Peter Bossuyt

European evidence based consensus for endoscopy in inflammatory bowel disease

Endoscopy plays an essential role in the diagnosis, management, prognosis, and surveillance of inflammatory bowel disease (IBD), but surprisingly there are few available guidelines.1,2 This prompted the ECCO Guidelines Committee (GuiCom) members to promote a Consensus on the appropriate indication and application of different endoscopic modalities in IBD. Since the development of guidelines is an expensive and time-consuming process, this Consensus may help to avoid duplication of effort in the future. It may also identify issues where the evidence is lacking and controlled studies are awaited. The strategy to reach the Consensus involved five steps: 1. Two members of the GuiCom (VA and RE) identified four main topics: a) Diagnosis and follow-up; b) Score of endoscopic activity; c) Small bowel endoscopy; and d) Surveillance. During 2012 a call for participants to the Guideline was made to ECCO members. In addition, expert endoscopists recognised for their active research in the field were invited. Participants were selected by the Guicom and four working groups were created. Each working group had a chair (VA, MD, MT, and RE), two ECCO members including young members (Y-ECCO) and one experienced endoscopist. For the development of the guideline, relevant questions on separate topics were devised by the chairmen and their working parties. The questions were focused on current practice and areas of controversy. Participants of the Consensus process were asked to answer the questions based on evidence from the literature as well as their experience (Delphi procedure)3; 2. The working parties working in parallel performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as other relevant sources; 3. Provisional guideline statements on their topic were then written by the chairmen. These were circulated and commented on first by working party members and …

Increasing incidence of Clostridium difficile -associated diarrhea in inflammatory bowel disease

INTRODUCTION AND AIM Over the last decade a rise in Clostridium difficile-associated diarrhea (CDAD) has been observed. A higher incidence of CDAD has also been suggested in patients with inflammatory bowel disease (IBD), and may be a challenging factor in the differential diagnosis of flares. It is unclear if the increase is caused by the enhanced use of immunosuppressive therapy in IBD. We investigated if CDAD infection is increasing in IBD patients and evaluated outcome and possible predisposing factors. METHODS Through an electronic database of the Laboratory of Microbiology of our hospital (tertiary referral center), all stool samples from patients admitted for diarrhea and hospitalized on gastroenterology wards between January 2000 and January 2008 were reviewed for diagnosis of CDAD. For analysis, we compared two periods of equal duration. RESULTS A total of 57 patients were diagnosed with CDAD, of whom 26.3% had concomitant IBD. A 3.75-fold increase in CDAD was observed between period 1 and period 2, irrespective of underlying IBD and with a comparable total number of analyzed stool samples between both periods. Non-IBD patients were significantly older. Antibiotic use three months prior to the infection was higher in non-IBD (29/42 or 69%) than in IBD patients (6/15 or 42%) (p = 0.047). Nine IBD patients were on concomitant immunomodulators, and this was not different between period 1 and period 2. Most patients had a successful outcome and only one patient with ulcerative colitis needed semi-urgent colectomy. Two patients died in the non-IBD group. The duration of hospital stay was significantly lower in IBD patients. CONCLUSION We observed a significant rise in CDAD in both IBD and non-IBD. The clinical outcome was favorable with only one IBD patient needing semi-urgent colectomy. Because C. difficile can mimic an IBD flare, it is essential that clinicians are vigilant to this complication. The use of immunosuppressive drugs in IBD does not influence the risk.

Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial

BACKGROUND Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohns 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 Crohns 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 Crohns disease (Crohns Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohns 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 Crohns 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 Crohns 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.

Comparison of six different calprotectin assays for the assessment of inflammatory bowel disease

Background and objectives Faecal calprotectin is a valuable noninvasive marker for inflammatory bowel disease (IBD). The aim of our study was to determine the correlation between six different calprotectin assays and compare their performance for diagnosis and follow up of IBD. Methods Thirty-one patients with suspected IBD and 31 patients in follow up were included. We determined calprotectin by means of three rapid immmunochromatographic tests, two enzyme-linked immunosorbent assays, and one automated fluoroimmunoassay. Results were correlated with endoscopic and histological findings. Results Although all methods correlated significantly, slopes and intercepts differed extensively, with up to 5-fold quantitative differences between assays. Sensitivity and specificity for diagnosis of IBD were 82–83 and 84–89%, respectively. For follow up, sensitivity in detecting mild ulcerative colitis was 71–100%. In moderate-to-severe ulcerative colitis, sensitivity was 100% for all assays. Specificity was 67–86% in both subgroups. In Crohn’s disease, only moderate-to-severe disease could be differentiated from remission, with sensitivity 83–86% and specificity 75% for all tests. Conclusions All calprotectin assays showed comparable clinical performance for diagnosis of IBD. For follow up, performance was acceptable, except for mild Crohn’s disease. Because of the large quantitative differences, further efforts are needed to standardize calprotectin assays.

Safety and Feasibility of Using the Second-Generation Pillcam Colon Capsule to Assess Active Colonic Crohn's Disease.

BACKGROUND & AIMS The second-generation Pillcam Colon Capsule Endoscope (PCCE-2; Given Imaging Ltd, Yoqneam, Israel) is an ingestible capsule for visualization of the colon. We performed a multicenter pilot study to assess its safety and feasibility in evaluating the severity of Crohns disease (CD). METHODS In a prospective study, 40 patients with active colonic CD underwent PCCE-2 and optical colonoscopy procedures. Using both techniques, we generated values for the Crohns Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for CD, and global evaluation of lesion severity. In the first stage of the study, we calculated the correlation between PCCE-2 and optical colonoscopy scores. In the second stage, we performed interobserver agreement analysis for a random subset of 20 PCCE-2 recordings, graded in duplicate by 2 independent readers. RESULTS There was substantial agreement between PCCE-2 and optical colonoscopy in the measurement of the CDEIS (intraclass correlation coefficient [ICC], 0.65; 95% confidence interval [CI], 0.43-0.80). There was substantial interobserver agreement between 2 independent PCCE-2 readers for the CDEIS (ICC, 0.67; 95% CI, 0.35-0.86) and the Simple Endoscopic Score for CD (ICC, 0.66; 95% CI, 0.32-0.85). However, the PCCE-2 scoring systematically underestimated the severity of disease compared with optical colonoscopy; based on our results, PCCE-2 detected colonic ulcerations with 86% sensitivity and 40% specificity. No adverse events were observed and PCCE-2 was better tolerated than colonoscopy. CONCLUSIONS PCCE-2 is feasible, safe, and well tolerated for the assessment of mucosal CD activity in selected populations. Larger studies are needed to assess its operating characteristics further. European clinical trials database number: 2014-003854-15.

Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease

ABSTRACT Introduction: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD). Areas covered: Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized. Expert opinion: Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.

Sa1198 Agreement Among Experts in the Endoscopic Evaluation of Postoperative Recurrence in Crohn's Disease Using the Rutgeerts Score

Geboes-Structural 0.70 (0.60 0.79) 0.80 (0.74 0.86) Geboes-Chronic inflammatory infiltrate 0.64 (0.54 0.74) 0.81 (0.75 0.86) Geboes-Lamina propria eosinophils 0.26 (0.18 0.37) 0.59 (0.52 0.66) Geboes & Modified Riley-Lamina propria neutrophils 0.37 (0.27 0.49) 0.59 (0.51 0.68) Modified Riley-Neutrophils in epithelium 0.47 (0.37 0.59) 0.71 (0.64 0