NSS et al. 2016. Placebo response and remission rates in randomised trials of induction and maintenance therapy for Crohn's disease Cochrane Database of Systematic Reviews, 2016 (7), | Show Abstract | Read more

© 2016 The Cochrane Collaboration. This is the protocol for a review and there is no abstract. The objectives are as follows: The objective of this review is to determine the factors that influence placebo response and remission rates in induction and maintenance trials of CD in which patients with active or quiescent disease were enrolled using the CDAI or Harvey-Bradshaw Index (HBI).

Sandborn W, Colombel J-F, D'Haens G, Ghosh S, Panaccione R, Panés J, Travis S, Peyrin-Biroulet L. 2016. The Crohn's Disease-Ulcerative Colitis Clinical Appraisal Update: Emerging Trends in Clinical Practice. Clin Gastroenterol Hepatol, 14 (9), pp. e121-e122. | Read more

Chen HH, Händel N, Ngeow J, Muller J, Hühn M, Yang H-T, Heindl M, Berbers R-M, Hegazy AN, Kionke J et al. 2017. Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells. J Allergy Clin Immunol, 139 (2), pp. 607-620.e15. | Show Abstract | Read more

BACKGROUND: Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. OBJECTIVES: Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). METHODS: Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. RESULTS: Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. CONCLUSION: Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency.

Wu K-C, Ran ZH, Gao X, Chen M, Zhong J, Sheng J-Q, Kamm MA, Travis S, Wallace K, Mostafa NM et al. 2016. Adalimumab induction and maintenance therapy achieve clinical remission and response in Chinese patients with Crohn's disease. Intest Res, 14 (2), pp. 152-163. | Show Abstract | Read more

BACKGROUND/AIMS: This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). METHODS: Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220-450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8-26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI <150), response (decrease in CDAI ≥70 points from baseline), and change from baseline in hs-CRP were assessed through week 26. Nonresponder imputation was used for missing categorical data and last observation carried forward for missing hs-CRP/FC values. No formal hypothesis was tested. Adverse events were monitored. RESULTS: Mean adalimumab serum concentrations during the induction phase were 13.9-18.1 µg/mL (160/80 mg group) and 7.5-9.5 µg/mL (80/40 mg group). During the double-blind period, higher remission/response rates and greater reductions from baseline in hs-CRP and FC were observed with adalimumab 160/80 mg compared to that with 80/40 mg. Adverse event rates were similar among all treatment groups. CONCLUSIONS: Adalimumab serum concentrations in Chinese patients with CD were comparable to those observed previously in Western and Japanese patients. Clinically meaningful remission rates and improvement in inflammatory markers were achieved with both dosing regimens; changes occurred rapidly with adalimumab 160/80 mg induction therapy. No new safety signals were reported.

Rowley A, Duggal A, Taylor M, Foster M, Solanke Y, Sirohi S, Walshe C, Webber S, Irving P, Travis S. 2016. A first-in-human randomised double-blind placebo-controlled clinical trial of a novel narrow spectrum kinase inhibitor JOURNAL OF CROHNS & COLITIS, 10 pp. S385-S385.

Travis S, Feagan B, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson A, Petersson J, Bereswill M, Skup M et al. 2016. Adalimumab improves treatment satisfaction with medication and work productivity amongst patients with ulcerative colitis in a clinical practice setting: results from INSPIRADA JOURNAL OF CROHNS & COLITIS, 10 pp. S335-S335.

Gwela A, Siddhanathi P, Chapman RW, Arancibia C, Travis SPL, Powrie F, Geremia A. 2016. Distinct inflammatory signatures in primary sclerosing cholangitis associated with inflammatory bowel disease JOURNAL OF CROHNS & COLITIS, 10 pp. S95-S95.

Siegel C, Whitman C, Spiegel B, Feagan B, Sands B, Loftus E, Panaccione R, D'Haens G, Bernstein C, Gearry R et al. 2016. Looking beyond symptoms and disease activity to define disease severity in inflammatory bowel disease: results of an IOIBD specialist panel JOURNAL OF CROHNS & COLITIS, 10 pp. S76-S78.

Watts G, Arasaradnam R, Travis S, Sharma A, Awasthi A, Limdi J, Finney-Hayward T. 2016. Real-world use of adalimumab in UK patients with ulcerative colitis: an observational retrospective study JOURNAL OF CROHNS & COLITIS, 10 pp. S412-S412.

Travis S, Feagan B, Peyrin-Biroulet L, Panaccione R, Danese S, Lazar A, Robinson A, Petersson J, Bereswill M, Skup M et al. 2016. The costs of care for patients with ulcerative colitis: effect of adalimumab on health care resources utilisation in clinical practice from INSPIRADA JOURNAL OF CROHNS & COLITIS, 10 pp. S298-S299.

Armuzzi A, Travis S. 2016. Swallowing anti-TNFα in Ulcerative Colitis: Potentially More Gain Than Pain. J Crohns Colitis, 10 (6), pp. 629-630. | Read more

Jairath V, Zou G, Parker CE, Macdonald JK, Mosli MH, Khanna R, Shackelton LM, Vandervoort MK, AlAmeel T, Al Beshir M et al. 2016. Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis. J Crohns Colitis, 10 (5), pp. 607-618. | Show Abstract | Read more

BACKGROUND AND AIMS: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E, Rogler G, Rovira M, Satsangi J, Danese S et al. 2015. Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial. JAMA, 314 (23), pp. 2524-2534. | Show Abstract | Read more

IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease. OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids. INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging. RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died. CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00297193.

Ket SN, Palmer R, Travis S. 2015. Endoscopic Disease Activity in Inflammatory Bowel Disease. Curr Gastroenterol Rep, 17 (12), pp. 50. | Show Abstract | Read more

Endoscopic scoring systems in Crohn's disease and ulcerative colitis aim to translate the assessment of mucosal disease activity into a quantified value. This value seeks to provide a clear, objective record of the endoscopic mucosal severity, which can then be used to guide medical management decisions. The primary driver of all endoscopic indices, however, is to define a scale of responsiveness for therapeutic endpoints in clinical trials. Mucosal healing now has widespread acceptance as a therapeutic and clinical endpoint, but despite the development of multiple endoscopic scoring systems, the endoscopic definition has yet to be resolved. This review describes recent advances in endoscopic scoring systems for ulcerative colitis (Mayo Clinic endoscopy subscore, UCEIS, and UCCIS among others) and for Crohn's disease.

Janecke AR, Heinz-Erian P, Yin J, Petersen B-S, Franke A, Lechner S, Fuchs I, Melancon S, Uhlig HH, Travis S et al. 2015. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet, 24 (23), pp. 6614-6623. | Show Abstract | Read more

Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.

Rushton S, Allen E, Curtis R, Darius FM, Butler A, Melendez HV, Friend P, Hind J, Middleton S, Gupte GL et al. 2015. INTESTINAL TRANSPLANTATION: 20 YEARS OF REGISTRY DATA IN THE UNITED KINGDOM TRANSPLANT INTERNATIONAL, 28 pp. 12-12.

East JE, Travis SPL, Leedham SJ. 2015. Causality and Chance in the Development of Cancer. N Engl J Med, 373 (16), pp. 1578-1579. | Read more

East JE, Travis SPL, Leedham SJ. 2015. Causality and Chance in the Development of Cancer NEW ENGLAND JOURNAL OF MEDICINE, 373 (16), pp. 1578-1579. | Read more

Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, Bastien C, Cahn V, Cadiot G, Diebold M-D, Danese S, Reinisch W, Schreiber S et al. 2017. Development and validation of the Nancy histological index for UC. Gut, 66 (1), pp. 43-49. | Show Abstract | Read more

OBJECTIVE: We developed a validated index for assessing histological disease activity in UC and established its responsiveness. METHODS: Two hundred biopsies were scored. The outcome was the Global Visual Evaluation (GVE). Eight histological features were tested. The Nancy index was developed by multiple linear regression and bootstrap process to create an index that best matched the GVE. Goodness of fit was assessed by the adjusted R squared (adjusted R2). The second step was the validation of the index: 100 biopsies were scored for the Nancy index by three pathologists from different centres. Inter-reader reliability was evaluated for each reader. The relationship between the change of the Nancy index and the Geboes index was assessed to assess the responsiveness. RESULTS: After backward selection with bootstrap validation, 3/8 items were selected: ulceration (adjusted R2=0.55), acute inflammatory infiltrate (adjusted R2=0.88) and chronic inflammatory infiltrate (adjusted R2=0.79). The Nancy index is defined by a 5-level classification ranging from grade 0 (absence of significant histological disease activity) to grade 4 (severely active disease). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.88 (95% CI 0.82 to 0.92) and the index had good inter-reader reliability (ICC=0.86 (0.81 to 0.99)). The correlation between the Nancy index and the Geboes score or the GVE was very good. The index had a good responsiveness with a high correlation between changes in the Geboes score and changes in the Nancy index (0.910 (0.813 to 0.955)). CONCLUSIONS: A three descriptor histological index has been validated for use in clinical practice and clinical trials.

Vuitton L, Marteau P, Sandborn WJ, Levesque BG, Feagan B, Vermeire S, Danese S, D'Haens G, Lowenberg M, Khanna R et al. 2016. IOIBD technical review on endoscopic indices for Crohn's disease clinical trials. Gut, 65 (9), pp. 1447-1455. | Show Abstract | Read more

BACKGROUND: Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD. METHODS: In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs. RESULTS: At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery.

Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, D'Haens G, Dotan I, Dubinsky M, Feagan B et al. 2015. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am J Gastroenterol, 110 (9), pp. 1324-1338. | Show Abstract | Read more

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Danese S, Fiorino G, Mary J-Y, Lakatos PL, D'Haens G, Moja L, D'Hoore A, Panes J, Reinisch W, Sandborn WJ et al. 2015. Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn's Disease: An IOIBD Initiative. J Crohns Colitis, 9 (8), pp. 601-606. | Show Abstract | Read more

BACKGROUND AND AIMS: Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis. METHODS: A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (<18 months) CD. Patients with CD were asked to recall symptoms and signs they experienced during the 12 months before diagnosis. Multiple logistic regression analyses selected and weighted independent items to construct the Red Flags index. A receiver operating characteristic curve was used to assess the threshold that discriminated CD from non-CD. Association with the Red Flags index relative to this threshold was expressed as the odds ratios (OR). RESULTS: Two hundred and one subjects, CD and non-CD, answered the questionnaire. The multivariate analysis identified eight items independently associated with a diagnosis of CD. A minimum Red Flags index value of 8 was highly predictive of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90-0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125), respectively. The association between CD diagnosis and a Red Flags index value of ≥8 corresponds to an OR of 290 (p < 0.0001). CONCLUSIONS: The Red Flags index using early symptoms and signs has high predictive value for the diagnosis of CD. These results need prospective validation prior to introduction into clinical practice.

Lichtenstein GR, Travis S, Danese S, D'Haens G, Moro L, Jones R, Huang M, Ballard ED, Bagin R, Hardiman Y et al. 2015. Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis. J Crohns Colitis, 9 (9), pp. 738-746. | Show Abstract | Read more

BACKGROUND AND AIMS: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. METHODS: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9 mg, 6 mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9 mg or placebo for 4 weeks, then open-label budesonide MMX 9 mg for 4 weeks]; and one open-label study [budesonide MMX 9 mg for 8 weeks] were pooled. RESULTS: Patients randomised to budesonide MMX 9 mg [n = 288], 6 mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9 mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. CONCLUSIONS: Budesonide MMX 9 mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.

Gottlieb K, Travis S, Feagan B, Hussain F, Sandborn WJ, Rutgeerts P. 2015. Central Reading of Endoscopy Endpoints in Inflammatory Bowel Disease Trials. Inflamm Bowel Dis, 21 (10), pp. 2475-2482. | Show Abstract | Read more

BACKGROUND: Central reading of endoscopy (CROE) is crucial in determining who qualifies for a trial but also has a role, independent of the selected scoring system, in decreasing measurement noise that can obscure separation between placebo and active drug. Benefits of CROE may not be independent of the method chosen, and controversy exists about the ideal approach. METHODS: Literature review and concept development. RESULTS: Components to be considered in the reading algorithm are blinding, number of central readers, independent voting versus consensus panel, video recordings versus still images, and involvement of the site reader. Key concepts considered are endpoints, bias, power, and sample size derived from the Food and Drug Administration and European Medicines Agency guidelines, as well as the technological requirements and recruitment, qualification, and revalidation of central readers as applied to CROE. CONCLUSIONS: Recording and CROE should be standardized, and an imaging charter developed with research on the different components and its overall impact.

Travis S, Corte C, Keshav S. 2015. Does Disease Extent Matter when Scoring the UCEIS? J Crohns Colitis, 9 (8), pp. 694. | Read more

Bryant RV, Burger DC, Delo J, Walsh AJ, Thomas S, von Herbay A, Buchel OC, White L, Brain O, Keshav S et al. 2016. Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut, 65 (3), pp. 408-414. | Show Abstract | Read more

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

Travis SPL, Schnell D, Feagan BG, Abreu MT, Altman DG, Hanauer SB, Krzeski P, Lichtenstein GR, Marteau PR, Mary J-Y et al. 2015. The Impact of Clinical Information on the Assessment of Endoscopic Activity: Characteristics of the Ulcerative Colitis Endoscopic Index Of Severity [UCEIS]. J Crohns Colitis, 9 (8), pp. 607-616. | Show Abstract | Read more

BACKGROUND AND AIMS: To determine whether clinical information influences endoscopic scoring by central readers using the Ulcerative Colitis Endoscopic Index of Severity [UCEIS; comprising 'vascular pattern', 'bleeding', 'erosions and ulcers']. METHODS: Forty central readers performed 28 evaluations, including 2 repeats, from a library of 44 video sigmoidoscopies stratified by Mayo Clinic Score. Following training, readers were randomised to scoring with ['unblinded', n = 20, including 4 control videos with misleading information] or without ['blinded', n 20] clinical information. A total of 21 virtual Central Reader Groups [CRGs], of three blinded readers, were created. Agreement criteria were pre-specified. Kappa [κ] statistics quantified intra- and inter-reader variability. RESULTS: Mean UCEIS scores did not differ between blinded and unblinded readers for any of the 40 main videos. UCEIS standard deviations [SD] were similar [median blinded 0.94, unblinded 0.93; p = 0.97]. Correlation between UCEIS and visual analogue scale [VAS] assessment of overall severity was high [r blinded = 0.90, unblinded = 0.93; p = 0.02]. Scores for control videos were similar [UCEIS: p ≥ 0.55; VAS: p ≥ 0.07]. Intra- [κ 0.47-0.74] and inter-reader [κ 0.40-0.53] variability for items and full UCEIS was 'moderate'-to-'substantial', with no significant differences except for intra-reader variability for erosions and ulcers [κ blinded: 0.47 vs unblinded: 0.74; p 0.047]. The SD of CRGs was lower than for individual central readers [0.54 vs 0.95; p < 0.001]. Correlation between blinded UCEIS and patient-reported symptoms was high [stool frequency: 0.76; rectal bleeding: 0.82; both: 0.81]. CONCLUSIONS: The UCEIS is minimally affected by knowledge of clinical details, strongly correlates with patient-reported symptoms, and is a suitable instrument for trials. CRGs performed better than individuals.

Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, Stanley AJ, Everett SM, Bailey AA, Dallal H et al. 2015. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet, 386 (9989), pp. 137-144. | Show Abstract | Read more

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

Corte C, Fernandopulle N, Catuneanu AM, Burger D, Cesarini M, White L, Keshav S, Travis S. 2015. Association between the ulcerative colitis endoscopic index of severity (UCEIS) and outcomes in acute severe ulcerative colitis. J Crohns Colitis, 9 (5), pp. 376-381. | Show Abstract | Read more

BACKGROUND: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) accounts for 86% of the variance between observers in the overall assessment of endoscopic severity, but has not been correlated with outcomes. METHODS: Consecutive cases of acute severe colitis (ASC) defined by Truelove and Witts (TW) criteria were retrospectively evaluated. Demographic details, number of TW criteria, prior medical therapy, UCEIS and inpatient medical therapy were recorded. Pre-specified (adverse) endpoints included rescue therapy, colectomy and readmission. RESULTS: Eighty-nine patients, 48 (54%) male, mean age 38 years, all received intravenous hydrocortisone 400mg/d (median 5 days [range 1-11]). Median follow-up was 14 months (2-33). Forty-eight (54%) were diagnosed the year prior to or at the time of admission. Thirty-six (40%) required rescue therapy (infliximab 25/36, ciclosporin 12/36, one receiving both). Twenty-one (24%) underwent colectomy on the index admission (9/21) or during follow-up (12/21). Median UCEIS score (possible range 0-8) was 5 (3-8). UCEIS was higher in patients requiring rescue therapy or colectomy (median score 6 [range 4-8] versus 5/8 [3-8], both p < 0.005). For UCEIS ≥5, 27/54 (50%) required rescue therapy, compared with 9/33 (27%) for UCEIS ≤4 (p = 0.037). When UCEIS was ≥5, 18/54 (33%) came to colectomy during follow-up, compared with 3/33 (9%) with UCEIS ≤4. Of 14 patients with UCEIS 7 or 8, 11/14 needed rescue therapy and 13/14 met any adverse endpoint. CONCLUSION: Endoscopic severity is associated with a worse outcome in ASC. When the UCEIS is ≥7 on admission, almost all patients will need treatment with infliximab or ciclosporin beyond steroids. This may mark a threshold for an early decision to use infliximab or ciclosporin.

Bryant RV, Winer S, Travis SPL, Riddell RH. 2015. Response to Villanacci et. al. J Crohns Colitis, 9 (5), pp. 429. | Read more

Jairath V, Zou GY, Parker CE, Macdonald JK, Alameel T, Al Beshir M, Almadi MA, Al-Taweel T, Atkinson NSS, Biswas S et al. 2015. Placebo response and remission rates in randomized trials of induction and maintenance therapy for ulcerative colitis Cochrane Database of Systematic Reviews, 2015 (3), | Show Abstract | Read more

© 2015 The Cochrane Collaboration. This is the protocol for a review and there is no abstract. The objectives are as follows: The objective of this review is to identify the factors that contribute to placebo response and remission rates in induction and maintenance trials of UC in which patients with active or quiescent disease were enrolled using the UCDAI.

Magee C, Blackwell V, Travis S. 2015. Toxic dilatation of the colon Medicine (United Kingdom), 43 (3), pp. 171-173. | Show Abstract | Read more

© 2015 Elsevier Ltd All rights reserved. Toxic megacolon (TM) is defined as total or non-segmental obstructive dilatation of the colon to an external diameter of 6.0 cm or greater, associated with systemic toxicity. It is a potentially fatal condition that represents the end of a spectrum of severe colitis. Typically a complication of ulcerative colitis, it is also seen as a consequence of infective colitis. Of particular concern, due to its high mortality, is TM associated with pseudomembranous colitis due to Clostridium difficile infection.

Sandborn WJ, Danese S, D'Haens G, Moro L, Jones R, Bagin R, Huang M, David Ballard E, Masure J, Travis S. 2015. Induction of clinical and colonoscopic remission of mild-to-moderate ulcerative colitis with budesonide MMX 9 mg: pooled analysis of two phase 3 studies. Aliment Pharmacol Ther, 41 (5), pp. 409-418. | Show Abstract | Read more

BACKGROUND: Conventional oral corticosteroids are effective at reducing inflammation associated with ulcerative colitis (UC); however, systemic adverse effects limit their use. Budesonide MMX is an extended-release, second-generation corticosteroid that targets delivery of budesonide to the entire colon. AIM: To analyse efficacy and safety outcomes from two phase 3 studies of budesonide MMX in patients with mild-to-moderate active UC. METHODS: Patients were assigned to budesonide MMX 9 mg, budesonide MMX 6 mg, or placebo once daily in two randomised, double-blind, placebo-controlled, 8-week studies (CORE I and II). Pooled data were analysed for pre-defined primary (combined clinical and colonoscopic remission), secondary and exploratory endpoints. Primary endpoint data were analysed to evaluate the potential influence of demographical and baseline disease characteristics on remission. RESULTS: Modified intent-to-treat population (histological evidence of baseline inflammation) had 232, 230 and 210 patients in budesonide MMX 9 mg, budesonide MMX 6 mg and placebo groups respectively. Combined clinical and colonoscopic remission rates were significantly greater than placebo (6.2%) for the budesonide MMX 9 mg group (17.7%; P = 0.0002), but not the budesonide MMX 6 mg group (10.9%). The primary endpoint of remission with budesonide MMX 9 mg was significantly greater than placebo in most subgroups analysed. Symptom resolution and colonoscopic improvement rates were significantly greater with budesonide MMX 9 mg vs. placebo. Budesonide MMX was safe and well tolerated. CONCLUSION: This pooled analysis showed that budesonide MMX 9 mg is efficacious, safe and well tolerated for inducing remission of mild-to-moderate UC.

Bryant RV, Sandborn WJ, Travis SPL. 2015. Introducing vedolizumab to clinical practice: who, when, and how? J Crohns Colitis, 9 (4), pp. 356-366. | Show Abstract | Read more

Vedolizumab (VDZ), a humanized monoclonal antibody that selectively targets α4β7 integrin, is approved for use in inflammatory bowel disease (IBD). Here we review the evidence for the safety and efficacy of VDZ in IBD, in order to identify patients likely to benefit from therapy and to integrate VDZ into clinical practice. A bibliographic search was performed of the online databases MEDLINE, EMBASE, PubMed, and the Cochrane Library, using the key words 'inflammatory bowel diseases' OR 'ulcerative colitis' OR 'Crohn's disease' AND 'vedolizumab' OR 'MLN0002' OR 'integrin alpha4beta7' OR 'anti-integrin'. Eight-nine articles were returned using the primary search. Eight randomized controlled trials, one Cochrane review, and two network meta-analyses were identified. VDZ is well tolerated with a low rate of adverse events (similar to placebo), and is associated with minimal systemic immunosuppression. VDZ is effective for induction and maintenance of remission in outpatients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) who have failed conventional and anti-tumor necrosis factor (anti-TNF) therapy. VDZ is also a first-line alternative to anti-TNF therapy in UC. The efficacy of VDZ is best assessed at, or beyond, 10 weeks of therapy. The safety, tolerability, and efficacy profile of VDZ place it as a new therapy in IBD, though further trials directly comparing VDZ with other biological agents as well as pragmatic studies to evaluate cost-effectiveness are necessary.

Cesarini M, Collins G, Ronnblom A, Santos A, Sjoberg D, Parkes M, Keshav S, Travis S. 2015. Predicting the risk of acute severe colitis (ASC) at diagnosis of Ulcerative Colitis (UC): external validation JOURNAL OF CROHNS & COLITIS, 9 pp. S117-S118.

Jairath V, Parker C, Zou G, MacDonald JK, Alameel T, Albeshir M, Almadi M, Altaweel T, Atkinson N, Biswas S et al. 2015. Placebo response and remission rates in Ulcerative Colitis clinical trials: Systematic review and meta-analysis JOURNAL OF CROHNS & COLITIS, 9 pp. S193-S194.

Griffiths B, Curry N, Desborough M, Henton S, Bryant RV, Travis SP, Jairath V. 2015. Evaluation of global coagulation profiles in patients with acute severe colitis: Implications for thromboprophylaxis JOURNAL OF CROHNS & COLITIS, 9 pp. S32-S32.

Wu K-C, Ran ZH, Gao X, Chen M, Zhong J, Sheng J-Q, Kamm MA, Travis S, Robinson AM, Wallace K et al. 2015. Adalimumab induction therapy achieves clinical remission and response in chinese patients with Crohn's Disease JOURNAL OF CROHNS & COLITIS, 9 pp. S277-S277.

Mosli M, Samaan M, Nelson SA, Feagan BG, Travis S, D'Haens G, Sandborn WJ, Zou G, MacDonald JK, Levesque BG. 2015. Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis Cochrane Database of Systematic Reviews, 2015 (1), | Show Abstract | Read more

© 2015 The Cochrane Collaboration. This is the protocol for a review and there is no abstract. The objectives are as follows: The primary objective is to systematically review the current literature describing the development and operating characteristics of endoscopic disease activity indices used to evaluate disease activity in UC.

van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollón F, Häuser W, Herrlinger K et al. 2015. Segundo consenso europeo basado en evidencia sobre el diagnóstico y tratamiento de la colitis ulcerosa crónica idiopática. Parte 3: situaciones especiales (versión española) Revista de Gastroenterología de México, 80 (1), pp. 74-106. | Read more

Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel J-F, Allez M, d’Haens G, d’Hoore A, Mantzanaris G, Novacek G et al. 2015. Segundo consenso europeo basado en evidencia sobre el diagnóstico y manejo de la colitis ulcerosa crónica idiopática. Parte 2: tratamiento actual (versión española) Revista de Gastroenterología de México, 80 (1), pp. 32-73. | Read more

Atkinson NSS, Reynolds DJM, Travis SPL. 2015. 'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intest Res, 13 (3), pp. 227-232. | Show Abstract | Read more

Proton pump inhibitors (PPIs) are widely used though an association with hypomagnesaemia and hypocalcaemia has only been described since 2006. Patients typically present after years of stable dosing with musculoskeletal, neurological or cardiac arrhythmic symptoms, but it is likely that many cases are under-recognised. Magnesium levels resolve rapidly on discontinuation of PPI therapy and hypomagnesaemia recurs rapidly on rechallenge with any agent in the class. The cellular mechanisms of magnesium homeostasis are increasingly being understood, including both passive paracellular absorption through claudins and active transcellular transporters, including the transient receptor potential channels (TRPM6) identified in the intestine and nephron. PPIs may alter luminal pH by modulating pancreatic secretions, affecting non-gastric H+K+ATPase secretion, altering transporter transcription or channel function. A small reduction in intestinal absorption appears pivotal in causing cumulative deficiency. Risk factors have been associated to help identify patients at risk of this effect but clinical vigilance remains necessary for diagnosis.

Campbell HE, Stokes EA, Bargo D, Logan RF, Mora A, Hodge R, Gray A, James MW, Stanley AJ, Everett SM et al. 2015. Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial. BMJ Open, 5 (4), pp. e007230. | Show Abstract | Read more

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.

Ford AC, Luthra P, Hanauer SB, Travis SP, Harris MS, Reinisch W. 2014. Placebo response rate in clinical trials of fistulizing Crohn's disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol, 12 (12), pp. 1981-1990. | Show Abstract | Read more

BACKGROUND & AIMS: It is important to determine the magnitude and identify modifiers of the rate of response to placebo in clinical trials of fistulizing Crohn's disease (CD), to understand disease progression, and to calculate sample size. We conducted a systematic review and meta-analysis of rates of response to placebo in trials of patients with fistulizing CD. METHODS: We searched MEDLINE, EMBASE, EMBASE CLASSIC, and the Cochrane central register of controlled trials for randomized controlled trials (RCTs) comparing pharmacologic agents with placebo in adults with fistulizing CD. We identified studies that reported complete fistula closure, partial closure, or response. Data were extracted as intention-to-treat analyses and pooled by using a random-effects model. Proportions of patients who received placebo and had complete or partial fistula(e) closure were calculated, with 95% confidence intervals (CIs). The effects of trial characteristics on the magnitude of response to placebo were examined. RESULTS: Thirteen RCTs were eligible for our analysis; these included 579 patients assigned to placebo groups. The pooled rate of response to placebo, among all RCTs, for complete fistula closure was 15.6% (95% CI, 10.9%-20.9%), with significant heterogeneity (I(2) = 62.5%, P = .001). The pooled rate of response to placebo for partial fistula closure or response in 9 trials, comprising 423 patients, was 18.3% (95% CI, 14.8%-22.1%). Rates of response to placebo were significantly lower in trials with shorter durations of therapy and shorter intervals to assessment of fistula closure. Neither exposure to the pharmacologic agent during the induction phase of the same (or related) RCT nor concomitant medications had any effect. CONCLUSIONS: In a meta-analysis of rate of response to placebo in patients with fistulizing CD, we found that fistulae closed in almost 1/6 patients given placebo in RCTs of pharmacologic agents. Future research should identify characteristics of patients that predict response to placebo.

Bryant RV, Winer S, Travis SPL, Riddell RH. 2014. Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis, 8 (12), pp. 1582-1597. | Show Abstract | Read more

BACKGROUND AND AIMS: Advances in the medical management of inflammatory bowel disease (IBD) have altered treatment targets. Endoscopic mucosal healing is associated with better outcomes in IBD, though less is known about the significance of achieving histological remission. Our aim was to perform a systematic review to investigate whether histological or 'complete' remission constitutes a further therapeutic target in IBD. METHODS: A bibliographic search was performed on the 1st of October 2013 and subsequently on the 1st of March 2014 of online databases (OVID SP MEDLINE, OVID EMBASE, National Pubmed Central Medline, Cochrane Library, ISI, conference abstracts), using MeSH terms and key words: ("inflammatory bowel diseases" OR "crohn disease" OR "ulcerative colitis" OR "colitis") AND ("mucosal healing" OR "histological healing" OR "pathological healing" OR "histological scoring" OR "pathological scoring"). RESULTS: The search returned 2951 articles. 120 articles were cited in the final analysis. There is no validated definition of histological remission in IBD. There are 22 different histological scoring systems for IBD, none of which are fully validated. Microscopic inflammation persists in 16-100% of cases of endoscopically quiescent disease. There is evidence that histological remission may predict risk of complications in ulcerative colitis beyond endoscopic mucosal healing, though data are scarce in Crohn's disease. CONCLUSIONS: Histological remission in IBD represents a target distinct from endoscopic mucosal healing, not yet routinely sought in clinical trials or practice. There remains a need for a standardized and validated histological scoring system and to confirm the prognostic value of histological remission as a treatment target in IBD.

Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson DC, Travis SP, Turner D et al. 2014. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology, 147 (5), pp. 990-1007.e3. | Show Abstract | Read more

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, Mantzaris G, Reinisch W, Colombel J-F, Vermeire S et al. 2014. Segundo Consenso Europeo basado en evidencia sobre el diagnóstico y tratamiento de la colitis ulcerosa crónica idiopática Parte 1: Definiciones y diagnóstico (versión española) Revista de Gastroenterología de México, 79 (4), pp. 263-289. | Read more

Jairath V, Thompson J, Kahan BC, Daniel R, Hearnshaw SA, Travis SPL, Murphy MF, Palmer KR, Logan RFA. 2014. Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity, and process of care The American journal of gastroenterology, 109 (10), pp. 1603-1612. | Show Abstract | Read more

OBJECTIVES: Previous studies have found higher mortality rates among inpatients (IPs) compared with new admissions (outpatients, OPs) with acute upper gastrointestinal bleeding (AUGIB), but no studies have investigated the cause for this. The objective of this study was to determine whether the difference in outcomes between IPs and OPs with AUGIB can be explained by differences in baseline characteristics, bleeding severity, or processes of care.METHODS: Data were collected from 6,657 presentations with all-cause AUGIB from 212 UK hospitals as part of a nationwide audit.RESULTS: IPs were older (77 vs. 65 years, P<0.001), had greater comorbidity, and presented with more severe bleeding. There was no difference in median time to endoscopy (24 vs. 24 h, P=0.67) or receipt of endotherapy (19% vs. 17%, P=0.29). IPs had an odds of mortality 4.8 times that of OPs (26% vs. 7%; odds ratio (OR) 4.8, 95% confidence interval (CI) 3.9-5.8); after adjusting for baseline characteristics, this fell by 24% to 3.3 (95% CI 3.2-4.9) and after adjusting for bleeding severity alone to 4.0 (95% CI 3.2-4.9); adjusting for care processes had minimal effect. IPs had more than a twofold increased odds of rebleeding (20% vs. 12%; OR 2.1, 95% CI 1.7-2.5); adjusting for both baseline characteristics and severity of bleeding reduced this by 50% (OR 1.4, 95% CI 1.3-2.4), but process of care had no additional impact.CONCLUSIONS: IPs present with both higher baseline risks and more severe bleeding. These differences in baseline characteristics explain some but not all of the greater mortality of IPs with AUGIB.

Gray A, Jairath V, Kahan B, Dore C, Palmer K, Travis S, Logan R, Walsh T, Murphy M. 2014. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (trigger): pragmatic, cluster randomised, feasibility trial. Emerg Med J, 31 (9), pp. 780. | Show Abstract | Read more

Transfusion thresholds for upper gastrointestinal bleeding (UGIB) are controversial. Observational studies suggest associations between liberal red blood cell (RBC) transfusion and adverse outcome. A recent trial reported increased mortality following liberal transfusion. We delivered a cluster randomised trial to evaluate the feasibility and safety of implementing a restrictive (transfusion when haemoglobin (Hb) <8 g dL) vs liberal (transfusion when Hb <10 g/dL) RBC transfusion policy for UGIB.

Jairath V, Thompson J, Kahan BC, Daniel R, Hearnshaw SA, Travis SPL, Murphy MF, Palmer KR, Logan RFA. 2014. Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity, and process of care. Am J Gastroenterol, 109 (10), pp. 1603-1612. | Show Abstract | Read more

OBJECTIVES: Previous studies have found higher mortality rates among inpatients (IPs) compared with new admissions (outpatients, OPs) with acute upper gastrointestinal bleeding (AUGIB), but no studies have investigated the cause for this. The objective of this study was to determine whether the difference in outcomes between IPs and OPs with AUGIB can be explained by differences in baseline characteristics, bleeding severity, or processes of care. METHODS: Data were collected from 6,657 presentations with all-cause AUGIB from 212 UK hospitals as part of a nationwide audit. RESULTS: IPs were older (77 vs. 65 years, P<0.001), had greater comorbidity, and presented with more severe bleeding. There was no difference in median time to endoscopy (24 vs. 24 h, P=0.67) or receipt of endotherapy (19% vs. 17%, P=0.29). IPs had an odds of mortality 4.8 times that of OPs (26% vs. 7%; odds ratio (OR) 4.8, 95% confidence interval (CI) 3.9-5.8); after adjusting for baseline characteristics, this fell by 24% to 3.3 (95% CI 3.2-4.9) and after adjusting for bleeding severity alone to 4.0 (95% CI 3.2-4.9); adjusting for care processes had minimal effect. IPs had more than a twofold increased odds of rebleeding (20% vs. 12%; OR 2.1, 95% CI 1.7-2.5); adjusting for both baseline characteristics and severity of bleeding reduced this by 50% (OR 1.4, 95% CI 1.3-2.4), but process of care had no additional impact. CONCLUSIONS: IPs present with both higher baseline risks and more severe bleeding. These differences in baseline characteristics explain some but not all of the greater mortality of IPs with AUGIB.

Taylor S, Mallett S, Bhatnagar G, Bloom S, Gupta A, Halligan S, Hamlin J, Hart A, Higginson A, Jacobs I et al. 2014. 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. BMC Gastroenterol, 14 (1), pp. 142. | Show Abstract | Read more

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.

Pavlides M, Cleland J, Rahman M, Christian A, Doyle J, Gaunt R, Travis S, Mortensen N, Chapman R. 2014. Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis Journal of Crohn's and Colitis, 8 (7), pp. 662-670. | Show Abstract | Read more

Background and aims: Outcomes after ileal pouch anal anastomosis (IPAA) are not well established in patients with primary sclerosing cholangitis (PSC). We conducted a comprehensive outcomes assessment in these patients. Methods: A retrospective case note review of complications in all PSC-IPAA (n=21) and matched ulcerative colitis patients with IPAA (UC-IPAA; n=79) after surgery in Oxford (1983-2012) was conducted, and functional outcomes (Öresland score) were evaluated (2012). Quality of life [Cleveland Global Quality of Life Questionnaire, Short Form-36 (SF-36)], and sexual function were also assessed (2012) including patients with PSC-associated UC without IPAA (PSC-UC; n=19). Sub-group analysis of patients with large duct (ld) PSC-IPAA (n=17) was also performed. Results: The 1-, 5-, 10- and 20-year risk of acute pouchitis for PSC-IPAA was 10%, 19%, 31% and 65% respectively, compared to 3%, 10%, 14% and 28% in UC-IPAA (p=0.03). More PSC-IPAA (36%) had poor nocturnal pouch function (vs 2% in UC-IPAA; p=0.0016). There were no differences in surgical complications, quality of life or sexual function between the 3 main groups. LdPSC-IPAA had poorer pouch function (Öresland score: 7.7 vs 5.4 in UC-IPAA; p=0.02), and worse quality of life [SF-36 Physical: 42 vs 50.5 in UC-IPAA; 47.7 in PSC-UC; p=0.03 and Mental Health summary scores: 41.6 vs 51.2 in UC-IPAA; 42.3 in PSC-UC; p=0.04]. Conclusions: PSC-IPAA suffer more acute pouchitis and have worse functional outcomes than UC-IPAA. LdPSC-IPAA also have poorer quality of life. © 2013 European Crohn's and Colitis Organisation.

Jairath V, Kahan B, Gray A, Dore C, Palmer K, Travis S, Logan R, Walsh T, Murphy M, TRIGGER Investigators. 2014. PTU-184 Restrictive Versus Liberal Blood Transfusion For Acute Upper Gastrointestinal Bleeding: Cluster Randomised Feasibility Trial. Gut, 63 Suppl 1 (Suppl 1), pp. A119-A120. | Show Abstract | Read more

Transfusion thresholds for upper gastrointestinal bleeding (UGIB) are controversial. Observational studies suggest associations between liberal red blood cell (RBC) transfusion and adverse outcome, and a recent trial reported increased mortality following liberal transfusion.

Cited:

26

Scopus

Jairath V, Rehal S, Logan R, Kahan B, Hearnshaw S, Stanworth S, Travis S, Murphy M, Palmer K, Burroughs A. 2014. Acute variceal haemorrhage in the United Kingdom: Patient characteristics, management and outcomes in a nationwide audit Digestive and Liver Disease, 46 (5), pp. 419-426. | Show Abstract | Read more

Background: Despite advances in treatment, acute variceal haemorrhage remains life-threatening. Aim: To describe contemporary characteristics, management and outcomes of patients with cirrhosis and acute variceal haemorrhage and risk factors for rebleeding and mortality. Methods: Multi-centre clinical audit conducted in 212 UK hospitals. Results: In 526 cases of acute variceal haemorrhage, 66% underwent endoscopy within 24. h with 64% (n= 339) receiving endoscopic therapy. Prior to endoscopy, 57% (n= 299) received proton pump inhibitors, 44% (n= 232) vasopressors and 27% (n= 144) antibiotics. 73% (n= 386) received red cell transfusion, 35% (n= 184) fresh frozen plasma and 14% (n= 76) platelets, with widely varying transfusion thresholds. 26% (n= 135) experienced further bleeding and 15% (n= 80) died by day 30. The Model for End Stage Liver Disease score was the best predictor of mortality (area under the receiver operating curve. = 0.74, P< 0.001). Neither the clinical nor full Rockall scores were useful predictors of outcome. Coagulopathy was strongly associated with rebleeding (odds ratio 2.23, 95% CI 1.22-4.07, P= 0.01, up to day 30) and mortality (odds ratio 3.06, 95% CI 1.29-7.26, P= 0.01). Conclusions: Although mortality has improved following acute variceal haemorrhage, rebleeding rates remain appreciably high. There are notable deficiencies in the use of vasopressors and endoscopic therapy. More work is needed to understand the optimum transfusion strategies. Better risk stratification tools are required to identify patients needing more intensive support. © 2013 Editrice Gastroenterologica Italiana S.r.l.

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56

Scopus

Wanders LK, Dekker E, Pullens B, Bassett P, Travis SPL, East JE. 2014. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: A meta-analysis Clinical Gastroenterology and Hepatology, 12 (5), pp. 756-764. | Show Abstract | Read more

Background & Aims: American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. Methods: MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. Results: Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. Conclusion: Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up. © 2014 AGA Institute.

Reinisch W, Travis S, Hanauer S, Wang H, Shara N, Harris MS. 2014. AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study. Inflamm Bowel Dis, 20 (5), pp. 872-881. | Show Abstract | Read more

BACKGROUND: AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn's disease. METHODS: To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebo-controlled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn's disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables. RESULTS: Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn's disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19-0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21-0.97; P = 0.04, respectively). CONCLUSIONS: In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn's disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response.

Harrison E, Allan P, Ramu A, Vaidya A, Travis S, Lal S. 2014. Management of intestinal failure in inflammatory bowel disease: small intestinal transplantation or home parenteral nutrition? World J Gastroenterol, 20 (12), pp. 3153-3163. | Show Abstract | Read more

Inflammatory bowel disease and Crohn's disease in particular, is a common cause of intestinal failure. Current therapeutic options include home parenteral nutrition and intestinal transplantation. For most patients, home intravenous therapy including parenteral nutrition, with a good probability of long-term survival, is the favoured choice. However, in selected patients, with specific features that may shorten survival or complicate home parenteral nutrition, intestinal transplantation presents a viable alternative. We present survival, complications, quality of life and economic considerations that currently influence individualised decision-making between home parenteral nutrition and intestinal transplantation.

Chan XHS, Koh CE, Glover M, Bryson P, Travis SPL, Mortensen NJ. 2014. Healing under pressure: hyperbaric oxygen and myocutaneous flap repair for extreme persistent perineal sinus after proctectomy for inflammatory bowel disease. Colorectal Dis, 16 (3), pp. 186-190. | Show Abstract | Read more

AIM: Persistent perineal sinus (PPS) following proctectomy for inflammatory bowel disease affects about 50% of patients. Up to 33% of cases of PPS remain unhealed at 12 months and the most refractory cases are unhealed at 24 months despite optimal conventional therapy. Reports of hyperbaric oxygen therapy (HBOT) for chronic wounds and Crohn's perianal disease led us to explore perioperative HBOT with rectus abdominis myocutaneous (RAM) flap repair in a highly selected group of patients with extreme PPS who had failed all other interventions. METHOD: Patients with extreme PPS received preoperative HBOT (a 90-min session at 2.2-2.4 atmospheres, five times per week for 5-6 weeks, for a total of up to 30 sessions), before abdominoperineal PPS excision and perineal reconstruction with vertical or transverse RAM flap repair within 2-4 weeks of completing HBOT. Postoperative HBOT (10 further 90-min sessions) was administered within 2 weeks where practicable. RESULTS: Between 2007 and 2011, four patients with extreme PPS underwent RAM flap repair with preoperative HBOT; two also received postoperative HBOT. The median (range) duration of PPS before HBOT was 88.5 (23-156) months. All patients had previously failed multiple (5 to > 35) surgical procedures. Complete healing occurred in all patients at a median (range) follow-up of 2.5 (2-3) months. There were no further hospital admissions for PPS at a median (range) follow-up of 35 (8-64) months. CONCLUSION: Hyperbaric oxygen therapy combined with PPS excision and perineal reconstruction with a RAM flap led to complete perineal healing in four patients with extreme PPS and appears a safe and effective extension to the therapeutic pathway for exceptionally treatment-refractory PPS.

Koslowsky B, Gupta A, Livovsky DM, Adar T, Turner D, Hartnell F, Pratico C, Travis S. 2014. The use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in adults with acute severe ulcerative colitis (ASC) JOURNAL OF CROHNS & COLITIS, 8 pp. S108-S108. | Read more

Kent A, Gray-Stephens H, Castaneanu A-M, Brooks J, Siddhanathi P, Travis S, Uhlig H, Keshav S. 2014. Intolerance to IBD treatment in over 1,800 patients in the Oxford IBD Cohort JOURNAL OF CROHNS & COLITIS, 8 pp. S249-S249. | Read more

Geremia A, Arancibia C, Gwela A, Chapman RW, Travis SPL, Powrie F. 2014. Innate lymphoid cells accumulate in IBD JOURNAL OF CROHNS & COLITIS, 8 pp. S1-S1. | Read more

Danese S, Fiorino G, Peyrin-Biroulet L, Lakatos PL, Mary JY, D'Haens G, Moja L, D'Hoore A, Panes J, Reinisch W et al. 2014. Development of red flags for early referral of adults with symptoms and signs suggestive of Crohn's disease: an IOIBD initiative JOURNAL OF CROHNS & COLITIS, 8 pp. S28-S28. | Read more

Bryant RV, Jairath V, Curry N, Travis SPL. 2014. Thrombosis in inflammatory bowel disease: Are we tailoring prophylaxis to those most at riskα Journal of Crohn's and Colitis, 8 (2), pp. 166-171. | Show Abstract | Read more

Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at riskα © 2013 European Crohn's and Colitis Organisation.

Jairath V, Rehal S, Logan R, Kahan B, Hearnshaw S, Stanworth S, Travis S, Murphy M, Palmer K, Burroughs A. 2014. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver Dis, 46 (5), pp. 419-426. | Show Abstract | Read more

BACKGROUND: Despite advances in treatment, acute variceal haemorrhage remains life-threatening. AIM: To describe contemporary characteristics, management and outcomes of patients with cirrhosis and acute variceal haemorrhage and risk factors for rebleeding and mortality. METHODS: Multi-centre clinical audit conducted in 212 UK hospitals. RESULTS: In 526 cases of acute variceal haemorrhage, 66% underwent endoscopy within 24h with 64% (n=339) receiving endoscopic therapy. Prior to endoscopy, 57% (n=299) received proton pump inhibitors, 44% (n=232) vasopressors and 27% (n=144) antibiotics. 73% (n=386) received red cell transfusion, 35% (n=184) fresh frozen plasma and 14% (n=76) platelets, with widely varying transfusion thresholds. 26% (n=135) experienced further bleeding and 15% (n=80) died by day 30. The Model for End Stage Liver Disease score was the best predictor of mortality (area under the receiver operating curve=0.74, P<0.001). Neither the clinical nor full Rockall scores were useful predictors of outcome. Coagulopathy was strongly associated with rebleeding (odds ratio 2.23, 95% CI 1.22-4.07, P=0.01, up to day 30) and mortality (odds ratio 3.06, 95% CI 1.29-7.26, P=0.01). CONCLUSIONS: Although mortality has improved following acute variceal haemorrhage, rebleeding rates remain appreciably high. There are notable deficiencies in the use of vasopressors and endoscopic therapy. More work is needed to understand the optimum transfusion strategies. Better risk stratification tools are required to identify patients needing more intensive support.

Pavlides M, Cleland J, Rahman M, Christian A, Doyle J, Gaunt R, Travis S, Mortensen N, Chapman R. 2014. Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis. J Crohns Colitis, 8 (7), pp. 662-670. | Show Abstract | Read more

BACKGROUND AND AIMS: Outcomes after ileal pouch anal anastomosis (IPAA) are not well established in patients with primary sclerosing cholangitis (PSC). We conducted a comprehensive outcomes assessment in these patients. METHODS: A retrospective case note review of complications in all PSC-IPAA (n=21) and matched ulcerative colitis patients with IPAA (UC-IPAA; n=79) after surgery in Oxford (1983-2012) was conducted, and functional outcomes (Öresland score) were evaluated (2012). Quality of life [Cleveland Global Quality of Life Questionnaire, Short Form-36 (SF-36)], and sexual function were also assessed (2012) including patients with PSC-associated UC without IPAA (PSC-UC; n=19). Sub-group analysis of patients with large duct (ld) PSC-IPAA (n=17) was also performed. RESULTS: The 1-, 5-, 10- and 20-year risk of acute pouchitis for PSC-IPAA was 10%, 19%, 31% and 65% respectively, compared to 3%, 10%, 14% and 28% in UC-IPAA (p=0.03). More PSC-IPAA (36%) had poor nocturnal pouch function (vs 2% in UC-IPAA; p=0.0016). There were no differences in surgical complications, quality of life or sexual function between the 3 main groups. LdPSC-IPAA had poorer pouch function (Öresland score: 7.7 vs 5.4 in UC-IPAA; p=0.02), and worse quality of life [SF-36 Physical: 42 vs 50.5 in UC-IPAA; 47.7 in PSC-UC; p=0.03 and Mental Health summary scores: 41.6 vs 51.2 in UC-IPAA; 42.3 in PSC-UC; p=0.04]. CONCLUSIONS: PSC-IPAA suffer more acute pouchitis and have worse functional outcomes than UC-IPAA. LdPSC-IPAA also have poorer quality of life.

Bryant RV, Brain O, Travis SPL. 2015. Conventional drug therapy for inflammatory bowel disease. Scand J Gastroenterol, 50 (1), pp. 90-112. | Show Abstract | Read more

Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.

Cited:

39

European Pubmed Central

Walsh A, Palmer R, Travis S. 2014. Mucosal healing as a target of therapy for colonic inflammatory bowel disease and methods to score disease activity. Gastrointest Endosc Clin N Am, 24 (3), pp. 367-378. | Show Abstract | Read more

Mucosal healing is an important therapeutic end point in clinical trials and clinical practice. There is no validated definition of mucosal healing in patients with inflammatory bowel disease, although the benefits of achieving mucosal healing include decreased need for corticosteroids, sustained clinical remission, decreased colectomy, and bowel resection. The Ulcerative Colitis Endoscopic Index of Severity is the only validated endoscopic index in ulcerative colitis. The Crohn's Disease Endoscopic Index of Severity and the Simple Endoscopic Score for Crohn's Disease are validated for Crohn disease, and the Rutgeerts Postoperative Endoscopic Index is used to predict recurrence after an ileocolic resection.

Chapman TP, Hadley G, Fratter C, Cullen SN, Bax BE, Bain MD, Sapsford RA, Poulton J, Travis SP. 2014. Unexplained gastrointestinal symptoms: Think mitochondrial disease Digestive and Liver Disease, 46 (1), pp. 1-8. | Show Abstract | Read more

Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic.We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic.The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected. © 2013 Editrice Gastroenterologica Italiana S.r.l.

Walsh AJ, Ghosh A, Brain AO, Buchel O, Burger D, Thomas S, White L, Collins GS, Keshav S, Travis SPL. 2014. Comparing disease activity indices in ulcerative colitis. J Crohns Colitis, 8 (4), pp. 318-325. | Show Abstract | Read more

BACKGROUND: Comparisons between disease activity indices for ulcerative colitis (UC) are few. This study evaluates three indices, to determine the potential impact of inter-observer variation on clinical trial recruitment or outcome as well as their clinical relevance. METHODS: One hundred patients with UC were prospectively evaluated, each by four specialists, followed by videosigmoidoscopy, which was later scored by each specialist. The Simple Clinical Colitis Activity (SCCAI), Mayo Clinic and Seo indices were compared by assigning a disease activity category from published thresholds for remission, mild, moderate and severe activity. Inter-observer variation was evaluated using Kappa statistics and its effect for each patient on recruitment and outcome measures for representative clinical trials calculated. Clinical relevance was assessed by comparing an independently assigned clinical category, taking all information into account as if in clinic, with the disease activity assigned by the indices. RESULTS: Inter-observer agreement for SCCAI (κ=0.75, 95% CI 0.70-0.81), Mayo Clinic (κ=0.72, 95% CI 0.67-0.78) and Seo (κ=0.89, 95% CI 0.83-0.95) indices was good or very good as was the agreement for rectal bleeding (κ=0.77) and stool frequency (κ=0.90). Endoscopy in the Mayo Clinic index had the greatest variation (κ=0.38). Inter-observer variation alone would have excluded up to 1 in 5 patients from recruitment or remission criteria in representative trials. Categorisation by the SCCAI, Mayo Clinic and Seo indices agreed with the independently assigned clinical category in 61%, 67% and 47% of cases respectively. CONCLUSIONS: Trial recruitment and outcome measures are affected by inter-observer variation in UC activity indices, and endoscopic scoring was the component most susceptible to variation.

Eliakim R, Dignass A, Travis S. 2013. Letter: inflammatory bowel disease guidelines and conflicts of interest. Aliment Pharmacol Ther, 38 (4), pp. 445. | Read more

Travis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel J-F, Feagan BG, Hanauer SB, Lichtenstein GR, Marteau PR et al. 2013. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterology, 145 (5), pp. 987-995. | Show Abstract | Read more

BACKGROUND & AIMS: We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. METHODS: We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors ("vascular pattern", "bleeding", and "erosions and ulcers") comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. RESULTS: There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. CONCLUSIONS: The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details.

Feagan BG, Sandborn WJ, D'Haens G, Pola S, McDonald JWD, Rutgeerts P, Munkholm P, Mittmann U, King D, Wong CJ et al. 2013. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology, 145 (1), pp. 149-157.e2. | Show Abstract | Read more

BACKGROUND & AIMS: Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. METHODS: We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. RESULTS: The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; P = .011). CONCLUSIONS: Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, Dyer C, Stokes EA, Llewelyn C, Bailey AA, Dallal H et al. 2013. restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: Rationale and protocol for a cluster randomized feasibility trial Transfusion Medicine Reviews, 27 (3), pp. 146-153. | Show Abstract | Read more

Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is < 8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is < 10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial. © 2013 Elsevier Inc.

Gecse KB, Khanna R, van den Brink GR, Ponsioen CY, Löwenberg M, Jairath V, Travis SPL, Sandborn WJ, Feagan BG, D'Haens GRAM. 2013. Biosimilars in IBD: hope or expectation? Gut, 62 (6), pp. 803-807. | Read more

Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, Dyer C, Stokes EA, Llewelyn C, Bailey AA, Dallal H et al. 2013. Restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: rationale and protocol for a cluster randomized feasibility trial. Transfus Med Rev, 27 (3), pp. 146-153. | Show Abstract | Read more

Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is <8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is <10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial.

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25

Scopus

Jairath V, Kahan BC, Stanworth SJ, Logan RFA, Hearnshaw SA, Travis SPL, Palmer KR, Murphy MF. 2013. Prevalence, management, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding in the United Kingdom Transfusion, 53 (5), pp. 1069-1076. | Show Abstract | Read more

BACKGROUND: Coagulopathy after major hemorrhage has been found to be an independent risk factor for mortality after traumatic bleeding. It is unclear whether similar associations are present in other causes of major hemorrhage. We describe the prevalence, use of plasma, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding (NVUGIB). STUDY DESIGN AND METHODS: This study was a multicenter UK national audit. Data were collected prospectively on consecutive admissions with upper gastrointestinal bleeding over a 2-month period to 212 UK hospitals. Coagulopathy was defined as an international normalized ratio (INR) of at least 1.5. Logistic regression was used to examine the relationship between coagulopathy and patient-related outcome measures of mortality, rebleeding, and need for surgery and/or radiologic intervention. RESULTS: A total of 4478 patients were included in the study. Coagulopathy was present in 16.4% (444/2709) of patients in whom an INR was recorded. Patients with coagulopathy were more likely to present with hemodynamic shock (45% vs. 36%), have a higher clinical Rockall score (4 vs. 2), receive red blood cell transfusion (79% vs. 48%) and have high-risk stigmata of hemorrhage at endoscopy (34% vs. 25%). After adjustment for confounders the presence of a coagulopathy was associated with a fivefold increased in the odds of mortality (odds ratio, 5.63; 95% confidence interval, 3.09-10.27; p < 0.001). Only 35% of patients with coagulopathy received fresh-frozen plasma transfusion. CONCLUSIONS: Coagulopathy was prevalent in 16% of patients after NVUGIB and independently associated with more than a fivefold increase in the odds of in-hospital mortality. Wide variation in plasma use exists indicates clinical uncertainty regarding optimal practice. © 2012 American Association of Blood Banks.

Reenaers C, Louis E, Belaiche J, Seidel L, Keshav S, Travis S. 2013. Letter: should immunosuppressive therapy be started with adalimumab in Crohn's disease? Authors' reply. Aliment Pharmacol Ther, 37 (7), pp. 752-753. | Read more

Sandborn WJ, Travis S, Ballard D. 2013. Reply: budesonide. Gastroenterology, 144 (3), pp. e23-e24. | Read more

Van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollón F, Häuser W, Herrlinger K et al. 2013. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis, 7 (1), pp. 1-33. | Read more

Wanders LK, Dekker E, Pullens B, Bassett P, Travis SPL, East JE. 2014. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol, 12 (5), pp. 756-764. | Show Abstract | Read more

BACKGROUND & AIMS: American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. METHODS: MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. RESULTS: Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. CONCLUSION: Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up.

Bryant RV, Jairath V, Curry N, Travis SPL. 2014. Thrombosis in inflammatory bowel disease: are we tailoring prophylaxis to those most at risk? J Crohns Colitis, 8 (2), pp. 166-171. | Show Abstract | Read more

Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?

Chapman TP, Hadley G, Fratter C, Cullen SN, Bax BE, Bain MD, Sapsford RA, Poulton J, Travis SP. 2014. Unexplained gastrointestinal symptoms: think mitochondrial disease. Dig Liver Dis, 46 (1), pp. 1-8. | Show Abstract | Read more

Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic. The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected.

Walsh AJ, Weltman M, Burger D, Vivekanandarajah S, Connor S, Howlett M, Radford-Smith G, Selby W, Veillard AS, Grimm MC et al. 2013. Implementing guidelines on the prevention of opportunistic infections in inflammatory bowel disease Journal of Crohn's and Colitis, 7 (10), pp. e449-e456. | Show Abstract | Read more

Introduction: Opportunistic infections are a key safety concern in the management of patients with inflammatory bowel disease (IBD). Despite the existence of international guidelines, many gastroenterologists have not adopted routine screening and vaccination. The aim of this study was to modify clinical behaviour by use of a simple screening tool. Methods: A screening and vaccination proforma for hepatitis B, varicella, Influenza, Pneumococcus, human papillomavirus, tuberculosis, hepatitis C and HIV was provided to each participating gastroenterologist. Gastroenterologists were surveyed for awareness of vaccine recommendations and current practice prior to and following the introduction of the proforma. Rates of immunity and the proportion of patients receiving the recommended screening and vaccinations were documented. Results: 30 gastroenterologists at 8 different IBD centres took part in the assessment. A total of 919 patients were included (55% female, 65% Crohn's, 33% ulcerative colitis, 2% indeterminate IBD). Introduction of the proforma increased self-reported gastroenterologist screening from 47% to 97% pre- and post-intervention respectively, p < 0.001. After the proforma was applied, vaccination against hepatitis B, varicella, Influenza, and Pneumococcus was recommended in 67%, 2.5%, 75% and 69% of the patients respectively. Of these, 42%, 39%, 66% and 49% patients followed the recommendations and were vaccinated. Cervical smears were recommended in 31%, with 62% of these obtaining the recommended cervical smear. Conclusions: Implementation of a screening and vaccination proforma significantly changed gastroenterologist self-reported behaviour. Patient compliance with these recommendations was not optimal and suggests the need for further patient education, in addition to other forms of support. Crown Copyright © 2013.

Travis SPL, Danese S, Kupcinskas L, Alexeeva O, D'Haens G, Gibson PR, Moro L, Jones R, Ballard ED, Masure J et al. 2014. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut, 63 (3), pp. 433-441. | Show Abstract | Read more

OBJECTIVE: Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). DESIGN: Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. RESULTS: 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. CONCLUSION: Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.

Sandborn WJ, Travis S, Ballard D. 2013. Reply Gastroenterology, 144 (3), pp. e23-e24. | Read more

Cited:

38

Scopus

Leedham SJ, Rodenas-Cuadrado P, Howarth K, Lewis A, Mallappa S, Segditsas S, Davis H, Jeffery R, Rodriguez-Justo M, Keshav S et al. 2013. A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts Gut, 62 (1), pp. 83-93. | Show Abstract | Read more

Objective: Wnt signalling is critical for normal intestinal development and homeostasis. Wnt dysregulation occurs in almost all human and murine intestinal tumours and an optimal but not excessive level of Wnt activation is considered favourable for tumourigenesis. The authors assessed effects of pan-intestinal Wnt activation on tissue homeostasis, taking into account underlying physiological Wnt activity and stem-cell number in each region of the bowel. Design: The authors generated mice that expressed temporally controlled, stabilised β-catenin along the crypt-villus axis throughout the intestines. Physiological Wnt target gene activity was assessed in different regions of normal mouse and human tissue. Human intestinal tumour mutation spectra were analysed. Results: In the mouse, β-catenin stabilisation resulted in a graduated neoplastic response, ranging from dysplastic transformation of the entire epithelium in the proximal small bowel to slightly enlarged crypts of non-dysplastic morphology in the colorectum. In contrast, stem and proliferating cell numbers were increased in all intestinal regions. In the normal mouse and human intestines, stem-cell and Wnt gradients were non-identical, but higher in the small bowel than large bowel in both species. There was also variation in the expression of some Wnt modulators. Human tumour analysis confirmed that different APC mutation spectra are selected in different regions of the bowel. Conclusions: There are variable gradients in stem-cell number, physiological Wnt activity and response to pathologically increased Wnt signalling along the cryptvillus axis and throughout the length of the intestinal tract. The authors propose that this variation influences regional mutation spectra, tumour susceptibility and lesion distribution in mice and humans.

Cited:

29

Scopus

Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Dore CJ, Travis SPL, Murphy MF, Palmer KR. 2012. National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding British Journal of Surgery, 99 (12), pp. 1672-1680. | Show Abstract | Read more

Background: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. Methods: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. Results: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). Conclusion: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. Re-bleeding after failed endoscopic treatment carries a high mortality Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel J-F, Allez M, D'Haens G, D'Hoore A, Mantzaris G, Novacek G et al. 2012. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management Journal of Crohn's and Colitis, 6 (10), pp. 991-1030. | Read more

Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, Mantzaris G, Reinisch W, Colombel J-F, Vermeire S et al. 2012. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis Journal of Crohn's and Colitis, 6 (10), pp. 965-990. | Read more

Peyrin-Biroulet L, Billioud V, D'Haens G, Panaccione R, Feagan B, Panés J, Danese S, Schreiber S, Ogata H, Hibi T et al. 2012. Development of the Paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process. Am J Gastroenterol, 107 (12), pp. 1770-1776. | Show Abstract | Read more

We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.

Walsh A, Travis S. 2012. Assessing disease activity in patients with ulcerative colitis. Gastroenterol Hepatol (N Y), 8 (11), pp. 751-754.

Reenaers C, Louis E, Belaiche J, Seidel L, Keshav S, Travis S. 2012. Does co-treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab? Aliment Pharmacol Ther, 36 (11-12), pp. 1040-1048. | Show Abstract | Read more

BACKGROUND: There is clear benefit from combination therapy with infliximab and immunosuppressive drugs (IS), but few data are available for adalimumab (ADA). AIM: To assess the efficacy of ADA monotherapy and ADA+IS for induction and maintenance therapy in Crohn's disease. METHODS: Retrospective study of patients with Crohn's disease treated with ADA in Oxford, UK or Liège, Belgium. Treatment periods were divided into 6-month semesters. A combination therapy semester was defined as ADA+IS for at least 3 months; successful induction meant clinical response; a semester with flare as ADA dose escalation, starting steroids, perianal complication, or surgery; and ADA failure as ADA withdrawal for secondary loss of response or intolerance. Semesters with and without flares were compared through univariate and multivariate analysis. RESULTS: Successful induction was achieved in 171/207 (83%) patients, with no significant difference between ADA+IS and ADA monotherapy (85% vs. 82%, P = 0.50). Five hundred and sixty-two semesters in 181 patients were included for maintenance analysis. ADA+IS was not associated with fewer semesters with flare (34% vs. 35%, P = 0.96), or with ADA failure (6% vs. 8%, P = 0.43). Nevertheless, combination therapy in the first semester was associated with a lower risk of ADA failure (5% vs. 10%, P = 0.04, OR = 0.48) and combination therapy beyond 6 months was associated with fewer semesters with flares (14% vs. 36%, P = 0.02, OR = 0.31). CONCLUSIONS: There may be a benefit from adalimumab+immunosuppressive drugs combination therapy during the first semester of initiating adalimumab, with a slight decrease in adalimumab failure and lower need for adalimumab dosage escalation.

Halliday J, Travis S, Chapman R. 2012. Has primary sclerosing cholangitis associated with Crohn's disease a better outcome? Reply JOURNAL OF CROHNS & COLITIS, 6 (9), pp. 957-957. | Read more

Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Dore CJ, Travis SPL, Murphy MF, Palmer KR. 2012. National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding. Br J Surg, 99 (12), pp. 1672-1680. | Show Abstract | Read more

BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.

Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Dore CJ, Travis SPL, Murphy MF, Palmer KR. 2012. Outcomes Following Acute Nonvariceal Upper Gastrointestinal Bleeding in Relation to Time to Endoscopy: Results from a Nationwide Study ENDOSKOPIE HEUTE, 25 (3), pp. 196-204. | Show Abstract | Read more

Background and study aims: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. Patients and methods: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. Results: In 4478 patients, earlier endoscopy (<12 hours) was not associated with a lower mortality or need for surgery compared with later (>24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95% confidence interval [CI] 0.88-1.09 for endoscopy >24 hours vs. <12 hours; p=0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95%CI 0.97-1.32 for endoscopy >24 hours vs. <12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95%CI 0.73-0.95 for endoscopy >24 hours vs.<12 hours; interaction p=0.003). Later endoscopy (>24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95%CI 1.39-1.99 vs. <12 hours; p<0.001). Conclusions: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision. © Georg Thieme Verlag KG Stuttgart. New York.

Jairath V, Kahan BC, Stanworth SJ, Logan RFA, Hearnshaw SA, Travis SPL, Palmer KR, Murphy MF. 2013. Prevalence, management, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding in the United Kingdom. Transfusion, 53 (5), pp. 1069-1076. | Show Abstract | Read more

BACKGROUND: Coagulopathy after major hemorrhage has been found to be an independent risk factor for mortality after traumatic bleeding. It is unclear whether similar associations are present in other causes of major hemorrhage. We describe the prevalence, use of plasma, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding (NVUGIB). STUDY DESIGN AND METHODS: This study was a multicenter UK national audit. Data were collected prospectively on consecutive admissions with upper gastrointestinal bleeding over a 2-month period to 212 UK hospitals. Coagulopathy was defined as an international normalized ratio (INR) of at least 1.5. Logistic regression was used to examine the relationship between coagulopathy and patient-related outcome measures of mortality, rebleeding, and need for surgery and/or radiologic intervention. RESULTS: A total of 4478 patients were included in the study. Coagulopathy was present in 16.4% (444/2709) of patients in whom an INR was recorded. Patients with coagulopathy were more likely to present with hemodynamic shock (45% vs. 36%), have a higher clinical Rockall score (4 vs. 2), receive red blood cell transfusion (79% vs. 48%) and have high-risk stigmata of hemorrhage at endoscopy (34% vs. 25%). After adjustment for confounders the presence of a coagulopathy was associated with a fivefold increased in the odds of mortality (odds ratio, 5.63; 95% confidence interval, 3.09-10.27; p < 0.001). Only 35% of patients with coagulopathy received fresh-frozen plasma transfusion. CONCLUSIONS: Coagulopathy was prevalent in 16% of patients after NVUGIB and independently associated with more than a fivefold increase in the odds of in-hospital mortality. Wide variation in plasma use exists indicates clinical uncertainty regarding optimal practice.

Logan RFA, Hearnshaw S, Jairath V, Travis S, Palmer KR. 2012. Upper gastrointestinal bleeding in the UK: does a dedicated bleed unit improve outcomes? response GUT, 61 (8), pp. 1238-1238. | Read more

Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Doré CJ, Travis SPL, Murphy MF, Palmer KR. 2012. Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study. Endoscopy, 44 (8), pp. 723-730. | Show Abstract | Read more

BACKGROUND AND STUDY AIMS: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. PATIENTS AND METHODS: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. RESULTS: In 4478 patients, earlier endoscopy ( < 12 hours) was not associated with a lower mortality or need for surgery compared with later ( > 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy ( > 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). CONCLUSIONS: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision.

Kent AJ, Blackwell VJ, Travis SPL. 2012. What is the optimal treatment for anemia in inflammatory bowel disease? Curr Drug Deliv, 9 (4), pp. 356-366. | Show Abstract | Read more

Anemia is common in inflammatory bowel disease (IBD), with a prevalence ranging from 8.8% to 73.7%. This wide range reflects the definitions used and the populations studied. Although many patients are reported to be asymptomatic, systematic studies have shown anemia to have a significant impact on quality of life. Consequently treatment should be instituted early. The commonest cause of anemia in IBD is iron deficiency, predominantly related to gastrointestinal blood loss. Anemia of chronic disease often occurs concomitantly, due to cytokine-mediated impaired erythropoiesis and dysregulated iron metabolism. Oral iron is a simple and effective method for treating iron deficiency, but requires long courses of treatment. It is also theoretically implicated with worsening intestinal inflammation, via the production of toxic reactive oxygen species. Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly. In patients failing to respond to intravenous iron, the anemia of chronic disease is most likely to be causative. In this setting evidence suggests that additional erythropoietin therapy can be effective. Blood transfusions should be avoided as part of routine management and reserved for patients with substantial acute gastro-intestinal bleeding, where there is a risk of hemodynamic compromise. This article discusses the underlying physiology of anemia in IBD, and presents the current evidence supporting treatment options available.

Cited:

26

European Pubmed Central

Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, Chapman RWG. 2012. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease. J Crohns Colitis, 6 (2), pp. 174-181. | Show Abstract | Read more

BACKGROUND AND AIMS: A distinct clinical phenotype has been demonstrated for ulcerative colitis with concomitant primary sclerosing cholangitis (PSC). The course and behaviour of Crohn's disease (CD) with PSC has, in contrast, never been defined. We aimed to define the characteristics of patients with concomitant PSC and CD. METHODS: The Oxford PSC and IBD databases were abstracted for: PSC subtype, date of diagnosis, symptom onset, smoking history, Mayo Clinic PSC score and outcomes (hepatic failure, liver transplantation, Montréal CD classification, treatment, cancer and death). Patients with PSC/CD were matched 1:2 to two control groups: one with PSC/UC and one with isolated CD. RESULTS: 240 patients with PSC were identified; 32 (13%) with CD, 129 (54%) with co-existing UC, and 79 had PSC without IBD. For PSC/CD vs. CD controls, isolated ileal CD was less common (6% vs. 31%, p=0.03). Smoking was less common in PSC/CD (13% vs. 34%, p=0.045). No difference in the distribution of CD, or treatment required was observed. For PSC/CD vs. PSC/UC controls, more patients with PSC/CD were female (50% vs. 28%, p=0.021). 22% of PSC/CD patients had small duct PSC compared with 6% with PSC/UC, (p=0.038). Major event-free survival was prolonged in the PSC/CD group compared with PSC/UC, (Cox regression p=0.04). CONCLUSION: Unlike PSC/UC, patients with PSC/CD were as likely to be female as male, more commonly had small duct PSC and less commonly progressed to cancer, liver transplantation, or death. Compared to patients with isolated CD, patients with PSC/CD were less likely to smoke or have ileal disease.

Travis S, Feagan BG, Rutgeerts P, van Deventer S. 2012. The future of inflammatory bowel disease management: combining progress in trial design with advances in targeted therapy. J Crohns Colitis, 6 Suppl 2 pp. S250-S259. | Show Abstract | Read more

Anti-tumour necrosis factor antagonists have appreciably improved patient outcomes in Crohn's disease, shifting the goals of treatment from control of symptoms to clinical remission (Crohn's disease activity index <150) combined with mucosal healing - the new concept of 'deep remission'. Achieving deep remission brings clinically meaningful benefits, including reduced hospitalization and reduced need for surgery. Aspects such as the dose, timing and intensification of anti-tumour necrosis factor therapy affect the likelihood of achieving deep remission, but definitive evidence on long-term benefits and the risk/benefit profile of treatment intensification is needed. A consequence of the success of anti-tumour necrosis factor therapies has been a change in the disease characteristics of the patient population entering clinical trials. Therefore, new clinical study paradigms, such as cluster randomization and therapeutic strategy trials, are needed. High placebo response rates and the ethics of testing emerging agents against placebo in an era of effective therapies are challenges to traditional randomized controlled trials. Overcoming these challenges will not only help to optimize anti-tumour necrosis factor therapy, but also advance development of emerging treatments for Crohn's disease.

Siffledeen J, Goldacre MJ, Travis S. 2012. Mortality in patients hospitalised with Crohn's disease. Aliment Pharmacol Ther, 35 (3), pp. 396-397. | Read more

Leedham SJ, Rodenas-Cuadrado P, Howarth K, Lewis A, Mallappa S, Segditsas S, Davis H, Jeffery R, Rodriguez-Justo M, Keshav S et al. 2013. A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts. Gut, 62 (1), pp. 83-93. | Show Abstract | Read more

OBJECTIVE: Wnt signalling is critical for normal intestinal development and homeostasis. Wnt dysregulation occurs in almost all human and murine intestinal tumours and an optimal but not excessive level of Wnt activation is considered favourable for tumourigenesis. The authors assessed effects of pan-intestinal Wnt activation on tissue homeostasis, taking into account underlying physiological Wnt activity and stem-cell number in each region of the bowel. DESIGN: The authors generated mice that expressed temporally controlled, stabilised β-catenin along the crypt-villus axis throughout the intestines. Physiological Wnt target gene activity was assessed in different regions of normal mouse and human tissue. Human intestinal tumour mutation spectra were analysed. RESULTS: In the mouse, β-catenin stabilisation resulted in a graduated neoplastic response, ranging from dysplastic transformation of the entire epithelium in the proximal small bowel to slightly enlarged crypts of non-dysplastic morphology in the colorectum. In contrast, stem and proliferating cell numbers were increased in all intestinal regions. In the normal mouse and human intestines, stem-cell and Wnt gradients were non-identical, but higher in the small bowel than large bowel in both species. There was also variation in the expression of some Wnt modulators. Human tumour analysis confirmed that different APC mutation spectra are selected in different regions of the bowel. CONCLUSIONS: There are variable gradients in stem-cell number, physiological Wnt activity and response to pathologically increased Wnt signalling along the crypt-villus axis and throughout the length of the intestinal tract. The authors propose that this variation influences regional mutation spectra, tumour susceptibility and lesion distribution in mice and humans.

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Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Doré CJ, Travis SPL, Murphy MF, Palmer KR. 2012. Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: Results from a nationwide study Endoscopy, 44 (8), pp. 723-730. | Show Abstract | Read more

Background and study aims: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. Patients and methods: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. Results: In 4478 patients, earlier endoscopy (< 12 hours) was not associated with a lower mortality or need for surgery compared with later (> 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy (> 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). Conclusions: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision. © Georg Thieme Verlag KG Stuttgart · New York.

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Reenaers C, Louis E, Belaiche J, Seidel L, Keshav S, Travis S. 2012. Does co-treatment with immunosuppressors improve outcome in patients with Crohn's disease treated with adalimumab? Alimentary Pharmacology and Therapeutics, 36 (11-12), pp. 1040-1048. | Show Abstract | Read more

Background: There is clear benefit from combination therapy with infliximab and immunosuppressive drugs (IS), but few data are available for adalimumab (ADA). Aim: To assess the efficacy of ADA monotherapy and ADA+IS for induction and maintenance therapy in Crohn's disease. Methods: Retrospective study of patients with Crohn's disease treated with ADA in Oxford, UK or Liège, Belgium. Treatment periods were divided into 6-month semesters. A combination therapy semester was defined as ADA+IS for at least 3 months; successful induction meant clinical response; a semester with flare as ADA dose escalation, starting steroids, perianal complication, or surgery; and ADA failure as ADA withdrawal for secondary loss of response or intolerance. Semesters with and without flares were compared through univariate and multivariate analysis. Results: Successful induction was achieved in 171/207 (83%) patients, with no significant difference between ADA+IS and ADA monotherapy (85% vs. 82%, P = 0.50). Five hundred and sixty-two semesters in 181 patients were included for maintenance analysis. ADA+IS was not associated with fewer semesters with flare (34% vs. 35%, P = 0.96), or with ADA failure (6% vs. 8%, P = 0.43). Nevertheless, combination therapy in the first semester was associated with a lower risk of ADA failure (5% vs. 10%, P = 0.04, OR = 0.48) and combination therapy beyond 6 months was associated with fewer semesters with flares (14% vs. 36%, P = 0.02, OR = 0.31). Conclusions: There may be a benefit from adalimumab+immunosuppressive drugs combination therapy during the first semester of initiating adalimumab, with a slight decrease in adalimumab failure and lower need for adalimumab dosage escalation. © 2012 Blackwell Publishing Ltd.

Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M et al. 2012. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut, 61 (12), pp. 1693-1700. | Show Abstract | Read more

OBJECTIVE: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. DESIGN: In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. RESULTS: 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). CONCLUSIONS: Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Neurath MF, Travis SPL. 2012. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut, 61 (11), pp. 1619-1635. | Show Abstract | Read more

Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted.

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Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M et al. 2012. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: Unexpected results of a randomised, double-blindplacebo- controlled trial Gut, 61 (12), pp. 1693-1700. | Show Abstract | Read more

Objective: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. Design: In a double-blind, randomised, placebocontrolled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2x10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (ΔCDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔDCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔDCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Logan RFA, Hearnshaw S, Lowe D, Travis SPL, Murphy MS, Palmer KR. 2012. Acute upper gastrointestinal bleeding: Identifying low risk patients Gut, 61 (11), pp. 1641. | Read more

Sandborn WJ, Travis S, Moro L, Jones R, Gautille T, Bagin R, Huang M, Yeung P, Ballard ED. 2012. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology, 143 (5), pp. 1218-1226.e2. | Show Abstract | Read more

BACKGROUND & AIMS: Budesonide is a corticosteroid with minimal systemic corticosteroid activity due to first-pass hepatic metabolism. Budesonide MMX® is a once-daily oral formulation of budesonide that extends budesonide release throughout the colon using multi-matrix system (MMX) technology. METHODS: We performed a randomized, double-blind, double-dummy, placebo-controlled trial to evaluate the efficacy of budesonide MMX for induction of remission in 509 patients with active, mild to moderate ulcerative colitis (UC). Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), mesalamine (2.4 g, as reference), or placebo for 8 weeks. The primary end point was remission at week 8. RESULTS: The rates of remission at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 17.9%, 13.2%, and 12.1%, respectively, compared with 7.4% for placebo (P = .0143, P = .1393, and P = .2200). The rates of clinical improvement at week 8 among patients given 9 mg or 6 mg budesonide MMX or mesalamine were 33.3%, 30.6%, and 33.9%, respectively, compared with 24.8% for placebo (P = .1420, P = .3146, and P = .1189). The rates of endoscopic improvement at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 41.5%, 35.5%, and 33.1%, respectively, compared with 33.1% for placebo. The rates of symptom resolution at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 28.5%, 28.9%, and 25.0%, respectively, compared with 16.5% for placebo (P = .0258, P = .0214, and P = .1025). Adverse events occurred at similar frequencies among groups. CONCLUSIONS: Budesonide MMX (9 mg) was safe and more effective than placebo in inducing remission in patients with active, mild to moderate UC.

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Sung J, Ho KY, Chiu HM, Ching J, Travis S, Peled R. 2012. The use of Pillcam Colon in assessing mucosal inflammation in ulcerative colitis: A multicenter study Endoscopy, 44 (8), pp. 754-758. | Show Abstract | Read more

Background and study aim: Treatment of ulcerative colitis should be tailored to the severity of colonic inflammation, which in the past has been gauged mainly by clinical features and biochemical parameters. Recently, mucosal healing has been proposed as a standard to guide therapy. The aim of this multicenter study was to test whether mucosal appearance, as reported by colon capsule endoscopy (CCE), can be used to differentiate active from inactive ulcerative colitis. Patients and methods: Adult patients from Hong Kong, Singapore, and Taiwan who were suspected or known to have ulcerative colitis were included in this prospective study. CCE and conventional optical colonoscopy were offered to these patients on the same day after receiving standard bowel preparation. The primary endpoint was the accuracy of CCE in assessing colonic inflammation (defined as the presence of ulcers, erythema, erosions, edema, exudates in mucosa), using optical colonoscopy as the gold standard. Results: At total of 100 patients (42 females; median age 50 years; range 22 - 68 years) were enrolled. Four cases were excluded from the analysis due to technical failure or slow transit of the capsule. In nine patients, the capsule was not excreted within 8.5 hours and required retrieval during colonoscopy. The sensitivity of CCE to detect active colonic inflammation was 89 % (95 % confidence interval [CI] 80 - 95) and specificity was 75 % (95 %CI 51 - 90). The positive and negative predictive values of CCE for colonic inflammation were 93 % (95 %CI 84 - 97) and 65 % (95 %CI 43 - 83), respectively. No serious adverse event related to the CCE procedure or preparation was reported. Conclusion: CCE is a safe procedure to monitor mucosal healing in ulcerative colitis. However, at this stage, CCE cannot be recommended to replace conventional colonoscopy in the management of this condition. © Georg Thieme Verlag KG Stuttgart · New York.

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Tzivanakis A, Singh JC, Guy RJ, Travis SP, Mortensen NJ, George BD. 2012. Influence of risk factors on the safety of ileocolic anastomosis in Crohn's disease surgery. Diseases of the colon and rectum, 55 (5), pp. 558-562. | Show Abstract | Read more

Ileocecal resection is the most commonly performed operation in patients with Crohn's disease. Anastomotic-associated complications, with their associated morbidity, are the most feared risks of surgery. This study aimed to assess the influence of a variety of putative risk factors in a homogenous group of patients undergoing first or subsequent surgery for Crohn's disease to quantify the cumulative risk for anastomotic-associated complications. All patients undergoing ileocecal or ileocolic resections for Crohn's disease from 2000 to 2010 were studied with the use of a prospective database. Demographics, operative details, possible risk factors, and anastomotic-associated complications were recorded. Patients having strictureplasties, multiple resections, or subtotal colonic resections were excluded from analysis. Statistical analysis was by univariate analysis (Mann-Whitney U test) and binary logistic regression. An anastomotic-associated complication was defined as a proven anastomotic leak, postoperative fistulation, or intra-abdominal abscess formation. Two hundred seven patients (109 female) with a median age of 35 years (range, 13-75 years) were identified. One hundred seventy-three underwent primary anastomosis, 94 as an emergency procedure. Fifty-three had laparoscopic (5 converted) procedures. Nineteen of 173 anastomotic complication events (11%) were recorded. Steroid usage (OR 2.67, 95% CI 1.0-7.2) and the presence of preoperative abscess formation (OR 3.4, 95% CI 1.2-9.8) were identified as independent predictors of anastomotic-associated complications. In the absence of both steroids and intra-abdominal abscess, the risk of anastomotic complications was 6%, which increased to 14% if either risk factor was present. When both risk factors were present, complication rates reached 40%. Steroid usage and preoperative abscess were associated with higher rates of anastomotic complications following ileocolic resection for Cohn's disease. When both risk factors are present, it is best to avoid primary anastomosis.

Sung J, Ho KY, Chiu HM, Ching J, Travis S, Peled R. 2012. The use of Pillcam Colon in assessing mucosal inflammation in ulcerative colitis: a multicenter study. Endoscopy, 44 (8), pp. 754-758. | Show Abstract | Read more

BACKGROUND AND STUDY AIM: Treatment of ulcerative colitis should be tailored to the severity of colonic inflammation, which in the past has been gauged mainly by clinical features and biochemical parameters. Recently, mucosal healing has been proposed as a standard to guide therapy. The aim of this multicenter study was to test whether mucosal appearance, as reported by colon capsule endoscopy (CCE), can be used to differentiate active from inactive ulcerative colitis. PATIENTS AND METHODS: Adult patients from Hong Kong, Singapore, and Taiwan who were suspected or known to have ulcerative colitis were included in this prospective study. CCE and conventional optical colonoscopy were offered to these patients on the same day after receiving standard bowel preparation. The primary endpoint was the accuracy of CCE in assessing colonic inflammation (defined as the presence of ulcers, erythema, erosions, edema, exudates in mucosa), using optical colonoscopy as the gold standard. RESULTS: At total of 100 patients (42 females; median age 50 years; range 22 - 68 years) were enrolled. Four cases were excluded from the analysis due to technical failure or slow transit of the capsule. In nine patients, the capsule was not excreted within 8.5 hours and required retrieval during colonoscopy. The sensitivity of CCE to detect active colonic inflammation was 89 % (95 % confidence interval [CI] 80 - 95) and specificity was 75 % (95 %CI 51 - 90). The positive and negative predictive values of CCE for colonic inflammation were 93 % (95 %CI 84 - 97) and 65 % (95 %CI 43 - 83), respectively. No serious adverse event related to the CCE procedure or preparation was reported. CONCLUSION: CCE is a safe procedure to monitor mucosal healing in ulcerative colitis. However, at this stage, CCE cannot be recommended to replace conventional colonoscopy in the management of this condition.

Logan RFA, Hearnshaw S, Lowe D, Travis SPL, Murphy MS, Palmer KR. 2012. Acute upper gastrointestinal bleeding: identifying low risk patients. Gut, 61 (11), pp. 1641. | Read more

Travis S, II BED, Bagin B, Gautille T, Huang M. 2011. Induction of remission with oral budesonide MMX (R) (9 mg) tablets in oatients with mild to moderate, active Ulcerative Colitis: A multicenter, open-label efficacy and safety study INFLAMMATORY BOWEL DISEASES, 17 pp. S20-S20. | Read more

Braden B, Halliday J, Aryasingha S, Sharifi Y, Checchin D, Warren BF, Kitiyakara T, Travis SPL, Chapman RW. 2012. Risk for colorectal neoplasia in patients with colonic Crohn's disease and concomitant primary sclerosing cholangitis. Clin Gastroenterol Hepatol, 10 (3), pp. 303-308. | Show Abstract | Read more

BACKGROUND & AIMS: Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn's disease of the colon. METHODS: We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn's disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn's disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. RESULTS: Only 1 patient with colonic Crohn's disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7-16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8-16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn's disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn's disease (P = 1.00). CONCLUSIONS: PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn's disease.

Travis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel J-F, Feagan BG, Hanauer SB, Lémann M, Lichtenstein GR et al. 2012. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut, 61 (4), pp. 535-542. | Show Abstract | Read more

BACKGROUND: Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). OBJECTIVE: To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. DESIGN: A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors. RESULTS: There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). CONCLUSION: The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

Van Assche G, Lewis JD, Lichtenstein GR, Loftus EV, Ouyang Q, Panes J, Siegel CA, Sandborn WJ, Travis SPL, Colombel J-F. 2011. The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: safety. Am J Gastroenterol, 106 (9), pp. 1594-1602. | Show Abstract | Read more

This paper in the series from the World Congress of Gastroenterology addresses the safety and immunogenicity of biological therapy. The safety profile in randomized controlled studies of all biological agents in Crohn's disease (CD) and ulcerative colitis has been generally favorable, but a small percentage of patients experience severe side effects on biological therapy, including pneumonia, tuberculosis, lymphoma, demyelination, drug-induced lupus, or hepatotoxicity. Although there is unequivocal evidence of an increased risk of serious infection among patients with rheumatoid arthritis treated with anti-tumor necrosis factor therapy, the evidence is less clear in CD. The risk of infection may be increased by combination therapy with steroids and/or immunomodulators. There is a specific risk of the rare γ δ hepatosplenic lymphoma that appears to have a predeliction for young males on combination therapy. The α4 integrin antagonist natalizumab also carries a specific risk of progressive multifocal leucoencephalopathy and reactivation of JC virus infection. The immunogenicity of biological therapy is complex: all agents are potentially immunogenic and this can be reduced by combination with immunomodulators. This may enhance both therapeutic efficacy and the risk of infection or malignancy, so the balance of risk and benefit must be judged for individual patients.

Jairath V, Kahan BC, Logan RFA, Travis SPL, Palmer KR, Murphy MF. 2011. Red blood cell transfusion practice in patients presenting with acute upper gastrointestinal bleeding: a survey of 815 UK clinicians. Transfusion, 51 (9), pp. 1940-1948. | Show Abstract | Read more

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) accounts for 14% of all red blood cell (RBC) transfusions in the United Kingdom, despite little evidence to guide optimal blood transfusion strategies and few data on the variation in practice. We aimed to survey UK clinicians about their RBC transfusion practice in AUGIB. STUDY DESIGN AND METHODS: A survey describing six clinical vignettes of AUGIB was sent to practicing gastroenterologists, acute care physicians, and upper gastrointestinal surgeons. Respondents were asked to select a hemoglobin (Hb) trigger at which they would ordinarily transfuse RBCs. RESULTS: The response rate was 48% (815/1709). Transfusion triggers differed significantly between all six cases (p < 0.001). There was significant variation in the selected Hb trigger between different clinical specialties for five of the six scenarios. Surgeons were more likely to select a lower Hb transfusion trigger than physicians across all six scenarios (p < 0.005), as were clinicians who had graduated more recently (p < 0.05 for Scenarios 1-3). The responses suggested the belief that restrictive use of RBCs is appropriate, which is in part discordant with actual observed practice. Only 70% of respondents reported familiarity with national guidelines for AUGIB. CONCLUSIONS: There is significant variation in the reported approach to transfusion practice among clinicians caring for patients with AUGIB, with both patient- and clinician-related factors accounting for these differences. Further studies are needed to evaluate the safety and efficacy of differing blood transfusion strategies in patients presenting with AUGIB.

Jairath V, Kahan BC, Logan RFA, Hearnshaw SA, Travis SPL, Murphy MF, Palmer KR. 2011. Mortality from acute upper gastrointestinal bleeding in the United kingdom: does it display a "weekend effect"? Am J Gastroenterol, 106 (9), pp. 1621-1628. | Show Abstract | Read more

OBJECTIVES: An increased mortality in patients presenting to hospital at weekends has been observed for several medical conditions. The aim of this study is to examine the relationship between weekend presentation to hospital following acute upper gastrointestinal bleeding and mortality. METHODS: Data were collected on 6,749 patients presenting to 212 UK hospitals. A logistic regression model was used to examine the relationship between weekend presentation to hospital and mortality. RESULTS: Patients presenting at the weekend were more likely to present with shock (39% vs. 36%), hematemesis (41% vs. 38%), and receive red cell transfusion (42% vs. 39%). Only 38% of those presenting at weekends underwent endoscopy within 24 h compared with 55% admitted on weekdays (adjusted odds ratio (OR)=0.47, 95% confidence interval (CI)=0.41-0.54), although the proportion of all patients receiving endoscopic therapy was identical at weekends compared with weekdays (24%). After adjustment for confounders, there was no evidence of a difference between weekend and weekday mortality (OR=0.93; 95% CI=0.75-1.16). Similar results were seen when restricting the analysis to those patients who underwent endoscopy (n=5,004) (OR=0.87, 95% CI=0.65-1.16). There was no difference in the OR for mortality for weekend compared with weekday presentation between patients presenting to hospitals with an out-of-hours (OOH) endoscopy rota compared with those presenting to hospitals without such a facility. CONCLUSIONS: In this large prospective study of acute upper gastrointestinal bleeding in the United Kingdom, there was no increase in mortality for weekend vs. weekday presentation despite patients being more critically ill and having greater delays to endoscopy at weekends. Provision of an OOH endoscopy service at weekends in the remaining UK hospitals may not lead to further reductions in case fatality, although a reduction in OOH endoscopy provision from current levels could lead to an increase in mortality at weekends.

Travis SPL, Higgins PDR, Orchard T, Van Der Woude CJ, Panaccione R, Bitton A, O'Morain C, Panés J, Sturm A, Reinisch W et al. 2011. Review article: defining remission in ulcerative colitis. Aliment Pharmacol Ther, 34 (2), pp. 113-124. | Show Abstract | Read more

BACKGROUND: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission. AIM: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes. METHODS: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions. RESULTS: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission. CONCLUSIONS: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission.

Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, Chowers Y, D'Haens G, Feagan BG, Hibi T et al. 2011. Development of the Crohn's disease digestive damage score, the Lémann score. Inflamm Bowel Dis, 17 (6), pp. 1415-1422. | Show Abstract | Read more

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.

Geremia A, Arancibia-Cárcamo CV, Fleming MPP, Rust N, Singh B, Mortensen NJ, Travis SPL, Powrie F. 2011. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med, 208 (6), pp. 1127-1133. | Show Abstract | Read more

Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3⁻ cells in IBD. IL17A and IL17F expression is restricted to CD56⁻ ILCs, whereas IL-23 induces IL22 and IL26 in the CD56⁺ ILC compartment. Furthermore, we observed a significant and selective increase in CD127⁺CD56⁻ ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23-responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.

Burger D, Travis S. 2011. Conventional medical management of inflammatory bowel disease. Gastroenterology, 140 (6), pp. 1827-1837.e2. | Show Abstract | Read more

Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti-tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively.

Orchard TR, van der Geest SAP, Travis SPL. 2011. Randomised clinical trial: early assessment after 2 weeks of high-dose mesalazine for moderately active ulcerative colitis - new light on a familiar question. Aliment Pharmacol Ther, 33 (9), pp. 1028-1035. | Show Abstract | Read more

BACKGROUND: Rapid resolution of rectal bleeding and stool frequency are important goals for ulcerative colitis therapy and may help guide therapeutic decisions. AIM: To explore patient diary data from ASCEND I and II for their relevance to clinical decision making. METHODS: Data from two randomised, double-blind, Phase III studies were combined. Patients received mesalazine (mesalamine) 4.8 g/day (Asacol 800 mg MR) or 2.4 g/day (Asacol 400 mg MR). Time to improvement or resolution of rectal bleeding and stool frequency was assessed and the proportion of patients experiencing symptom improvement or resolution at day 14 evaluated using survival analysis. Symptoms after 14 days were compared to week 6. A combination of prespecified and post hoc analyses were used. RESULTS: Median times to resolution and improvement of both rectal bleeding and stool frequency were shorter with 4.8 g/day than 2.4 g/day (resolution, 19 vs. 29 days, P = 0.020; improvement, 7 vs. 9 days, P = 0.024). In total, 73% of patients experienced improvement in both rectal bleeding and stool frequency by day 14 with 4.8 g/day, compared to 61% with 2.4 g/day. More patients achieved symptom resolution by day 14 with 4.8 g/day than 2.4 g/day (43% vs. 30%; P = 0.035). Symptom relief after 14 days was associated with a high rate of symptom relief after 6 weeks. CONCLUSIONS: High-dose mesalazine 4.8 g/day provides rapid relief of the cardinal symptoms of moderately active ulcerative colitis. Symptom relief within 14 days was associated with symptom relief at 6 weeks in the majority of patients. Day 14 is a practical timepoint at which response to treatment may be assessed and decisions regarding therapy escalation made (Clinicaltrials.gov: NCT00577473, NCT00073021).

Burger DC, Travis S. 2011. Colon salvage therapy for acute severe colitis: cyclosporine or infliximab? Curr Opin Gastroenterol, 27 (4), pp. 358-362. | Show Abstract | Read more

PURPOSE OF REVIEW: Steroid-refractory acute severe colitis (ASC) poses a significant clinical challenge to both physicians and surgeons alike. This review highlights advances in management of these patients and the role of cyclosporine compared to infliximab. RECENT FINDINGS: ASC affects 25% of patients with ulcerative colitis and is associated with measurable morbidity and mortality. Simple clinical and laboratory measures predict steroid refractoriness (such as stool frequency 3-8/day and C-reactive protein > 45 mg/l on day 3) and salvage therapy is appropriate at this stage. Preliminary data from randomized controlled trials suggest that early (7 and 98 day) response to cyclosporine and infliximab are comparable. Serum trough infliximab concentrations may correlate with outcome. Sequential therapy cannot usually be recommended due to limited response (70% colectomy at 3 years) and high rate of serious adverse events. SUMMARY: Optimal salvage therapy will depend on detailed results of randomized controlled trials. Meanwhile, patients with ASC should receive either cyclosporine or infliximab before surgery as long as there is specialist expertise that allows early decision-making.

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Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, Chapman RWG. 2012. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease JOURNAL OF CROHNS & COLITIS, 6 (2), pp. 174-181. | Read more

Ferrante M, Karmiris K, Newnham E, Siffledeen J, Zelinkova Z, van Assche G, Lakatos PL, Panés J, Sturm A, Travis S et al. 2012. Physician perspectives on unresolved issues in the use of conventional therapy in Crohn's disease: results from an international survey and discussion programme. J Crohns Colitis, 6 (1), pp. 116-131. | Show Abstract | Read more

BACKGROUND AND AIMS: Data on the optimal use of conventional therapies in Crohn's disease are lacking in guidelines. An educational programme was established to explore questions raised in clinical practice and to provide practical answers. METHODS: Telephone interviews with 96 gastroenterologists and a web survey of 1370 gastroenterologists identified 26 key questions. Ten questions were taken forward to the next stage based on the opinion of an International Steering Committee. Draft answers to the questions were prepared from available evidence following a literature search. The draft answers were debated in national meetings of participating countries (n=36) and voted on using a standard scoring system. Revised answers went forward to an international meeting and were debated and voted on using the same methodology. Final answers were developed, based on evidence and clinical experience of the participants. RESULTS: Evidence on corticosteroid and immunomodulator use such as dosage, timing and duration, choice of drug or regimen, and safety is scarce. Key points of the answers included the importance of: identifying patients with poor prognosis; early intervention with optimal doses of immunomodulators; avoiding prolonged or repetitive corticosteroid therapy; achieving corticosteroid-free remission; achieving a balance between clinical benefit and safety when intensifying or prolonging therapy or combining different agents; re-evaluating therapy at appropriate time points; and considering the role of biomarkers and mucosal healing. CONCLUSIONS: The answers to 10 key questions were based on available evidence and clinical experience of programme participants. It is hoped they will be of practical use in everyday gastroenterology practice.

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Scopus

Hearnshaw SA, Logan RFA, Lowe D, Travis SPL, Murphy MF, Palmer KR. 2011. Acute upper gastrointestinal bleeding in the UK: Patient characteristics, diagnoses and outcomes in the 2007 UK audit Gut, 60 (10), pp. 1327-1335. | Show Abstract | Read more

Objective: To describe the patient characteristics, diagnoses and clinical outcomes of patients presenting with acute upper gastrointestinal bleeding (AUGIB) in the 2007 UK Audit. Design: Multi-centre survey. Setting: All UK hospitals admitting patients with AUGIB. Participants: All adults (>16 years) presenting in or to UK hospitals with AUGIB between 1 May and 30 June 2007. Results: Data on 6750 patients (median age 68 years) was collected from 208 participating hospitals. New admissions (n=5550) were younger (median age 65 years) than inpatients (n=1107, median age 71 years), with less co-morbidity (any co-morbidity 46% vs 71%, respectively). At presentation 9% (599/6750) had known cirrhosis, 26% a history of alcohol excess, 11% were taking non-steroidal anti-inflammatory drugs and 28% aspirin. Peptic ulcer disease accounted for 36% of AUGIB and bleeding varices 11%. In 13% there was evidence of further bleeding after the first endoscopy. 1.9% underwent surgery and 1.2% interventional radiology for AUGIB. Median length of stay was 5 days. Overall mortality in hospital was 10% (675/6750, 95% CI 9.3 to 10.7), 7% in new admissions and 26% among inpatients. Mortality was highest in those with variceal bleeding (15%) and with malignancy (17%). Conclusions: AUGIB continues to result in substantial mortality although it appears to be lower than in 1993. Mortality is particularly high among inpatients and those bleeding from varices or upper gastrointestinal malignancy. Surgical or radiological interventions are little used currently.

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Dhalla F, da Silva SP, Lucas M, Travis S, Chapel H. 2011. Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme Clinical and Experimental Immunology, 165 (1), pp. 1-7. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy. © 2011 The Authors; Clinical and Experimental Immunology © 2011 British Society for Immunology.

Hearnshaw SA, Logan RFA, Lowe D, Travis SPL, Murphy MF, Palmer KR. 2011. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut, 60 (10), pp. 1327-1335. | Show Abstract | Read more

OBJECTIVE: To describe the patient characteristics, diagnoses and clinical outcomes of patients presenting with acute upper gastrointestinal bleeding (AUGIB) in the 2007 UK Audit. DESIGN: Multi-centre survey. SETTING: All UK hospitals admitting patients with AUGIB. PARTICIPANTS: All adults (>16 years) presenting in or to UK hospitals with AUGIB between 1 May and 30 June 2007. RESULTS: Data on 6750 patients (median age 68 years) was collected from 208 participating hospitals. New admissions (n=5550) were younger (median age 65 years) than inpatients (n=1107, median age 71 years), with less co-morbidity (any co-morbidity 46% vs 71%, respectively). At presentation 9% (599/6750) had known cirrhosis, 26% a history of alcohol excess, 11% were taking non-steroidal anti-inflammatory drugs and 28% aspirin. Peptic ulcer disease accounted for 36% of AUGIB and bleeding varices 11%. In 13% there was evidence of further bleeding after the first endoscopy. 1.9% underwent surgery and 1.2% interventional radiology for AUGIB. Median length of stay was 5 days. Overall mortality in hospital was 10% (675/6750, 95% CI 9.3 to 10.7), 7% in new admissions and 26% among inpatients. Mortality was highest in those with variceal bleeding (15%) and with malignancy (17%). CONCLUSIONS: AUGIB continues to result in substantial mortality although it appears to be lower than in 1993. Mortality is particularly high among inpatients and those bleeding from varices or upper gastrointestinal malignancy. Surgical or radiological interventions are little used currently.

Travis S. 2011. Does it all ADA up? Adalimumab for ulcerative colitis. Gut, 60 (6), pp. 741-742. | Read more

Turner D, Travis SPL, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, Dubinsky M, Alex G, Baldassano RN, Langer JC et al. 2011. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol, 106 (4), pp. 574-588. | Show Abstract | Read more

OBJECTIVES: Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN. METHODS: A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature. RESULTS: The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points. CONCLUSIONS: These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.

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Travis S, Satsangi J, Lémann M. 2011. Predicting the need for colectomy in severe ulcerative colitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut, 60 (1), pp. 3-9. | Read more

Thamizhmani R, Bhattacharya D, Sugunan AP. 2012. Authors' response. Indian J Med Res, 136 (5), pp. 884-885.

Sandborn WJ, Colombel JF, Frankel M, Hommes D, Lowder JN, Mayer L, Plevy S, Stokkers P, Travis S, Van Assche G et al. 2010. Anti-CD3 antibody visilizumab is not effective in patients with intravenous corticosteroid-refractory ulcerative colitis. Gut, 59 (11), pp. 1485-1492. | Show Abstract | Read more

BACKGROUND AND AIMS: Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was warranted. METHODS: A randomised, double-blind, placebo-controlled study evaluated the efficacy of visilizumab induction treatment in 127 patients with severely active UC despite treatment with ≥5 days of intravenous corticosteroids. Patients received placebo or visilizumab 5μg/kg intravenously on days 1 and 2. Corticosteroids were tapered according to disease activity. Patients were followed up for 90 days. The primary end point was induction of response at day 45. Secondary end points included remission and mucosal healing at day 45, symptomatic response at day 15 and colectomy. RESULTS: Response at day 45 occurred in 55% of patients receiving visilizumab compared with 47% of those who received placebo (p=0.475). Remission at day 45 occurred in 8% of patients receiving visilizumab compared with 9% of those who received placebo (p=0.704). Mucosal healing at day 45 occurred in 29% of patients receiving visilizumab compared with 26% of those who received placebo (p=0.799). Symptomatic response at day 15 occurred in 82% of patients receiving visilizumab compared with 74% of those who received placebo (p=0.244). Colectomy was performed in 18% of patients receiving visilizumab compared with 7% of those who received placebo (p=0.130). Cardiac disorders and vascular disorders occurred more frequently in the patients who received visilizumab. CONCLUSION: Visilizumab at a dose of 5μg/kg for two consecutive days was not effective for severe, corticosteroid-refractory UC and was associated with increased cardiac and vascular adverse events. (Registered at http://www.clinicaltrials.govNCT00279422/).

Dinesen LC, Walsh AJ, Protic MN, Heap G, Cummings F, Warren BF, George B, Mortensen NJM, Travis SPL. 2010. The pattern and outcome of acute severe colitis. J Crohns Colitis, 4 (4), pp. 431-437. | Show Abstract | Read more

BACKGROUND: The prognosis of acute severe ulcerative colitis (ASC) influences therapeutic decisions, but data on prevalence or long-term outcome are few. METHODS: A systematic review of all patients with UC diagnosed in Oxford was performed to assess the prevalence of ASC defined by Truelove and Witts' (TW) criteria and determine whether outcome is related to disease activity on admission, likelihood of recurrence and long-term prognosis. RESULTS: 750 patients (median follow up 12.7 yr, range 0-648 mo) met inclusion criteria out of a total cohort of 1853 patients. 24.8% (186/750) had at least one admission for ASC (294 admissions in 186 patients). Overall, 12% (93/750) had a colectomy, compared to 39.8% (74/186) of patients with one or more episodes of ASC (p<0.0001) and 3.4% (19/564) in those with no admission. The colectomy rate on first admission (37/186, 19.9%) was lower than on the second or subsequent admissions (OR 2.35, 95% CI 1.33-4.14, p=0.003), being 29.0%, 36.6%, 38.2% after two, three, or subsequent episodes respectively. It was 8.5% (11/129) if patients had one TW criterion in addition to ≥6 bloody bowel motions/day, compared to 31% (29/94) if two additional criteria were present and 48% (34/71) if three or more additional criteria were present (p=1.4 × 10⁻⁵; OR 4.35, 95% CI 2.20-8.56 one criterion vs two or more). CONCLUSIONS: A quarter of all patients with ulcerative colitis experience at least one episode of ASC; 20% come to colectomy on first admission, but 40% after two admissions. The likelihood of colectomy is related to biological severity on admission.

Hearnshaw SA, Logan RFA, Lowe D, Travis SPL, Murphy MF, Palmer KR. 2010. Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit. Gut, 59 (8), pp. 1022-1029. | Show Abstract | Read more

OBJECTIVES: To examine the use of endoscopy in the UK for acute upper gastrointestinal bleeding (AUGIB) and compare with published standards. To assess the organisation of endoscopy services for AUGIB in the UK. To examine the relationship between outcomes and out of hours (OOH) service provision. DESIGN: Multi-centre cross sectional clinical audit. SETTING: All UK hospitals accepting admissions with AUGIB. PATIENTS: All adults (>or=16 yrs) presenting with AUGIB between 1st May and 30th June 2007. DATA: Collection A custom designed web-based reporting tool was used to collect data on patient characteristics, comorbidity and haemodynamic status at presentation to calculate the Rockall score, use and timing of endoscopy, treatment including endoscopic, rebleeding and in-hospital mortality. A mailed questionnaire was used to collect data on facilities and service organisation. RESULTS: Data on 6750 patients (median age 68 years) were analysed from 208 hospitals. 74% underwent inpatient endoscopy; of these 50% took place within 24 h of presentation, 82% during normal working hours and 3% between midnight and 8 am. Of patients deemed high-risk (pre-endoscopy Rockall score >or=5) only 55% were endoscoped within 24 h and 14% waited >or=72 h for endoscopy. Lesions with a high risk of rebleeding were present in 28% of patients of whom 74% received endoscopic therapy. Further bleeding was evident in 13% and mortality in those endoscoped was 7.4% (95% CI 6.7% to 8.1%). In 52% of hospitals a consultant led out of hours (OOH) endoscopy rota existed; in these hospitals 20% of first endoscopies were performed OOH compared with 13% in those with no OOH rota and endoscopic therapy was more likely to be administered (25% vs 21% in hospitals with no OOH rota). The risk adjusted mortality ratio was higher (1.21, p=0.10, (95%CI 0.96 to 1.51)) in hospitals without such rotas. CONCLUSIONS: This audit has found continuing delays in performing endoscopy after AUGIB and underutilisation of standard endoscopic therapy particularly for variceal bleeding. In hospitals with a formal OOH endoscopy rota patients received earlier endoscopy, were more likely to receive endoscopic therapy and may have a lower mortality.

Hearnshaw SA, Logan RFA, Palmer KR, Card TR, Travis SPL, Murphy MF. 2010. Outcomes following early red blood cell transfusion in acute upper gastrointestinal bleeding. Aliment Pharmacol Ther, 32 (2), pp. 215-224. | Show Abstract | Read more

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) accounts for 14% of RBC units transfused in the UK. In exsanguinating AUGIB the value of RBC transfusion is self evident, but in less severe bleeding its value is less obvious. AIM: To examine the relationship between early RBC transfusion, re-bleeding and mortality following AUGIB, which is one of the most common indications for red blood cell (RBC) transfusion. METHOD: Data were collected on 4441 AUGIB patients presenting to UK hospitals. The relationship between early RBC transfusion, re-bleeding and death was examined using logistic regression. RESULTS: 44% were transfused RBCs within 12 hours of admission. In patients transfused with an initial haemoglobin of <8 g/dl, re-bleeding occurred in 23% and mortality was 13% compared with a re-bleeding rate of 15%, and mortality of 13% in those not transfused. In patients transfused with haemoglobin >8 g/dl, re-bleeding occurred in 24% and mortality was 11% compared with a re-bleeding rate of 6.7%, and mortality of 4.3% in those not transfused. After adjusting for Rockall score and initial haemoglobin, early transfusion was associated with a two-fold increased risk of re-bleeding (Odds ratio 2.26, 95% CI 1.76-2.90) and a 28% increase in mortality (Odds ratio 1.28, 95% CI 0.94-1.74). CONCLUSIONS: Early RBC transfusion in AUGIB was associated with a two-fold increased risk of re-bleeding and an increase in mortality, although the latter was not statistically significant. Although these findings could be due to residual confounding, they indicate that a randomized comparison of restrictive and liberal transfusion policies in AUGIB is urgently required.

Randall J, Singh B, Warren BF, Travis SPL, Mortensen NJ, George BD. 2010. Delayed surgery for acute severe colitis is associated with increased risk of postoperative complications. Br J Surg, 97 (3), pp. 404-409. | Show Abstract | Read more

BACKGROUND: This study determined the long-term outcome after colectomy for acute severe ulcerative colitis (ASUC) and assessed whether the duration of in-hospital medical therapy is related to postoperative outcome. METHODS: All patients who underwent urgent colectomy and ileostomy for ASUC between 1994 and 2000 were identified from a prospective database. Patient details, preoperative therapy and complications to last follow-up were recorded. RESULTS: Eighty patients were identified, who were treated with intravenous steroids for a median of 6 (range 1-22) days before surgery. Twenty-three (29 per cent) also received intravenous ciclosporin. There were 23 complications in 22 patients in the initial postoperative period. Sixty-eight patients underwent further planned surgery, including restorative ileal pouch-anal anastomosis in 57. During a median follow-up of 5.4 (range 0.5-9.0) years, 48 patients (60 per cent) developed at least one complication. Patients with a major complication at any time during follow-up had a significantly longer duration of medical therapy before colectomy than patients with no major complications (median 8 versus 5 days; P = 0.036). CONCLUSION: Delayed surgery for patients with ASUC who do not respond to medical therapy is associated with an increased risk of postoperative complications.

Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, Guslandi M, Oldenburg B, Dotan I, Marteau P et al. 2010. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations. J Crohns Colitis, 4 (1), pp. 63-101. | Read more

Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, Ochsenkühn T, Orchard T, Rogler G, Louis E et al. 2010. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. J Crohns Colitis, 4 (1), pp. 7-27. | Read more

Travis S, Van Assche G, Dignass A, Cabré E, Gassull MA. 2010. On the second ECCO Consensus on Crohn's disease Journal of Crohn's and Colitis, 4 (1), pp. 1-6. | Read more

Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D'Hoore A, Gassull M, Gomollón F et al. 2010. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis, 4 (1), pp. 28-62. | Read more

Culver EL, Travis SPL. 2010. How to manage the infectious risk under anti-TNF in inflammatory bowel disease. Curr Drug Targets, 11 (2), pp. 198-218. | Show Abstract | Read more

The advent of biological therapy has had a significant impact on the management of patients with inflammatory bowel disease. Nevertheless, anti-TNF-alpha agents are still used with caution, driven by concerns about the risk of infection. Stringent post-marketing surveillance programmes and registries have allowed early recognition of problems, highlighting an increased risk of infectious complications. Although the focus is on biological drugs, other immunomodulators have been less well scrutinised and similarly carry considerable risks of infection. It remains unclear whether the risk of infection from anti-TNF therapy is any different from conventional immunomodulators such as azathioprine or methotrexate, although it appears to be less than that ascribed to corticosteroids. The majority of patients on anti-TNF agents are on concomitant immunosuppressive medication, which makes ascribing risk to a specific drug more difficult. The risk of life-threatening opportunistic infections associated with anti-TNF therapy has obliged us to re-consider methods of prevention of infection and to develop guidelines for risk-stratification of patients with a diagnosis of inflammatory bowel disease. This encompasses vaccination and chemoprevention, appropriate treatment of underlying infection, patient education, travel advice and careful monitoring whilst on anti-TNF therapy. Contingency planning is essential. Implementing these preventative strategies will have an appreciable impact on the organisation of care and on current clinical practice.

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Mahadevan U, Cucchiara S, Hyams JS, Steinwurz F, Nuti F, Travis SPL, Sandborn WJ, Colombel J-F. 2011. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: pregnancy and pediatrics. Am J Gastroenterol, 106 (2), pp. 214-223. | Show Abstract | Read more

Women with inflammatory bowel disease (IBD) have similar rates of fertility to the general population, but have an increased rate of adverse pregnancy outcomes compared with the general population, which may be worsened by disease activity. Infertility is increased in those undergoing ileal pouch-anal anastomosis. Anti-tumor necrosis factor therapy in pregnancy is considered to be low risk and compatible with use during conception in men and women and during pregnancy in at least the first two trimesters. Infliximab (IFX) and certolizumab pegol are also compatible with breastfeeding, but safety data for adalimumab (ADA) are awaited. The safety of natalizumab during pregnancy is unknown. For children with Crohn's disease (CD), IFX is effective at inducing and maintaining remission. Episodic therapy is not as effective as scheduled infusions. Disease duration in children does not appear to affect the efficacy of IFX. IFX promotes growth in prepubertal and early pubertal Crohn's patients. It is also effective for the treatment of extraintestinal manifestations. ADA is effective for children with active CD and for maintaining remission, even if they have lost response to IFX, although there are fewer data. Vaccination of infants exposed to biological therapy in utero should be given at standard schedules during the first 6 months of life, except for live-virus vaccines such as rotavirus. Inactivated vaccines may be safely administered to children with IBD, even when immunocompromised.

D'Haens GR, Panaccione R, Higgins PDR, Vermeire S, Gassull M, Chowers Y, Hanauer SB, Herfarth H, Hommes DW, Kamm M et al. 2011. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol, 106 (2), pp. 199-212. | Show Abstract | Read more

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Jairath V, Hearnshaw S, Brunskill SJ, Doree C, Hopewell S, Hyde C, Travis S, Murphy MF. 2010. Red cell transfusion for the management of upper gastrointestinal haemorrhage. Cochrane Database Syst Rev, 9 (9), pp. CD006613. | Show Abstract | Read more

BACKGROUND: Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year, with a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is unknown. OBJECTIVES: To assess the effects of red blood cell (RBC) transfusion in adults with upper gastrointestinal haemorrhage. SEARCH STRATEGY: For this update, we re-ran the initial search strategies from the last issue/month searched until March 2010.We previously searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials (RCTs), haematology and gastroenterology conference proceedings, and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing RBC transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three trials involving 126 patients were included, with complete data available for 93 patients. The participants were heterogeneous, none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to RBC transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study fewer than half the participants were included in the final analysis.One RCT of restrictive versus liberal RBC transfusion aims to recruit 860 patients but has yet to be completed. AUTHORS' CONCLUSIONS: There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed RCTs of sufficient power are urgently needed.

Trivedi PJ, Canavan J, Holloway C, Slater A, Travis S. 2010. An unusual case of dyspnoea in an elderly man. BMJ Case Rep, 2010 (feb02 1), pp. bcr0920092247-bcr0920092247. | Show Abstract | Read more

Defective closure of the posterolateral pleuroperitoneal canal during embryogenesis gives rise to a congenital hernia (usually left sided) which was originally described by Bochdalek in 1948. It manifests primarily in children with respiratory symptoms and pulmonary hypoplasia. It is exceptionally rare for this defect to present in adulthood, with just over 50 symptomatic cases being described in the literature. Most adolescent and adult cases are diagnosed incidentally during imaging for upper gastrointestinal symptoms. It is unusual for adults to present with respiratory symptoms. We describe the case of a 71-year-old man who presented with features of left ventricular failure due to an exceptionally large, right sided Bochdalek hernia. This is the oldest clinical presentation of a right sided Bochdalek hernia, which uniquely included trans-diaphragmatic herniation of the pancreas.

Latella G, Caprilli R, Travis S. 2011. In favour of early surgery in Crohn's disease: a hypothesis to be tested. J Crohns Colitis, 5 (1), pp. 1-4. | Read more

Brain O, Rajaguru C, Warren B, Booth J, Travis S. 2009. Collagenous gastritis: reports and systematic review. Eur J Gastroenterol Hepatol, 21 (12), pp. 1419-1424. | Show Abstract | Read more

Collagenous gastritis is a rare disorder first described in 1989. After encountering two cases, we decided to review the literature and evaluate the collagen band. A systematic review of PubMed and EMBASE databases was performed. Twenty-eight cases have been previously described and two patterns of presentations are identifiable: children or young adults (median age 12 years, range 2-22 years) presenting with symptoms attributable to the gastritis (anaemia and pain); and older adults (median age 52 years, range 35-77 years) presenting with loose stools, often associated with collagenous colitis or coeliac disease. Our two cases (one child and one adult) matched this pattern. Immunostaining of the collagen band for collagens II, III, IV and VI, and tenascin showed that the band in our cases was predominantly tenascin. In conclusion, collagenous gastritis is a rare entity whose presentation depends on the age of the patient. An autoimmune aetiology seems possible given its associations. Treatment is empirical. The 30 cases now reported show that the disorder can relapse or persist for years.

Cassinotti A, Keshav S, Ardizzone S, Mortensen N, Sampietro G, Fociani P, Duca P, George B, Lazzaroni M, Manes G et al. 2009. IBD care in Europe: A comparative audit of the inpatient management of Crohn's disease and ulcerative colitis using the national UK IBD audit tool. J Crohns Colitis, 3 (4), pp. 291-301. | Show Abstract | Read more

BACKGROUND AND AIMS: The National UK IBD audit tool is an electronic database created to improve the quality and safety of care for IBD patients by auditing individual patient care, service resources and organisation against national standards. We used the National UK IBD audit tool to compare the organisation and process of IBD care between services in Oxford (UK) and Milan (Italy), as a pilot study to evaluate its application outside national boundaries. METHODS: Clinical and demographic data of patients with CD and UC, consecutively admitted during a 2month period, were collected and compared between the centres, to each other and to the UK IBD standards obtained by previous audit analyses performed in Oxford in 2006. RESULTS: 20 and 26 patients with UC were admitted in Oxford and Milan, as well as 21 and 20 patients with CD, respectively. Most admissions in Milan were planned admissions for moderately active treatment-refractory disease. No patient died. Oxford had a higher surgery rate. Endoscopy for UC consisted mainly of colonoscopy in Milan (92%) and flexible sigmoidoscopy in Oxford (64%). In CD, Oxford data revealed a higher use of immununomodulators and CT scan, compared with higher use of bowel ultrasound in Milan. CRP was the preferred biomarker of disease activity. The following areas did not reach the standards set for the 2006 UK IBD Audit: the lack in Milan of IBD specialist nurses and few dietitian visits, as well as little attention to heparin prophylaxis and abdominal radiography in UC. Both sites paid little attention to stool cultures and revealed a high rate of active smokers in CD and little attention to bone protection in steroids users. Since the 2006 audit in Oxford, improvements include IBD specialist nurse visits, dietitian visits, number of active smokers, stool samples, prophylactic heparin, bone protection and nutritional assessment. CONCLUSIONS: Consistent procedural differences between Oxford and Milan identified by audits of both UC and CD could be resolved by organisational change, with an improvement in the service. The UK IBD audit tool is an easy instrument to assess the processes and outcomes of care delivery in IBD and can be applied also outside UK.

Cassinotti A, Actis GC, Duca P, Massari A, Colombo E, Gai E, Annese V, D'Albasio G, Manes G, Travis S et al. 2009. Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J Gastroenterol, 104 (11), pp. 2760-2767. | Show Abstract | Read more

OBJECTIVES: Whether the duration of maintenance treatment with azathioprine (AZA) affects the outcome of ulcerative colitis (UC) is unclear. We investigated clinical outcomes and any predictive factors after withdrawal of AZA in UC. METHODS: In this multicenter observational retrospective study, 127 Italian UC patients, who were in steroid-free remission at the time of withdrawal of AZA, were followed-up for a median of 55 months or until relapse. The frequency of clinical relapse or colectomy after AZA withdrawal was analyzed according to demographic, clinical, and endoscopic variables. RESULTS: After drug withdrawal, a third of the patients relapsed within 12 months, half within 2 years and two-thirds within 5 years. After multivariable analysis, predictors of relapse after drug withdrawal were lack of sustained remission during AZA maintenance (hazard ratio, HR 2.350, confidence interval, CI 95% 1.434-3.852; P=0.001), extensive colitis (HR 1.793, CI 95% 1.064-3.023, P=0.028 vs. left-sided colitis; HR 2.024, CI 95% 1.103-3.717, P=0.023 vs. distal colitis), and treatment duration, with short treatments (3-6 months) more disadvantaged than >48-month treatments (HR 2.783, CI 95% 1.267-6.114, P=0.008). Concomitant aminosalicylates were the only predictors of sustained remission during AZA therapy (P=0.009). The overall colectomy rate was 10%. Predictors of colectomy were drug-related toxicity as the cause of AZA withdrawal (P=0.041), no post-AZA drug therapy (P=0.031), and treatment duration (P<0.0005). CONCLUSIONS: Discontinuation of AZA while UC is in remission is associated with a high relapse rate. Disease extent, lack of sustained remission during AZA, and discontinuation due to toxicity could stratify relapse risk. Concomitant aminosalicylates were advantageous. Prospective randomized controlled trials are needed to confirm whether treatment duration is inversely associated with outcome.

D'Haens GR, Fedorak R, Lémann M, Feagan BG, Kamm MA, Cosnes J, Rutgeerts PJ, Marteau P, Travis S, Schölmerich J et al. 2009. Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease. Inflamm Bowel Dis, 15 (10), pp. 1599-1604. | Show Abstract | Read more

The management of Crohn's disease is rapidly changing. The advent of potent immunomodulatory and biologic therapies has led to more demanding endpoints for clinical trials than only clinical response and remission. Complete withdrawal of corticosteroids, healing of endoscopically visible lesions, and prevention of structural damage are only a few new endpoints that are finding their way into the clinical trials of today and those that are being developed for the future. Given the importance of selecting the most appropriate and relevant endpoints, the International Organization for Inflammatory Bowel Diseases (IOIBD) decided to develop guidelines that could be used by individual researchers, the pharmaceutical industry, and the regulatory bodies. The current document is to be read as a "position paper," which is the result of several years of discussion and consensus finding that was finally approved by the entire membership of the group. The proposed instruments will need further validation and standardization to demonstrate that they are reliable in stable disease and responsive to change, and to determine the cutoff points for response and remission.

Rahier J-F, Yazdanpanah Y, Colombel J-F, Travis S. 2009. The European (ECCO) Consensus on infection in IBD: what does it change for the clinician? Gut, 58 (10), pp. 1313-1315. | Read more

Murphy CL, Gibson D, Meyers LS. 2009. Inflammatory bowel disease and acne. Am J Gastroenterol, 104 (9), pp. 2370. | Read more

Ayre K, Warren BF, Jeffery K, Travis SPL. 2009. The role of CMV in steroid-resistant ulcerative colitis: A systematic review. J Crohns Colitis, 3 (3), pp. 141-148. | Show Abstract | Read more

BACKGROUND AND AIMS: Steroid-resistance presents a management challenge in ulcerative colitis. How steroid-resistance occurs is unknown, but cytomegalovirus infection, often unrecognised, may be the cause in some patients. Current evidence and therapeutic recommendations are examined. METHODS: A systematic review of PubMed and EMBASE databases was performed. Search and exclusion criteria are defined in the text. RESULTS: Heterogeneity of experimental design and definitions of key terms were notable. Criteria for cytomegalovirus disease, infection or detection varied, as did definitions of steroid-resistance. CMV infection defined by antigenaemia or serology was common in patients on steroids and associated with a higher rate of steroid-resistance (41.66-61% versus 0-68% in steroid-responsive patients). Colonic mucosal cytomegalovirus disease detected by histopathology was associated with intravenous steroid-resistance in 5-36%, compared to 0-10% of steroid-responsive patients. CMV colitis has rarely been reported in association with ulcerative colitis without steroids or other immunomodulators. CMV colitis in healthy individuals is so exceptional as to be the topic of case reports. CONCLUSION: Ulcerative colitis and its treatment put patients at risk of CMV infection or reactivation. A distinction is necessary between CMV disease (colitis) and CMV infection. Only colonic mucosal CMV infection detected by histopathology appears clinically relevant and appropriate for antiviral therapy. CMV antigenaemia may be associated with steroid-resistance, but may also be a self-limiting marker of viral reactivation. The impact of CMV on steroid-resistance is complicated by inconsistencies in the literature. Coherent definitions of clinically relevant CMV infection and steroid-resistance are needed.

Connolly MP, Nielsen SK, Currie CJ, Marteau P, Probert CSJ, Travis SPL. 2009. An economic evaluation comparing concomitant oral and topical mesalazine versus oral mesalazine alone in mild-to-moderately active ulcerative colitis based on results from randomised controlled trial. J Crohns Colitis, 3 (3), pp. 168-174. | Show Abstract | Read more

INTRODUCTION: A previous randomised controlled trial has demonstrated that oral plus topical mesalazine enema is more effective than oral mesalazine alone for achieving clinical remission in mild-to-moderately active extensive ulcerative colitis (UC). To evaluate whether this strategy is cost-effective we conducted an economic evaluation comparing 1 g topical mesalazine in combination with 4 g oral mesalazine compared to 4 g mesalazine monotherapy in mild-to-moderately active UC. METHODS: The economic evaluation was based on the ability to achieve remission using changes from baseline in the ulcerative colitis disease activity instrument (UCDAI). A cost-utility analysis was used where the main outcome was quality-adjusted life years to reflect improved quality of life associated with achieving remission compared with active disease. A simulated Markov model with five health states was constructed to model cost and outcome changes over time: (1) active UC; (2) mesalazine-refractory active UC; (3) steroid-refractory active UC; (4) infliximab-responsive active UC; and (5) remission. To reflect parameter uncertainty in the cost-effectiveness analysis probabilistic sensitivity analysis (PSA) was conducted by varying relevant clinical parameters. RESULTS: Average treatment costs required to transition a patient from active UC to remission using oral and topical mesalazine compared with oral alone were £1812 and £2390, respectively. Improved remission rates attributed to oral and topical mesalazine resulted in moderate improvements in quality-adjusted life years (QALYs) compared to oral mesalazine alone. Disaggregation of medical costs indicated that medical consultations and diagnostic costs were similar for both treatment arms. An abbreviated analysis which considered costs up to steroid-refractory patients in subacute UC indicated that combination therapy offered a cost-savings of £285 over 16 weeks of therapy compared with monotherapy. CONCLUSIONS: The results indicate that the addition of 1 g topical mesalazine results in significant cost-savings and moderate quality of life improvements. We have also shown that irrespective of which treatment modality is used in steroid-refractory patients (eg, infliximab, azathioprine, ciclosporine) that topical mesalazine is cost-saving.

Cassinotti A, Travis S. 2009. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis, 15 (8), pp. 1264-1275. | Show Abstract | Read more

BACKGROUND: Infliximab (IFX) is a chimeric (mouse/human) anti-TNF-alpha monoclonal antibody approved for the treatment of refractory luminal and fistulizing Crohn's disease (CD). It is a source of potential immunogenicity for humans, with the occurrence of anti-infliximab antibodies (ATIs), which are thought to interfere with the pharmacodynamics and/or pharmacokinetics of the compound. It remains unclear whether ATIs have any clinical importance for drug efficacy or safety. We review studies specifically evaluating the incidence of ATIs in CD and their impact on the efficacy and safety of IFX. METHODS: A systematic review was undertaken by electronic searches of the PubMed and SCOPUS databases from earliest records to October 2008, as well as reference lists of all relevant articles and relevant abstracts from meetings. RESULTS: The biological and clinical mechanisms of ATI development are poorly understood. The incidence of ATIs in vivo depends on multiple analytical and clinical factors, both patient- and treatment-related. The presence of ATIs is weakly and variably associated with clinical response or infusion reactions, but not with reactions relevant to clinical decision-making. Enormous variation in the methods of reporting ATIs and immunogenicity of IFX make almost any interpretation possible from different studies, but few have clinical relevance. CONCLUSIONS: There is no clear evidence that ATIs have an impact on efficacy or safety, nor a need to measure or prevent them in clinical practice. Circulating drug concentration may be a more relevant measure of immunogenicity.

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European Pubmed Central

Bourreille A, Ignjatovic A, Aabakken L, Loftus EV, Eliakim R, Pennazio M, Bouhnik Y, Seidman E, Keuchel M, Albert JG et al. 2009. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED-ECCO consensus. Endoscopy, 41 (7), pp. 618-637. | Show Abstract | Read more

Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world. Whereas ulcerative colitis is a chronic inflammatory condition causing diffuse and continuous mucosal inflammation of the colon, Crohn's disease is a heterogeneous entity comprised of several different phenotypes, but can affect the entire gastrointestinal tract. A change in diagnosis from Crohn's disease to ulcerative colitis during the first year of illness occurs in about 10 % - 15 % of cases. Inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis or Crohn's disease is termed IBD-unclassified (IBDU). The advent of capsule and both single- and double-balloon-assisted enteroscopy is revolutionizing small-bowel imaging and has major implications for diagnosis, classification, therapeutic decision making and outcomes in the management of IBD. The role of these investigations in the diagnosis and management of IBD, however, is unclear. This document sets out the current Consensus reached by a group of international experts in the fields of endoscopy and IBD at a meeting held in Brussels, 12-13th December 2008, organised jointly by the European Crohn's and Colitis Organisation (ECCO) and the Organisation Mondiale d'Endoscopie Digestive (OMED). The Consensus is grouped into seven sections: definitions and diagnosis; suspected Crohn's disease; established Crohn's disease; IBDU; ulcerative colitis (including ileal pouch-anal anastomosis [IPAA]); paediatric practice; and complications and unresolved questions. Consensus guideline statements are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not read in isolation.

Bojic D, Radojicic Z, Nedeljkovic-Protic M, Al-Ali M, Jewell DP, Travis SPL. 2009. Long-term outcome after admission for acute severe ulcerative colitis in Oxford: the 1992-1993 cohort. Inflamm Bowel Dis, 15 (6), pp. 823-828. | Show Abstract | Read more

BACKGROUND: To determine the long-term outcome of patients admitted with acute severe colitis (ASC) who avoided colectomy on the index admission, a retrospective cohort study was performed. METHODS: Patients admitted for intensive treatment of ASC in 1992-1993 previously described for a predictive index of short-term outcome in severe ulcerative colitis (UC) were followed for a median 122 months (range 3-144). Complete responders (CR) to intensive therapy had <3 nonbloody stools/day on day 7 of the index admission; incomplete responders (IR) were all others who avoided colectomy on that admission. Main outcome measures were colectomy-free survival, time to colectomy, and duration of steroid-free remission. RESULTS: In all, 6/19 CR (32%) came to colectomy compared to 10/13 IR (P = 0.016; relative risk 3.33, 95% confidence interval [CI] 1.12-9.9). The median +/- interquartile range time to colectomy was 28 +/- 47 months (range 6-99) for CR who came to colectomy versus 7.5 +/- 32 (3-72) months for IR (P = 0.118). Among the IR, 7/13 came to colectomy within 12 months, and all within 6 years from the index admission. The longest period of steroid-free remission was 42 +/- 48 (0-120) months for CR, but 9 +/- 20 (1-35) months for IR (P = 0.011). CONCLUSIONS: One week after admission with ASC in the prebiologic era, IRs had a 50% chance of colectomy within a year and 70% within 5 years, despite cyclosporin and azathioprine where appropriate. The maximum duration of remission in CRs was almost 5 times longer than IRs. It is unknown whether biologics change the long-term outcome.

Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D'Haens G, Domènech E, Eliakim R, Eser A, Frater J et al. 2009. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis, 3 (2), pp. 47-91. | Read more

Andrews JM, Travis SPL, Gibson PR, Gasche C. 2009. Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes? Aliment Pharmacol Ther, 29 (5), pp. 459-469. | Show Abstract | Read more

BACKGROUND: With greater use of immunomodulators in inflammatory bowel disease (IBD), it is uncertain whether concurrent therapy with both 5-aminosalicylic acid [5-ASA, mesalazine (mesalamine)] and an immunomodulator is necessary. AIM: To determine whether concurrent therapy with both 5-ASA and immunomodulator(s) improves outcomes in IBD. METHODS: Systematic review with search terms 'azathioprine, 6-mercaptopurine, thiopurine(s), 5 aminosalicylic acid, mesalazine, inflammatory bowel disease, ulcerative colitis, Crohn's disease, immunosuppressant(s), immunomodulator and methotrexate' in November 2007 to identify clinical trials on concurrent 5-ASA and immunomodulator therapy. RESULTS: Two small controlled studies were found. Neither showed a benefit on disease control beyond immunomodulator monotherapy. Potential pharmacological interactions exist between 5-ASA and thiopurines. Whilst circumstantial, epidemiological and laboratory evidence suggests that 5-ASA may assist colorectal cancer (CRC) chemoprevention, it may simply be via anti-inflammatory effects. With changes in practice, ethical issues and the long lead-time needed to demonstrate or disprove an effect, no clinical studies can/will directly answer this. The costs of avoiding one CRC in IBD may be as low as 153 times the annual cost of 5-ASA therapy. CONCLUSIONS: It is unclear whether concurrent 5-ASA and immunomodulator therapy improves outcomes of disease control, drug toxicity or compliance. Concurrent therapy of 5-ASA and immunomodulators may decrease CRC risk at 'acceptable' cost.

Connolly MP, Nielsen SK, Currie CJ, Poole CD, Travis SPL. 2009. An economic evaluation comparing once daily with twice daily mesalazine for maintaining remission based on results from a randomised controlled clinical trial. J Crohns Colitis, 3 (1), pp. 32-37. | Show Abstract | Read more

BACKGROUND AND AIMS: Standard practice to maintain remission in ulcerative colitis (UC) consists of daily mesalazine therapy. However, frequent dosing is associated with poor adherence and increased failure rates. The PODIUM (Pentasa™ Once Daily In UC Maintenance) randomised control trial showed 2 g once daily (OD) to be superior to twice daily (BD) dosing for maintaining remission. We sought to determine whether this alternative dosing regimen is cost-effective. METHODS: An economic evaluation was conducted to compare costs and outcomes of OD with twice daily (BD) dosing. The main outcome considered was quality-adjusted life years (QALYs) based on health state utilities derived from the primary outcome measure, remission without relapse at 12 months defined by a UCDAI score ≤1. The economic evaluation consisted of two health states: (1) remission and (2) active UC. RESULTS: Annual average treatment costs for OD and BD dosing were £654 (95% CI: £536-£759) and £747 (£620-£860), respectively with an average per person savings of £93 per year. Average annual costs of ancillary care for relapse for OD and BD dosing were £307 (£241-£383) and £396 (£320-£483), respectively. Treatment with OD 2 g mesalazine resulted in an incremental QALY improvement of 0.004 units, indicating that it was the dominant treatment option (i.e. improved outcomes and cost-saving). Variations in parameter estimates in the sensitivity analysis indicated that mesalazine had >0.95 probability of being cost-effective compared to BD based on accepted willingness to pay thresholds applied by the UK National Health Service. CONCLUSIONS: Once daily 2 g mesalazine for maintaining remission in UC is cost-saving compared with 1 g twice daily. Cost-savings with 2 g once daily were achieved by differences in ancillary care attributed to higher failure rates observed with 1 g twice daily.

Hearnshaw S, Brunskill S, Doree C, Hyde C, Travis S, Murphy MF. 2009. Red cell transfusion for the management of upper gastrointestinal haemorrhage. Cochrane database of systematic reviews (Online), (2), | Show Abstract

BACKGROUND: Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year and has a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is not known. OBJECTIVES: To assess the effects of red blood cell transfusion in adults with upper gastrointestinal haemorrhage. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials, haematology and gastroenterology conference proceedings, and reference lists of articles. We also searched databases of ongoing clinical trials. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing red blood cell transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three trials involving 126 patients were included in the review, with complete data available for 93 patients. The participants were heterogeneous and none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to red blood cell transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study less than half the participants were included in the final analysis.One randomised controlled trial of restrictive versus liberal red blood cell transfusion, which aims to recruit 860 patients, has yet to be completed. AUTHORS' CONCLUSIONS: There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed randomised controlled trials of sufficient power are urgently needed.

Rahier J-F, Yazdanpanah Y, Viget N, Travis S, Colombel J-F. 2010. Review article: influenza A (H1N1) virus in patients with inflammatory bowel disease. Aliment Pharmacol Ther, 31 (1), pp. 5-10. | Show Abstract | Read more

BACKGROUND: Infection with influenza A (H1N1)v (swine flu) has caused widespread anxiety, among patients who are potentially immunocompromised, such as those being treated for inflammatory bowel disease. AIM: To provide guidance for physicians and their patients on the risk, prevention and management of influenza A (H1N1)v infection. METHODS: Medline was searched using the following key words: 'swine flu', 'immunosuppression', inflammatory bowel disease', 'recommendations', 'immunization', 'vaccination'. Organizations such as European Centre for Disease Prevention and Control, the Centers for Disease Control and Prevention and the World Health Organization were consulted for recent papers and recommendations regarding immunocompromised patients and influenza A (H1N1)v infection. RESULTS: Pandemic influenza A (H1N1) virus predominantly affects young patients. Those who are immunocompromised because of underlying disease or treatment are considered at higher risk of complications from influenza A (H1N1). They should be offered prevention (vaccination, postexposure prophylaxis) or treatment with antiviral drugs, if affected. Pneumococcal infection is a complication of influenza infection; therefore, pneumococcal vaccination appears advisable. Seasonal influenza vaccination is also recommended. Withdrawal of immunosuppressive treatment appears advisable during severe active infection if possible. CONCLUSIONS: Pragmatic advice is the best that can be offered in the current circumstances because of paucity of evidence. Investigation into the impact of influenza A (H1N1)v infection in young people with chronic conditions is needed.

Hearnshaw S, Brunskill S, Doree C, Hyde C, Travis S, Murphy MF. 2009. Red cell transfusion for the management of upper gastrointestinal haemorrhage. Cochrane Database Syst Rev, (2), pp. CD006613. | Show Abstract | Read more

BACKGROUND: Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year and has a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is not known. OBJECTIVES: To assess the effects of red blood cell transfusion in adults with upper gastrointestinal haemorrhage. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials, haematology and gastroenterology conference proceedings, and reference lists of articles. We also searched databases of ongoing clinical trials. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing red blood cell transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three trials involving 126 patients were included in the review, with complete data available for 93 patients. The participants were heterogeneous and none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to red blood cell transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study less than half the participants were included in the final analysis.One randomised controlled trial of restrictive versus liberal red blood cell transfusion, which aims to recruit 860 patients, has yet to be completed. AUTHORS' CONCLUSIONS: There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed randomised controlled trials of sufficient power are urgently needed.

Rajoriya N, Wotton CJ, Yeates DGR, Travis SPL, Goldacre MJ. 2009. Immune-mediated and chronic inflammatory disease in people with sarcoidosis: disease associations in a large UK database. Postgrad Med J, 85 (1003), pp. 233-237. | Show Abstract | Read more

BACKGROUND: Sarcoidosis is a multi-system disorder characterised by non-caseating granulomas. Coexistence of sarcoidosis with immune-mediated and chronic inflammatory diseases has been described in case series. However, the coexistence of two different diseases in individuals can occur by chance, even if each of the diseases is rare. AIM: To determine whether sarcoidosis necessitating hospital admission or day-case care coexists with a range of immune-mediated and chronic inflammatory diseases more commonly than expected by chance. DESIGN: Analysis of an epidemiological database of hospital admission and day-case statistics, spanning 30 years. RESULTS: 1510 patients with sarcoidosis were identified (mean age 44 years, median follow-up 19 years) who had been admitted to hospital or day-case care. Significant associations in the sarcoidosis cohort were identified with systemic lupus erythematosus (odds ratio (OR) 8.3; 95% CI 2.7 to 19.4), autoimmune chronic hepatitis (OR 6.7; 95% CI 1.8 to 17.1), multiple sclerosis (OR 3.3; 95% CI 1.7 to 5.6), coeliac disease (OR 3.1; 95% CI 1.01 to 7.3), thyrotoxicosis (OR 2.5; 95% CI 1.4 to 4.0), myxoedema (OR 2.2; 95% CI 1.2 to 3.7) and ulcerative colitis (OR 2.1; 95% CI 1.1 to 3.7). Weaker associations were found for diabetes mellitus with a first admission aged 30-49 years (OR 2.9; 95% CI 2.1 to 4.0) or age >50 (OR 1.7; 95% CI 1.2 to 2.3), but not for people age <30. No significant association with Crohn's disease (OR 1.52; 95% CI 0.61 to 3.14) or primary biliary cirrhosis (OR 3.75; 95% CI 0.77 to 11.0),was found. When all immune-mediated and chronic inflammatory diseases for which associations were sought were combined, the overall rate ratio associated with sarcoidosis was 2.2 (95% CI 1.9 to 2.6). CONCLUSION: This study adds epidemiological evidence to information from clinical reports that there is a connection between sarcoidosis and other immune-mediated and chronic inflammatory diseases.

Culver EL, Salmon JF, Frith P, Travis SPL. 2008. Recurrent posterior scleritis and orbital myositis as extra-intestinal manifestations of Crohn's disease: Case report and systematic literature review. J Crohns Colitis, 2 (4), pp. 337-342. | Show Abstract | Read more

BACKGROUND: Ocular episcleritis and uveitis are well-recognised extra-intestinal manifestations of Crohn's disease. Orbital myositis is rare: to our knowledge it has been associated with Crohn's disease in thirteen cases. Posterior scleritis, orbital myositis and Crohn's disease have been reported as coexisting in only two cases. METHODS AND RESULTS: We describe a third case, that of a 31-year old female with Crohn's colitis for 8 years, complicated by enteropathic arthritis and pyoderma gangrenosum. She presented with intense and intractable periorbital pain, particularly at night and worse on eye movements. B-scan ultrasonography confirmed posterior scleritis and treatment with high dose oral steroids (up to 60 mg prednisolone) was initially effective, but subsequently failed to control the inflammation. There was only a partial response to infliximab. Five months after presentation, diplopia developed, with failure of abduction of the left eye. MRI scan of the orbits confirmed orbital myositis involving the left lateral and medial rectus muscles. Pulsed intravenous methylprednisolone and six cycles of intravenous cyclophosphamide over a three month period resulted in complete resolution of inflammatory symptoms. CONCLUSIONS: This case highlights a rare combination of ocular abnormality secondary to Crohn's disease and reports successful resolution with aggressive immunosuppressive therapy.

Brown SR, Haboubi N, Hampton J, George B, Travis SPL, ACPGBI. 2008. The management of acute severe colitis: ACPGBI position statement. Colorectal Dis, 10 Suppl 3 pp. 8-29. | Read more

Travis S. 2008. How do you avoid and treat steroid side effects? Inflamm Bowel Dis, 14 Suppl 2 pp. S214-S215. | Read more

Travis S. 2008. Is IBD different in the elderly? Inflamm Bowel Dis, 14 Suppl 2 pp. S12-S13. | Read more

Dunckley P, Travis S. 2008. Is IBD associated with a stressful lifestyle? Inflamm Bowel Dis, 14 Suppl 2 pp. S33-S34. | Read more

Stange EF, Travis SPL. 2008. The European consensus on ulcerative colitis: new horizons? Gut, 57 (8), pp. 1029-1031. | Read more

Brain O, Travis SPL. 2008. Therapy of ulcerative colitis: state of the art. Curr Opin Gastroenterol, 24 (4), pp. 469-474. | Show Abstract | Read more

PURPOSE OF REVIEW: Advances in conventional therapy, novel targets and therapeutic goals are the highlights of treatment for ulcerative colitis in the last year. There have also been disappointments. This review summarizes the highs and lows, with an emphasis on strategy as opposed to seeking the newest treatment option. RECENT FINDINGS: In conventional therapy, once daily therapy for 5-aminosalicylic acid is generally sufficient. Furthermore, a new 5-aminosalicylic acid (mesalamine MMX) has been released that effectively induces and maintains remission. There have been reappraisals of immunomodulators and further evaluation of (yes, now conventional!) infliximab for ulcerative colitis. Opportunistic infections, long-term outcomes and the burden of disease are being characterized. New therapeutic targets included an antibody against T cells (anti-CD3), but trials on visilizumab for acute severe colitis have been suspended. T-cell costimulation, phosphatidylcholine to promote barrier function, new anti-tumour necrosis factor agents, B-cell (anti-CD20) depletion and complementary therapies represent new therapeutic horizons. International agreement is needed on activity indices, definitions of remission, therapeutic goals (including mucosal healing) and outcomes that matter to patients, so that trials can be compared. SUMMARY: Advances will take time to alter mainstream practice, but 2007-2008 is the year of organized strategies, with European, American and British guidelines on ulcerative colitis published or in press. These should be the platform for better outcomes for patients.

Maggs JRL, Browning LC, Warren BF, Travis SPL. 2008. Obstructing giant post-inflammatory polyposis in ulcerative colitis: Case report and review of the literature. J Crohns Colitis, 2 (2), pp. 170-180. | Show Abstract | Read more

BACKGROUND: Post-inflammatory polyps >15 mm in diameter or length are termed "giant". This benign and rare sequel of ulcerative colitis or colonic Crohn's disease can mimic colorectal carcinoma. OBJECTIVE: To illustrate this rare complication of inflammatory bowel disease and outline the characteristic radiological, endoscopic and histopathological features, by reviewing all previously published cases of giant post-inflammatory polyps in the English literature. RESULTS: Reports of 81 giant post-inflammatory polyps in 78 patients were identified by systematic review of the literature. The incidence of giant post-inflammatory polyps is related to the extent of ulcerative colitis (incidence: 0%, 30%, and 70%, in proctitis, left-sided, and extensive disease, respectively). These lesions are typically located in the transverse or descending colon. Giant post-inflammatory polyps are as common in Crohn's disease (n=36) as in ulcerative colitis (n=42, 54%). Clinical presentations varies, including pain (n=29), rectal bleeding (n=20), diarrhoea (n=19), luminal obstruction (n=15), or a palpable mass (n=11). Symptomatic presentation results in surgical resection. Clinical details and outcomes are comprehensively tabulated. CONCLUSION: Recognition of this rare entity will prevent unnecessary radical surgical resection for presumed carcinoma. It highlights the need for clinical, radiological, endoscopic and histopathological correlation.

Cummings JRF, Keshav S, Travis SPL. 2008. Medical management of Crohn's disease. BMJ, 336 (7652), pp. 1062-1066. | Read more

Travis SPL, Stange EF, Lémann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P et al. 2008. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis, 2 (1), pp. 24-62. | Read more

Stange EF, Travis SPL, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Fléjou JF, Herfarth H, Hommes DW et al. 2008. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohns Colitis, 2 (1), pp. 1-23. | Read more

Biancone L, Michetti P, Travis S, Escher JC, Moser G, Forbes A, Hoffmann JC, Dignass A, Gionchetti P, Jantschek G et al. 2008. European evidence-based Consensus on the management of ulcerative colitis: Special situations. J Crohns Colitis, 2 (1), pp. 63-92. | Read more

Goldacre MJ, Duncan M, Cook-Mozaffari P, Griffith M, Travis S. 2008. Inflammatory bowel disease, peptic ulcer and diverticular disease as certified causes of death in an English population 1979-2003. Eur J Gastroenterol Hepatol, 20 (2), pp. 96-103. | Show Abstract | Read more

BACKGROUND: When gastrointestinal diseases are certified as causes of death, they are often not selected as the underlying cause. Until recently, only one underlying cause of death has been coded and analysed in official national statistics in England and many other countries. AIMS: To report on the total 'burden of mortality' from some common gastrointestinal diseases, and whether it has changed over time, including all certified causes of death as well as underlying causes, (i) in the Oxford region from 1979 to 2003, (ii) in England from 1996 to 2003; and to quantify the under-ascertainment of cause-specific mortality when based on underlying cause alone. METHODS: We searched death certificate data from the Oxford Record Linkage Study database, and from English national data, for specified gastrointestinal diseases certified as underlying or contributory causes of death. RESULTS: For all the conditions studied, underlying-cause-coded mortality missed a substantial percentage of all certified deaths. The extent of underestimation varied according to the periods in which different criteria were used for the selection of the underlying cause. For example, in Oxford, in the latest period 1993-2003, underlying-cause-coded mortality identified only 37% of all death certificates with ulcerative colitis, 47% of Crohn's disease, between 62 and 68% for the different types of peptic ulcer and 66% of diverticular disease. CONCLUSIONS: Studies of mortality for these diseases should take account of all certified causes as well as underlying-cause mortality. This is particularly important for analyses that go across periods of change to the rules for selecting the underlying cause of death.

Gasche C, Berstad A, Befrits R, Beglinger C, Dignass A, Erichsen K, Gomollon F, Hjortswang H, Koutroubakis I, Kulnigg S et al. 2007. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis, 13 (12), pp. 1545-1553. | Show Abstract | Read more

Anemia is a common complication of inflammatory bowel diseases. An international working party has formed and developed guidelines for evaluation and treatment of anemia and iron deficiency that should serve practicing gastroenterologists. Within a total of 16 statements, recommendations are made regarding diagnostic measures to screen for iron- and other anemia-related deficiencies regarding the triggers for medical intervention, treatment goals, and appropriate therapies. Anemia is a common cause of hospitalization, prevents physicians from discharging hospitalized patients, and is one of the most frequent comorbid conditions in patients with inflammatory bowel disease. It therefore needs appropriate attention and specific care.

McGovern D, Travis S. 2007. 6-Mercaptopurine Or Azathioprine? pp. 45-47. | Read more

van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MCNM, Bethel G, Holmes GKT et al. 2007. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet, 39 (7), pp. 827-829. | Show Abstract | Read more

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

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Clark M, Colombel J-F, Feagan BC, Fedorak RN, Hanauer SB, Kamm MA, Mayer L, Regueiro C, Rutgeerts P, Sandborn WJ et al. 2007. American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease, June 21-23, 2006. Gastroenterology, 133 (1), pp. 312-339. | Show Abstract | Read more

The American Gastroenterological Association (AGA) convened a panel of gastroenterologists expert in the area of inflammatory bowel disease (IBD) that developed this consensus statement based on expert presentations of current scientific knowledge about IBD and through subsequent group discussion. This statement reflects the panel's assessment of medical knowledge available when written. Thus, readers should view this statement in the context of data that will accumulate after its creation. The opinions, conclusions, and recommendations expressed in this report are those of the consensus panel members and may or may not reflect the official opinion of the American Gastroenterological Association Institute. The conference upon which this report is based was funded through an unrestricted educational grant from Abbott Laboratories. Abbott Laboratories representatives did not attend the conference, nor did they participate in any way in the development of this report.

Cooney RM, Warren BF, Altman DG, Abreu MT, Travis SPL. 2007. Outcome measurement in clinical trials for Ulcerative Colitis: towards standardisation. Trials, 8 (1), pp. 17. | Show Abstract | Read more

Clinical trials on novel drug therapies require clear criteria for patient selection and agreed definitions of disease remission. This principle has been successfully applied in the field of rheumatology where agreed disease scoring systems have allowed multi-centre collaborations and facilitated audit across treatment centres. Unfortunately in ulcerative colitis this consensus is lacking. Thirteen scoring systems have been developed but none have been properly validated. Most trials choose different endpoints and activity indices, making comparison of results from different trials extremely difficult. International consensus on endoscopic, clinical and histological scoring systems is essential as these are the key components used to determine entry criteria and outcome measurements in clinical trials on ulcerative colitis. With multiple new therapies under development, there is a pressing need for consensus to be reached.

Steinhart AH, Forbes A, Mills EC, Rodgers-Gray BS, Travis SPL. 2007. Systematic review: the potential influence of mesalazine formulation on maintenance of remission in Crohn's disease. Aliment Pharmacol Ther, 25 (12), pp. 1389-1399. | Show Abstract | Read more

AIM: To evaluate the effectiveness of pH 6-/pH 7-dependent and controlled-release mesalazines in maintaining medically and surgically induced Crohn's disease remission. METHODS: A systematic search identified 13 randomized controlled trials (RCTs). The rate of symptomatic relapse (Crohn's disease activity index >150, or an increase in baseline by at least 60-100 points) was extracted from each randomized controlled trial. Pooled odds ratios (OR), the number needed to treat (NNT), and percentage therapeutic benefit (absolute risk reduction) were calculated. RESULTS: Treatment with pH 7-dependent mesalazine significantly reduced the risk of relapse in patients with either surgically [OR 0.28; 95% confidence interval (CI) 0.12-0.65; P = 0.0032] or medically induced remission (OR 0.38; 95% CI 0.17-0.85; P = 0.0113). However, treatment with controlled-release mesalazine and pH 6-dependent mesalazine failed to show any significant advantage over placebo. The NNT to maintain surgically or medically induced remission was lowest for pH 7-dependent mesalazine (NNT = 4 and 5, respectively; NNT = 15 and 16 for controlled-release mesalazine and NNT = 11 and 23 for pH 6-dependent mesalazine). Therapeutic benefit was highest for pH 7-dependent mesalazine (surgical = 30.6%, medical = 22.8%). This compared with 6.9% (surgical) and 6.4% (medical) for controlled-release mesalazine, and 9.8% and 4.4%, respectively, for pH 6-dependent mesalazine. CONCLUSION: Further trials of pH 7-dependent mesalazine formulations are warranted in the maintenance of remission in Crohn's disease.

Jakobovits SL, Jewell DP, Travis SPL. 2007. Infliximab for the treatment of ulcerative colitis: outcomes in Oxford from 2000 to 2006. Aliment Pharmacol Ther, 25 (9), pp. 1055-1060. | Show Abstract | Read more

BACKGROUND: Infliximab has been shown to be of benefit in the treatment of ulcerative colitis but long-term colectomy rates remain unknown. AIMS: To review the rate of colectomy after infliximab for ulcerative colitis and to identify factors that might predict the need for colectomy. METHODS: We conducted a retrospective cohort study of patients with active ulcerative colitis treated with infliximab between 2000 and 2006. The primary outcome was colectomy-free survival. Disease and treatment characteristics and complications were documented. RESULTS: Thirty patients were treated with infliximab for refractory ulcerative colitis. Sixteen (53%) came to colectomy a median of 140 days after their first infusion (range 4-607). There was no difference in colectomy between those receiving infliximab for acute severe ulcerative colitis failing intravenous steroids (8/14) and out-patients with steroid-refractory ulcerative colitis (8/16). Only 17% (5/30) achieved a steroid-free remission after a median follow-up of 13 months (range 2-72). Univariate analysis showed that a younger age at diagnosis of colitis was significantly associated with an increased rate of colectomy (27.5 years vs. 38.7 years, P = 0.016). CONCLUSION: Over half the patients studied came to colectomy. Of those avoiding colectomy, only five (17%) sustained a steroid-free remission.

Oefferlbauer-Ernst A, Miehsler W, Eckmüllner O, Travis S, Waldhoer T, Dejaco C, Gangl A, Vogelsang H, Reinisch W. 2007. Impact of interobserver disagreement on phenotype-genotype associations in Crohn's disease. Inflamm Bowel Dis, 13 (2), pp. 156-163. | Show Abstract | Read more

BACKGROUND: Nonvalidated definitions of disease-related parameters in inflammatory bowel disease cause variations in diagnosis and disease classification. We determined interobserver agreement on applications of definitions of the Vienna Classification variables and computed the potential influence of misclassification on genotype/phenotype associations. METHODS: Ten records of patients with Crohn's disease (CD) were independently evaluated by 19 observers using a standardized inflammatory bowel disease documentation system, which included the Vienna Classification. Interobserver agreement (IOA) was calculated as a percentage of the observers' agreement with a predetermined reference observer and by Cohen's kappa. Randomized reclassifications were then computed with 10,000 simulation runs using the IOA results and published NOD2/CARD15 gene status. A chi-square independence test was calculated for each simulation run. RESULTS: IOA for location and behavior was 70% (K = 0.57) and 95% (K = 0.91), respectively. IOA for location subgroups ranged from 48% to 88% and for behavior from 91% to 97%. By including the results of histopathology into the evaluation of location, the overall IOA increased significantly, to 80% (P = 0.019). Assuming a true genotype/phenotype association, the proportion of studies with nonsignificant findings (P > 0.05) because of the observed misclassification of location ranged from 13.3% to 63.8% and of behavior from 0.2% to 22.2%, depending on a study sample size of 500 or 150 patients respectively. CONCLUSIONS: We concluded that there is appreciable interobserver disagreement on the location of CD according to the original Vienna Classification that may obscure true genotype/phenotype associations. Definitions of disease parameters have to be validated before being used as the bases for classifications.

Travis S. 2007. Immunomodulator therapy of IBD Gastroenterological Endoscopy, 49 pp. 2073-2076. | Read more

Hyder SA, Travis SPL, Jewell DP, McC Mortensen NJ, George BD. 2006. Fistulating anal Crohn's disease: results of combined surgical and infliximab treatment. Dis Colon Rectum, 49 (12), pp. 1837-1841. | Show Abstract | Read more

INTRODUCTION: Infliximab is a monoclonal antibody against tumor necrosis factor-alpha, which has been shown to be effective in fistulating Crohn's disease. The safety of infliximab in patients with potential perianal sepsis is uncertain. This study was designed to assess the safety and outcome of infliximab therapy combined with surgery for patients with fistulating anal Crohn's disease. METHODS: All patients receiving infliximab for fistulating anal Crohn's disease between 2000 and 2004 were studied. Patients' demographics, clinical findings, magnetic resonance imaging, and examination under anesthesia were recorded. Perianal Crohn's disease activity index before and 8 to 12 weeks after three infusions of infliximab (5 mg/kg) were recorded. Routine policy was to insert drainage seton sutures at the time of preinfliximab examination under anesthesia and then remove it after the second infusion. Complications of treatment and outcome at the last clinic follow-up were recorded. RESULTS: Twenty-two patients underwent infliximab treatment (6 males; median age, 35 (range, 16-60) years). Twenty-one patients had preinfliximab examination under anesthesia: 12 required abscess drainage; 17 had at least one drainage seton suture inserted. Fourteen patients underwent pretreatment magnetic resonance imaging to identify clinically occult collections. All but one patient were established on immunomodulator therapy before infliximab treatment. Perianal Crohn's disease activity index improved significantly after infliximab infusion (preinfusion: median, 11, range, 8-17; postinfusion: median, 8, range, 5-16; P<0.001). There were no serious complications of infliximab treatment. At median follow-up of 21 (range, 4-31) months, only four patients achieved sustained fistula healing. Five patients have required defunctioning or proctectomy. Four patients have required repeated infusions of infliximab. CONCLUSIONS: Infliximab therapy in combination with examination under anesthesia/seton drainage is a safe and effective short-term treatment for fistulating anal Crohn's disease. Long-term fistula healing rates are low.

Travis S. 2006. Review article: saving the colon in severe colitis - the case for medical therapy. Aliment Pharmacol Ther, 24 Suppl 3 (s3), pp. 68-73. | Show Abstract | Read more

The choice between ciclosporin (CsA), infliximab (IFX) and surgery for severe colitis not responding to intensive intravenous treatment, is challenging. With the advent of vislizumab and alternatives such as tacrolimus or leucocytapheresis, decisions will get harder. This article reviews the evidence for each intervention, draws attention to disparities in the definition of severe colitis between different trials and gives practical guidance. Early medical decision making is critical. Standard intensive treatment with intravenous steroids is still the first-line approach. Progress should be monitored objectively using a simple predictive index. Rescue therapy with CsA (oral 5 mg/kg or 2 mg/kg iv) or IFX (5 mg/kg) should be started on the third day of intensive treatment if predictive factors are poor (e.g. C-reactive protein > 45 mg/L). Physicians should discuss with their patients that there is just one attempt at rescue therapy, because only one patient death, as a consequence of delayed colectomy, changes the balance of benefit between medicine and surgery.

McGovern DPB, Butler H, Ahmad T, Paolucci M, van Heel DA, Negoro K, Hysi P, Ragoussis J, Travis SPL, Cardon LR, Jewell DP. 2006. TUCAN (CARD8) genetic variants and inflammatory bowel disease. Gastroenterology, 131 (4), pp. 1190-1196. | Show Abstract | Read more

BACKGROUND & AIMS: The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor kappaB (NFkappaB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFkappaB, making it an excellent candidate gene for gastrointestinal inflammation. METHODS: Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data. RESULTS: We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility. CONCLUSIONS: We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients.

Hunt KA, Monsuur AJ, McArdle WL, Kumar PJ, Travis SPL, Walters JRF, Jewell DP, Strachan DP, Playford RJ, Wijmenga C, van Heel DA. 2006. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut, 55 (7), pp. 969-972. | Show Abstract | Read more

BACKGROUND AND AIMS: Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS: Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS: UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS: Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.

Travis S. 2006. Infliximab and azathioprine: bridge or parachute? Gastroenterology, 130 (4), pp. 1354-1357. | Read more

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Travis SPL, Stange EF, Lémann M, Oresland T, Chowers Y, Forbes A, D'Haens G, Kitis G, Cortot A, Prantera C et al. 2006. European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut, 55 Suppl 1 (suppl_1), pp. i16-i35. | Show Abstract | Read more

This second section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The third section on special situations in Crohn's disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn's disease.

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Stange EF, Travis SPL, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, Barakauskiene A, Villanacci V, Von Herbay A, Warren BF et al. 2006. European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Gut, 55 Suppl 1 (suppl_1), pp. i1-15. | Read more

Hamad N, Travis SPL. 2006. Weight loss at high altitude: pathophysiology and practical implications. Eur J Gastroenterol Hepatol, 18 (1), pp. 5-10. | Show Abstract | Read more

Climbers at high altitude (>5000 m) lose weight. This impairs performance and safety, but the mechanisms are not entirely due to an imbalance between energy intake and expenditure. There is some evidence of carbohydrate malabsorption, but there are also changes in fat metabolism and total body water. This paper considers the physiological control of weight and then discusses the changes in each parameter before addressing the practical implications.

Travis S. 2005. What is the optimal dosage of mesalazine to maintain remission in patients with ulcerative colitis? Nat Clin Pract Gastroenterol Hepatol, 2 (12), pp. 564-565. | Read more

Travis S. 2005. Advances in therapeutic approaches to ulcerative colitis and Crohn's disease. Curr Gastroenterol Rep, 7 (6), pp. 475-484. | Show Abstract | Read more

Advances (from 2004 to 2006) in the use of conventional agents include the molecular mechanisms of action, which have implications for monitoring (azathioprine and thioguanosine triphosphate) and chemoprevention (mesalamine and peroxisome proliferator activated receptor gamma). Advances in biotherapy include new data on monoclonal antibodies (infliximab in ulcerative colitis, adalimumab, certolizumab pegol, fontolizumab, selective anti-adhesion molecules, and others), antisense oligonucleotides, the development of small molecules, and cell-gene therapy (including helminth ova, leukocytapheresis, stem cell transplantation, and probiotic intestinal mucosal delivery systems). However, management of inflammatory bowel disease is about more than drug therapy, dose, and timing. The goals remain induction of remission, limitation of side effects, modification of the pattern of disease, and avoidance of complications. With the cost and complexity of biotherapy, inflammatory bowel disease is emerging as a specific subspecialty.

Travis S, Yap LM, Hawkey C, Warren B, Lazarov M, Fong T, Tesi RJ, RDP Investigators Study Group. 2005. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm Bowel Dis, 11 (8), pp. 713-719. | Show Abstract | Read more

BACKGROUND: RDP58 is a novel anti-inflammatory d-amino acid decapeptide that inhibits synthesis of proinflammatory cytokines by disrupting cell signaling at the pre-MAPK MyD88-IRAK-TRAF6 protein complex. We therefore evaluated its efficacy and safety in parallel multicenter, double-blind, randomized concept studies in ulcerative colitis (UC). METHODS: In the first trial, 34 patients with mild to moderate active UC were randomized (1:2) to placebo (n = 13) or RDP58 100 mg (n = 21). In the second trial, 93 similar patients were randomized (1:1:1) to placebo (n = 30) RDP58 200 mg (n = 31), or RDP 300 mg (n = 32). In both studies, treatment success was defined as a simple clinical colitis activity index score of no more than 3 at 28 days. Sigmoidoscopy and rectal biopsy (at baseline and 28 days) and safety measures (baseline and 28 and 56 days) were other endpoints. RESULTS: Treatment success on RDP 100 mg was 29% versus 46% on placebo (P = 0.46). There were no significant differences in sigmoidoscopy or histology score. In the second study, treatment success on the higher doses of RDP58 (200 and 300 mg) was 71% and 72%, respectively, versus 43% on placebo (P = 0.016). Improvements in sigmoidoscopy scores (41% on 200 mg and 46% on 300 mg versus 32% on placebo) did not reach significance, but histology scores improved significantly (P = 0.002) versus placebo. Overall, adverse events were no different between placebo (3.3 +/- 2.4) and RDP58 (2.7 +/- 1.4, 300-mg group). CONCLUSIONS: RDP58 at a dose of 200 or 300 mg, but not 100 mg, was effective in mild-to-moderate UC. RDP58 was safe and well tolerated, and its novel action makes it an attractive potential therapy.

McGovern DPB, Travis SPL. 2005. Smoking status in therapeutic trials in Crohn's disease. Gut, 54 (7), pp. 1047-1048. | Read more

Frenz MB, Dunckley P, Camporota L, Jewell DP, Travis SPL. 2005. Comparison between prospective and retrospective evaluation of Crohn's disease activity index. Am J Gastroenterol, 100 (5), pp. 1117-1120. | Show Abstract | Read more

The Crohn's disease activity index (CDAI) is the most widely used measure of clinical disease activity in patients entered into clinical trials. The prospective nature of the CDAI calculation precludes its use as a clinical assessment tool. We compared the retrospective evaluation of the CDAI with the prospective evaluation in a heterogeneous patient population of 100 patients with Crohn's disease. The correlation between the two assessment methods was good with an r-value of 0.84 (p < 0,0001). There was a tendency of patients with a high retrospective CDAI to have a lower prospective CDAI which is explained by intention to treat. This study shows that a retrospective assisted evaluation of the CDAI is as accurate as the traditional prospective evaluation.

Hunt KA, McGovern DPB, Kumar PJ, Ghosh S, Travis SPL, Walters JRF, Jewell DP, Playford RJ, van Heel DA. 2005. A common CTLA4 haplotype associated with coeliac disease. Eur J Hum Genet, 13 (4), pp. 440-444. | Show Abstract | Read more

Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 3' region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants (-1722 C/T, -658 T/C, -318 C/T, +49 A/G, +1822 C/T, CT60 A/G) to tag all common haplotypes (>5% frequency) and an ICOS variant (IVS+173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 +1822T (P=0.019) and CT60 G (P=0.047) alleles. Strong association was seen with a common CTLA4 haplotype (P=0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.

Cummings JRF, Herrlinger KR, Travis SPL, Gorard DA, McIntyre AS, Jewell DP. 2005. Oral methotrexate in ulcerative colitis. Aliment Pharmacol Ther, 21 (4), pp. 385-389. | Show Abstract | Read more

BACKGROUND: We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. METHODS: Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). RESULTS: There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). CONCLUSION: Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.

Travis SPL. 2005. Dose escalation of 5ASA: does it work? Dig Liver Dis, 37 (2), pp. 82-84. | Read more

Campbell S, Travis S, Jewell D. 2005. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol, 17 (1), pp. 79-84. | Show Abstract | Read more

BACKGROUND: Within a lifetime, approximately 15% of ulcerative colitis (UC) patients will have a severe relapse necessitating admission to hospital. Despite intravenous steroid treatment, approximately 25% will require either surgery or ciclosporin (CsA) rescue therapy. Initial response rates to CsA have been encouraging, but remission rates have been disappointing. There is a paucity of long-term data on UC patients who have been brought into remission with CsA. OBJECTIVES: To report our 7 year experience on the use of CsA in acute UC and to highlight long-term follow-up data on these patients. PATIENTS AND METHODS: A retrospective database of 76 UC patients requiring CsA between 1996 and 2003 was constructed. CsA was started on the basis of their C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone. The patients (33 female, 43 male, mean age 44.5 years) were followed up for a median 2.9 years (range 0.2-7.0 years). Fifty-four patients received i.v. CsA (4 mg/kg), while 22 received oral CsA (5 mg/kg). Long-term outcome was evaluated by Kaplan-Meier survival analysis: time to first relapse and time to surgery. RESULTS: Median disease duration was 6.6 years. Median CRP and stool frequency at day 3 was 20 mg/l and 6 per day, respectively. Fifty-six patients (74%) achieved initial remission. CsA was discontinued in only four patients due to side effects. Duration of i.v. steroids or the addition of AZA did not improve time to first relapse or time to surgery. Comparison between i.v. CsA and oral CsA revealed a statistically significant difference in time to first relapse (P < 0.01) and time to surgery (P < 0.05) in favour of oral CsA. CONCLUSIONS: These data describe the long-term outcome of the largest series of patients so far reported that have had treatment with CsA for severe refractory UC. If patients achieved initial remission with CsA, after 1 year, 65% had relapsed and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy. Minor side effects were frequent, but none were life threatening. There was no increase in post-operative complications in those who came to colectomy.

Travis SPL. 2004. Review article: the management of mild to severe acute ulcerative colitis. Aliment Pharmacol Ther, 20 Suppl 4 pp. 88-92. | Show Abstract | Read more

The goals for the management of acute ulcerative colitis are the objective evaluation of disease activity, induction of remission, prevention of relapse and treatment of complications. Clinical practice should be guided by simple activity indices, as it is easy to underestimate severity. For the induction of remission, topical treatment with mesalazine (mesalamine) is appropriate initial therapy for distal disease but, if symptoms persist for over a fortnight, decisive treatment is usually appreciated by the patient. For mild to moderate disease, corticosteroids have been the mainstay in Europe, although high-dose aminosalicylates (such as Pentasa, 4 g orally daily and 1 g rectally) are an alternative for symptoms not interfering with daily activity. Novel therapeutic approaches in ulcerative colitis have lagged behind those used for Crohn's disease, but several (epidermal growth factor, RDP 58, basiliximab, leucocytapheresis) are on the horizon. Severe colitis, defined as a bloody stool frequency of more than six per day with any one of tachycardia (pulse > 90 beats/min), temperature (> 37.8 degrees C), anaemia (haemoglobin < 10.5 g/dL) or raised erythrocyte sedimentation rate (> 30 mm/h), is an indication for intensive intravenous treatment. National UK figures indicate that 30% of ulcerative colitis cases progress to colectomy, and objective criteria for predicting the need for colectomy have been validated. The timing of colectomy is the most important decision that a physician is called upon to make, in conjunction with the patient and surgical colleagues. For the maintenance of remission, aminosalicylates continue to be first-line therapy, although the choice of 5-aminosalicylate appears to be influenced as much by geography as by theoretical considerations. Steroids have no place in the maintenance of remission. Indications for azathioprine include patients after a severe relapse of ulcerative colitis, those with early relapse after steroids (dose of < 15 mg/day, or within 6 weeks of stopping) and those needing a second course of steroids within a year. Therapeutic decisions should have a strategy, aimed at navigating the patient around relapses and through to sustained remission. Good management depends on clinical skills, compassion and care of the individual, in addition to pharmaceuticals.

Carter MJ, Lobo AJ, Travis SPL, IBD Section, British Society of Gastroenterology. 2004. Guidelines for the management of inflammatory bowel disease in adults. Gut, 53 Suppl 5 (suppl_5), pp. V1-16. | Read more

Frenz MB, Heinsohn P, Siuda G, Travis SPL. 2004. A reliable method of single-pass endoscopic gastrostomy replacement. Endoscopy, 36 (8), pp. 754. | Read more

Travis SPL. 2004. Predicting outcome in severe ulcerative colitis. Dig Liver Dis, 36 (7), pp. 448-449. | Read more

Van Staa TP, Travis S, Leufkens HGM, Logan RF. 2004. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology, 126 (7), pp. 1733-1739. | Show Abstract | Read more

BACKGROUND & AIMS: This study was performed to quantify the risk of renal disease in patients using aminosalicylates (5-ASA). METHODS: Data from the United Kingdom General Practice Research Database were used to estimate the incidence of renal disease in adult patients with inflammatory bowel disease (IBD) or prescription for 5-ASA and in patients without IBD. In a nested case-control analysis, each case of renal disease was matched to 5 controls. RESULTS: Among the 19,025 5-ASA users with IBD, 130 patients developed renal disease (incidence rate of 0.17 cases per 100 patients per year). The incidence among patients with IBD but without 5-ASA use was 0.25 and among patients without IBD was 0.08. In the case-control analysis, the crude odds ratio (OR) for renal disease in current 5-ASA users was 1.60 (95% confidence interval [95% CI]: 1.14-2.26); the adjusted OR was 0.86 (95% CI: 0.53-1.41). For recent users, the crude OR was 4.18 (95% CI: 2.59-6.76) and adjusted OR 2.48 (95% CI: 1.33-4.61); for past users (last prescription more than 12 months before), 1.71 (95% CI: 1.09-2.70) and 0.99 (95% CI: 0.55-1.76), respectively. Although the numbers were small, mesalazine and sulfasalazine users had comparable risks (crude OR for current and recent users of OR 2.08 [95% CI: 1.44-3.01] and 1.84 [95% CI: 1.20-2.82], respectively). In only a few records was renal disease attributed to interstitial nephritis or 5-ASA use. CONCLUSIONS: Users of 5-ASA have an increased risk of renal disease that may be partly attributable to the underlying disease. Although renal disease is a recognized adverse effect of 5-ASA, the incidence appears to be low and does not appear to be related to either the dose or type of 5-ASA used.

Frenz MB, van Heel D, Siuda G, Travis SPL. 2004. Unusual malfunction of percutaneous endoscopic jejunostomy feeding tubes in patients with intestinal dysmotility. Endoscopy, 36 (3), pp. 234-235. | Show Abstract | Read more

We report the complication of knotted percutaneous endoscopic jejunostomy (PEJ) feeding tubes in three patients with intestinal dysmotility. The management of PEJ tube dysfunction and strategies to prevent this complication are discussed.

Frenz MB, Siuda G, McIntyre AS, Travis SPL. 2004. A simple and safe method of transcutaneous gastrostomy replacement using the Seldinger technique. Endoscopy, 36 (3), pp. 250. | Read more

Travis SPL. 2002. Which 5-ASA? Gut, 51 (4), pp. 548-549. | Read more

De Silva AP, Ahmad T, Vermiere S, Armuzzi A, Mulcahy-Hawes K, Travis S, Welsh K, Rutgeerts P, Jewell D. 2002. The genetic prediction of the clinical response to infliximab in Crohn's disease (CD): A role for polymorphisms in the TNFa and LTA genes? GUT, 50 pp. A80-A80.

Hawthorne AB, Travis SPL, Network BSGIBDC. 2002. Outcome of in-patient management of severe colitis: A BSG IBD clinical network survey GUT, 50 pp. A16-A16.

Warren BF, Edwards CM, Travis SPL. 2002. 'Microscopic colitis': classification and terminology. Histopathology, 40 (4), pp. 374-376. | Read more

Green JR, Lobo AJ, Giaffer M, Travis S, Watkins HC, Freedom Investigator Group. 2001. Maintenance of Crohn's disease over 12 months: fixed versus flexible dosing regimen using budesonide controlled ileal release capsules. Aliment Pharmacol Ther, 15 (9), pp. 1331-1341. | Show Abstract | Read more

BACKGROUND: It may be possible to achieve more effective management of Crohn's Disease by introducing a flexible dosage regimen sensitive to patients' needs. AIM: Comparison of the efficacy and tolerability of a fixed vs. flexible budesonide controlled ileal release treatment regimen for the prevention and management of relapse in Crohn's disease patients. Budesonide controlled ileal release is an oral formulation which delivers drug directly to disease sites in the ileum and ascending colon, by preventing more proximal release and absorption. METHODS: A randomized, double-blind comparison of a fixed dose of budesonide controlled ileal release (6 mg o.m.) and a flexible dose of budesonide controlled ileal release (3, 6 or 9 mg o.m.) for 12 months, in 143 patients in remission from ileal or ileo-caecal Crohn's Disease. RESULTS: Very low rates of clinical relapse in Crohn's disease were achieved with budesonide controlled ileal release 6 mg o.m. There was no significant difference between the treatment groups with respect to the survival estimate of percentage of treatment failures (flexible group 15%, fixed group 19%; P=0.61). The average consumed dose of budesonide was comparable in both groups (5.8 mg flexible, 6.0 mg fixed). Similar proportions of patients reported adverse events (flexible 100%, fixed 97%). There were 33 serious adverse events (flexible 19, fixed 14) and 13 withdrawals due to significant adverse events (flexible 9, fixed 4). CONCLUSION: Maintenance treatment with budesonide controlled ileal release 6 mg o.m. is well-tolerated and is associated with low rates of clinical relapse in stable Crohn's disease over 12 months. Flexible dosing remains an option for individual patients, but this study has shown no advantage over a standard fixed dosing regimen.

Travis SP, Czajkowski M, McGovern DP, Watson RG, Bell AL. 2001. Treatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody. Gut, 49 (5), pp. 725-728. | Show Abstract | Read more

Few patients with Behçet's syndrome have gastrointestinal ulceration. Such patients are difficult to treat and have a higher mortality. Faced with refractory symptoms in two patients with intestinal Behçet's, we used the tumour necrosis factor alpha (TNF-alpha) monoclonal antibody infliximab to induce remission. Both women (one aged 27 years, the other 30 years) presented with orogenital ulceration, pustular rash, abdominal pain, bloody diarrhoea due to colonic ulceration, weight loss, and synovitis. One had thrombophlebitis, digital vasculitis, perianal fistula, and paracolic abscess; the other had conjunctivitis and an ulcer in the natal cleft. Treatment with prednisolone, methyl prednisolone, and thalidomide in one and prednisolone, colchicine, and cyclosporin in the other was ineffective. After full discussion, infliximab (3 mg/kg, dose reduced because of recent sepsis in one, and 5 mg/kg in the other) was administered. Within 10 days the ulcers healed, with resolution of bloody diarrhoea and all extraintestinal manifestations. A second infusion of infliximab was necessary eight weeks later in one case, followed by sustained (>15 months) remission on low dose thalidomide. Remission was initially sustained for 12 months in the other but thalidomide had to be stopped due to intolerance, and a good response to retreatment lasted only 12 weeks without immunosuppression, before a third infusion. The cause of Behçet's syndrome is unknown but peripheral blood CD45 gammadelta T cells in Behçet's produce >50-fold more TNF-alpha than controls when stimulated with phorbol myristate acetate and anti-CD3. Infliximab could have a role for inducing remission in Behçet's syndrome.

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Travis S, Innes N, Davies MG, Daneshmend T, Hughes S. 1997. Sweet's syndrome: an unusual cutaneous feature of Crohn's disease or ulcerative colitis. The South West Gastroenterology Group. Eur J Gastroenterol Hepatol, 9 (7), pp. 715-720. | Show Abstract

Sweet's syndrome is characterized by tender, red inflammatory nodules or papules, usually affecting the upper limbs, face or neck. It is part of the group of acute neutrophilic dermatoses that includes pyoderma gangrenosum, but can be distinguished by its appearance, distribution and histological features. Four patients with Sweet's syndrome and Crohn's disease are reported. A total of 30 cases from the literature suggest that Sweet's syndrome is an unusual extraintestinal manifestation of either Crohn's disease or ulcerative colitis. There is a strong predilection for women (87%), patients with colonic disease (100%) and those with other extraintestinal features (77%). The rash is associated with active disease in 67-80%, but may precede the onset of intestinal symptoms in 21% and has been reported 3 months after proctocolectomy for ulcerative colitis.

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Travis SP. 1997. Review article: insurance risks for patients with ulcerative colitis or Crohn's disease. Aliment Pharmacol Ther, 11 (1), pp. 51-59. | Show Abstract | Read more

Prospective population-based studies have allowed a re-evaluation of the risks of insuring patients with ulcerative colitis or Crohn's disease. Life expectancy, the risk of cancer and working capacity are very much better than previously recognised and are normal for many patients. Three population-based studies in ulcerative colitis have shown a mortality similar to or slightly less than the general population except in the first year after diagnosis, whilst two have shown a slightly higher mortality (standardized mortality ratio, SMR = 1.4), except for those with proctitis. In Crohn's disease, two population-based studies have also shown an increased mortality (SMR = 1.4), which is similar to that of unskilled manual labourers (SMR = 1.43) from all causes of death. Three other studies have shown no increase in overall mortality, except in the first 5 years after diagnosis, in those with proximal small intestinal disease and in some patients needing multiple operations. Insurance risks should be evaluated on an individual basis, after details of the extent and pattern of disease have been obtained. Although the 'standard life' in insurance terms differs from that of the general population, because people who seek life assurance are self-selected from a more affluent section of society, many patients can be identified who have a particularly good prognosis. These include patients with ulcerative proctitis, those with left-sided colitis in extended remission (> 12 months), and patients more than 30 years old with localized ileal or ileocaecal Crohn's disease that has responded to treatment. From the published data, it is difficult to justify increasing the insurance premium in such patients.

Travis SP, Farrant JM, Ricketts C, Nolan DJ, Mortensen NM, Kettlewell MG, Jewell DP. 1996. Predicting outcome in severe ulcerative colitis. Gut, 38 (6), pp. 905-910. | Show Abstract | Read more

BACKGROUND: Simple criteria are needed to predict which patients with severe ulcerative colitis will respond poorly to intensive medical treatment and require colectomy. AIMS: To find out if the early pattern of change in inflammatory markers or other variables could predict the need for surgery and to evaluate the outcome of medical treatment during one year follow up. PATIENTS: 51 consecutive episodes of severe colitis (Truelove and Witts criteria) affecting 49 patients admitted to John Radcliffe Hospital, Oxford. METHODS: Prospective study monitoring 36 clinical, laboratory, and radiographic variables. All episodes treated with intravenous and rectal hydrocortisone and 14 of 51 with cyclosporine. RESULTS: Complete response in 21 episodes (< or = 3 stools on day 7, without visible blood), incomplete response in 15 (> 3 stools or visible blood on day 7, but no colectomy), and colectomy on that admission in 15. During the first five days, stool frequency and C reactive protein (CRP) distinguished between outcomes (p < 0.00625, corrected for multiple comparisons) irrespective of whether patients or the number of episodes were analysed. It could be predicted on day 3, that 85% of patients with more than eight stools on that day, or a stool frequency between three and eight together with a CRP > 45 mg/l, would require colectomy. For patients given cyclosporine, four of 14 avoided colectomy but two continued to have symptoms. After admission, complete responders remained in remission for a median nine months and had a 5% chance of colectomy. Incomplete responders had a 60% chance of continuous symptoms and 40% chance of colectomy. CONCLUSIONS: After three days intensive treatment, patients with frequent stools (> 8/day), or raised CRP (> 45 mg/l) need to be identified, as most will require colectomy on that admission. The role of cyclosporine for treating severe colitis has yet to be defined. After seven days' treatment, patients with > 3 stools/day of visible blood have a 60% chance of continuous symptoms and 40% chance of colectomy in the following months.

A'Court CH, Stables RH, Travis S. 1995. Doctor on a mountaineering expedition. BMJ (Clinical research ed.), 310 (6989), pp. 1248-1252. | Show Abstract | Read more

Doctors are welcome members on mountaineering expeditions to remote areas, but practical advice on how to prepare and what kit to take can be difficult to find. This article is a ragbag of useful advice on diverse topics. It explains the necessary preparation, provides tips for a healthy expedition, and summarises the common disorders encountered at high altitude. The comprehensive drug and equipment lists and first aid kit for climbers were used for the 1992 Everest in winter expedition. They are there to be sacrificed to personal preference and the experience and size of individual expeditions.

A'Court CH, Stables RH, Travis S. 1995. Doctor on a mountaineering expedition. BMJ, 310 (6989), pp. 1248-1252. | Show Abstract

Doctors are welcome members on mountaineering expeditions to remote areas, but practical advice on how to prepare and what kit to take can be difficult to find. This article is a ragbag of useful advice on diverse topics. It explains the necessary preparation, provides tips for a healthy expedition, and summarises the common disorders encountered at high altitude. The comprehensive drug and equipment lists and first aid kit for climbers were used for the 1992 Everest in winter expedition. They are there to be sacrificed to personal preference and the experience and size of individual expeditions.

Rees DC, Satsangi J, Cornelissen PL, Travis SP, White J, Jewell DP. 1995. Are serum concentrations of nitric oxide metabolites useful for predicting the clinical outcome of severe ulcerative colitis? Eur J Gastroenterol Hepatol, 7 (3), pp. 227-230. | Show Abstract

OBJECTIVE: To determine serum concentrations of nitric oxide metabolites (NOX) in patients with severe ulcerative colitis and to assess whether these concentrations predict clinical outcome. PATIENTS: Twenty-six patients (16 men and 10 women, mean age 46 years) with severe ulcerative colitis requiring hospitalization for parenteral steroid therapy. Thirteen patients had a complete clinical response and symptoms resolved after 5 days of parenteral steroid administration; 13 made an incomplete recovery and needed further treatment (six cyclosporin, seven colectomy). METHODS: Serum concentrations of NOX and C-reactive protein (CRP) were measured daily for 3 days in all patients and as clinically indicated thereafter. The normal range for NOX was established by measuring the concentration in 25 healthy controls. RESULTS: Mean serum NOX and CRP concentrations were significantly elevated in both the patients with a complete and those with an incomplete response compared with controls (P < 0.001) on day 1 and fell during the first 3 days of therapy. On day 3, mean serum concentrations of NOX and CRP were lower in the patients with a complete response, but only the difference in CRP attained statistical significance (P = 0.02). There was no correlation between NOX and CRP concentrations. CONCLUSIONS: In the majority of patients with severe ulcerative colitis, circulating concentrations of NOX are increased at presentation and fall promptly during parenteral steroid therapy, irrespective of clinical outcome. However, in a small number of patients NOX concentrations do not fall during steroid treatment and such patients will probably require additional medical therapy or surgery.

Haggett PJ, Moore NR, Shearman JD, Travis SP, Jewell DP, Mortensen NJ. 1995. Pelvic and perineal complications of Crohn's disease: assessment using magnetic resonance imaging. Gut, 36 (3), pp. 407-410. | Show Abstract | Read more

This study evaluated the role of magnetic resonance imaging (MRI) in the demonstration of the pelvic and perianal complications of Crohn's disease. Twenty five patients with active Crohn's disease were studied (12 male; mean age 41.1 years). MRI examinations were performed using a 1.5 Tesla system, within 14 days after clinical assessment. T1 and T2 weighted fast spin echo sequences in two or three orthogonal planes were performed, with fat suppression in some cases. The MRI results were correlated with surgical and clinical findings. In 16 patients, cutaneous, deep perineal or enterovesical fistulas or abscesses were diagnosed at MRI which showed close correlation with findings at examination under anaesthetic. In eight patients no fistulas or abscesses were seen at MRI nor was there any evidence of complications on clinical examination and flexible sigmoidoscopy. There was one false negative examination in a patient who had a colovesical fistula. In conclusion, MRI can accurately show the pelvic and perineal complications of Crohn's disease and may render examination under anaesthetic unnecessary.

Travis SP, Crotty B, Jewell DP. 1995. Site of action of platelet-activating factor within the mucosa of rabbit distal colon. Clin Sci (Lond), 88 (1), pp. 51-57. | Show Abstract | Read more

1. To determine how platelet-activating factor stimulates colonic anion secretion and increases epithelial permeability, epithelial sheets of rabbit distal colon excluding the submucosal neural plexus were mounted in Ussing chambers. The influence of specific inhibitors and 50 nmol/l platelet-activating factor on short-circuit current and transepithelial resistance was then investigated. 2. Pretreatment with 1 mumol/l indomethacin or 1 mumol/l doxantrazole abolished the biphasic stimulation of the short-circuit current and decrease in transepithelial resistance induced by platelet-activating factor. Addition of 10 mumol/l mepyramine attenuated the early phase and completely inhibited the late phase. Pretreatment with 1 mumol/l ranitidine, 0.1 mumol/l tetrodotoxin, 0.1 mumol/l ritanserin or a 5-lipoxygenase inhibitor (1 mumol/l MK886) had no effect. 3. To assess the influence of platelet-activating factor on epithelial function isolated from lamina propria elements, monolayers were cultured from a human colonic epithelial cell line (T-84). 4. The short-circuit current across monolayers mounted in Ussing chambers stimulated by 10 mumol/l ionomycin could be inhibited by pretreatment with ouabain or frusemide, consistent with the capacity for chloride secretion. Addition of platelet-activating factor (up to 500 nmol/l) had no effect on short-circuit current or transepithelial resistance. Receptor expression was examined with [3H] platelet-activating factor in isolated T-84 and HT-29 cells and found to be absent. 5. The influence of physiological concentrations of platelet-activating factor on colonic epithelial anion secretion and increased permeability in rabbit distal colon is indirect and consistent with mediation by prostaglandins released from mucosal mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Travis SP, Tysk C, de Silva HJ, Sandberg-Gertzén H, Jewell DP, Järnerot G. 1994. Optimum dose of olsalazine for maintaining remission in ulcerative colitis. Gut, 35 (9), pp. 1282-1286. | Show Abstract | Read more

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.

Travis SP, Jewell DP. 1994. Salicylates for inflammatory bowel disease. Baillieres Clin Gastroenterol, 8 (2), pp. 203-231. | Show Abstract | Read more

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.

Dinmore AJ, Edwards JS, Menzies IS, Travis SP. 1994. Intestinal carbohydrate absorption and permeability at high altitude (5,730 m). J Appl Physiol (1985), 76 (5), pp. 1903-1907. | Show Abstract | Read more

To investigate the effects of high altitude on intestinal function, the absorption and permeation of nonmetabolizable carbohydrates were measured in 14 volunteers (median age 21 yr, range 19-37 yr) at sea level in Oxford, UK; at 1,050 m in Nepal; at 5,570 m after 5 days at > 5,500 m; and at 5,730 m after 11 days at > 5,500 m. Body weight decreased 5.7 +/- 1.19 kg from sea level to 5,570 m (P < 0.001 by paired t test) despite 72-h dietary records showing no change in energy intake. Absorption of carbohydrates by mediated transport was measured by urinary xylose and 3-O-methyl-D-glucose excretion. Xylose excretion (%oral dose) decreased from 31.4 +/- 4.5% to 20.7 +/- 4.5% (P < 0.001) and 3-O-methyl-D-glucose excretion decreased from 39.7 +/- 6.1 to 33.7 +/- 7.0% (P = 0.003) from sea level to 5,730 m. Monosaccharide permeation measured by L-rhamnose excretion decreased from 11.3 +/- 2.5 to 6.2 +/- 2.0% (P = 0.001). Intestinal permeability, a measure of barrier function (ratio of lactulose to L-rhamnose), increased from 0.036 +/- 0.014 at sea level to 0.084 +/- 0.042 at 1,050 m (P = 0.006), possibly due to infective enteropathy after arrival in Nepal, but reverted to normal (0.045 +/- 0.013; P = 0.062) at 5,730 m. Absorption of all carbohydrates returned to normal after return to the UK. This study showed that a decrease in mediated (D-xylose or 3-O-methyl-D-glucose) and diffusional (L-rhamnose) monosaccharide absorption occurs at high altitude but that intestinal permeability at 5,730 m is unchanged.

Travis SP, Jewell DP. 1994. The role of platelet-activating factor in the pathogenesis of gastrointestinal disease. Prostaglandins Leukot Essent Fatty Acids, 50 (3), pp. 105-113. | Read more

Travis SP, Jewell DP. 1994. Salicylates for ulcerative colitis--their mode of action. Pharmacol Ther, 63 (2), pp. 135-161. | Show Abstract | Read more

Delivery of 5-aminosalicylic acid to the colon by sulphasalazine, other azo-bonded compounds and controlled-release preparations is introduced in the context of metabolism by epithelial cells and therapeutic efficacy in ulcerative colitis. Potential modes of action are then reviewed, including actions on luminal bacteria, epithelial cell surface receptors, cellular events (such as nitric oxide release or butyrate oxidation), electrolyte transport and epithelial permeability. Evidence for an influence of salicylates on circulating and lamina propria inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides and inflammatory mediators, such as eicosanoids, platelet-activating factor, cytokines or reactive oxygen metabolites. The precise mechanism will remain uncertain as long as the aetiology of ulcerative colitis is unknown, but a pluripotential mode of action of salicylates is an advantage when influencing the network of events that constitute chronic inflammation.

Travis SP, McGrath JA, Turnbull AJ, Schofield OM, Chan O, O'Connor AF, Mayou B, Eady RA, Thompson RP. 1992. Oral and gastrointestinal manifestations of epidermolysis bullosa. Lancet, 340 (8834-8835), pp. 1505-1506. | Show Abstract | Read more

The mouth, oesophagus, and anus are often involved in dystrophic and junctional epidermolysis bullosa, but the frequency is unknown. Among 246 patients with epidermolysis bullosa, dysphagia developed in 76% of those with recessive dystrophic, in 20% of those with dominant dystrophic, in 15% of those with junctional, and in 2% of those with simplex forms. Lingual adhesions or microstomia occurred in dystrophic epidermolysis bullosa only, but were eight times more common in recessive than in dominant subtypes. These lesions are provoked by the trauma of eating and further reduce food intake, which exacerbates constipation caused by anal blisters and results in malnutrition. Management requires specialised multidisciplinary care.

Travis SP, Jewell DP. 1992. Regional differences in the response to platelet-activating factor in rabbit colon. Clin Sci (Lond), 82 (6), pp. 673-680. | Show Abstract | Read more

1. Platelet-activating factor is an inflammatory mediator related to eicosanoids which is known to stimulate anion secretion in the distal colon. Since there are regional differences in ion transport within the colon, the influence of platelet-activating factors on ion transport and epithelial permeability has been studied in rabbit caecum and distal colon mounted in Ussing chambers. 2. The effect of platelet-activating factor (1-50 nmol/l) on net electrogenic ion transport was to stimulate a biphasic increase in short-circuit current in the distal colon but not in the caecum. The platelet-activating factor-induced rise in short-circuit current was shown by ion replacement and pharmacological inhibitor studies to be consistent with chloride and bicarbonate secretion in the early phase, but with chloride secretion alone in the later phase. The effect on ion transport was specific and reversible and was enhanced by 0.25% BSA. 3. Colonic permeability, assessed by transmucosal resistance and mannitol flux, was increased by platelet-activating factor in both the distal colon and the caecum. This was consistent with an effect on platelet-activating factor on the paracellular pathway, because resistance decreased even when transcellular chloride transport was inhibited by frusemide or ion replacement. A specific platelet-activating factor antagonist (U66985) inhibited the effects of platelet-activating factor in both the distal colon and the caecum. 4. The results show that platelet-activating factor stimulates anion secretion only in the distal colon, but increases permeability in both the caecum and the distal colon.

Travis S, Menzies I. 1992. Intestinal permeability: functional assessment and significance. Clin Sci (Lond), 82 (5), pp. 471-488. | Read more

TRAVIS SPL, CROTTY B, JEWELL DP. 1991. SITE OF PLATELET-ACTIVATING-FACTOR ACTION ON COLONIC MUCOSA GUT, 32 (10), pp. A1234-A1234.

TRAVIS SPL, JEWELL DP. 1991. REGIONAL DIFFERENCES IN COLONIC PERMEABILITY GUT, 32 (10), pp. A1234-A1234.

Travis S. 1991. Treatment of hiccoughs. Lancet, 338 (8765), pp. 520. | Read more

Travis S. 1991. Treatment of hiccoughs The Lancet, 338 (8765), pp. 520. | Read more

Travis SP, Eady RA, Thompson RP. 1991. Oesophageal complications in epidermolysis bullosa. Gut, 32 (12), pp. 1569-1570. | Read more

Bryant RV, Burger DC, Delo J, Walsh AJ, Thomas S, von Herbay A, Buchel OC, White L, Brain O, Keshav S et al. 2016. Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut, 65 (3), pp. 408-414. | Show Abstract | Read more

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, Stanley AJ, Everett SM, Bailey AA, Dallal H et al. 2015. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet, 386 (9989), pp. 137-144. | Show Abstract | Read more

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

Bryant RV, Sandborn WJ, Travis SPL. 2015. Introducing vedolizumab to clinical practice: who, when, and how? J Crohns Colitis, 9 (4), pp. 356-366. | Show Abstract | Read more

Vedolizumab (VDZ), a humanized monoclonal antibody that selectively targets α4β7 integrin, is approved for use in inflammatory bowel disease (IBD). Here we review the evidence for the safety and efficacy of VDZ in IBD, in order to identify patients likely to benefit from therapy and to integrate VDZ into clinical practice. A bibliographic search was performed of the online databases MEDLINE, EMBASE, PubMed, and the Cochrane Library, using the key words 'inflammatory bowel diseases' OR 'ulcerative colitis' OR 'Crohn's disease' AND 'vedolizumab' OR 'MLN0002' OR 'integrin alpha4beta7' OR 'anti-integrin'. Eight-nine articles were returned using the primary search. Eight randomized controlled trials, one Cochrane review, and two network meta-analyses were identified. VDZ is well tolerated with a low rate of adverse events (similar to placebo), and is associated with minimal systemic immunosuppression. VDZ is effective for induction and maintenance of remission in outpatients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) who have failed conventional and anti-tumor necrosis factor (anti-TNF) therapy. VDZ is also a first-line alternative to anti-TNF therapy in UC. The efficacy of VDZ is best assessed at, or beyond, 10 weeks of therapy. The safety, tolerability, and efficacy profile of VDZ place it as a new therapy in IBD, though further trials directly comparing VDZ with other biological agents as well as pragmatic studies to evaluate cost-effectiveness are necessary.

Travis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel J-F, Feagan BG, Hanauer SB, Lichtenstein GR, Marteau PR et al. 2013. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterology, 145 (5), pp. 987-995. | Show Abstract | Read more

BACKGROUND & AIMS: We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. METHODS: We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors ("vascular pattern", "bleeding", and "erosions and ulcers") comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. RESULTS: There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. CONCLUSIONS: The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details.

Travis SPL, Danese S, Kupcinskas L, Alexeeva O, D'Haens G, Gibson PR, Moro L, Jones R, Ballard ED, Masure J et al. 2014. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut, 63 (3), pp. 433-441. | Show Abstract | Read more

OBJECTIVE: Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). DESIGN: Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. RESULTS: 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. CONCLUSION: Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.

Neurath MF, Travis SPL. 2012. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut, 61 (11), pp. 1619-1635. | Show Abstract | Read more

Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted.

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Scopus

Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M et al. 2012. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: Unexpected results of a randomised, double-blindplacebo- controlled trial Gut, 61 (12), pp. 1693-1700. | Show Abstract | Read more

Objective: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. Design: In a double-blind, randomised, placebocontrolled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2x10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (ΔCDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔDCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔDCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Travis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel J-F, Feagan BG, Hanauer SB, Lémann M, Lichtenstein GR et al. 2012. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut, 61 (4), pp. 535-542. | Show Abstract | Read more

BACKGROUND: Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). OBJECTIVE: To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. DESIGN: A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors. RESULTS: There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). CONCLUSION: The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

Travis SPL, Higgins PDR, Orchard T, Van Der Woude CJ, Panaccione R, Bitton A, O'Morain C, Panés J, Sturm A, Reinisch W et al. 2011. Review article: defining remission in ulcerative colitis. Aliment Pharmacol Ther, 34 (2), pp. 113-124. | Show Abstract | Read more

BACKGROUND: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission. AIM: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes. METHODS: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions. RESULTS: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission. CONCLUSIONS: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission.

Burger D, Travis S. 2011. Conventional medical management of inflammatory bowel disease. Gastroenterology, 140 (6), pp. 1827-1837.e2. | Show Abstract | Read more

Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti-tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively.

Turner D, Travis SPL, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, Dubinsky M, Alex G, Baldassano RN, Langer JC et al. 2011. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol, 106 (4), pp. 574-588. | Show Abstract | Read more

OBJECTIVES: Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN. METHODS: A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature. RESULTS: The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points. CONCLUSIONS: These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.

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European Pubmed Central

Travis S, Satsangi J, Lémann M. 2011. Predicting the need for colectomy in severe ulcerative colitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut, 60 (1), pp. 3-9. | Read more

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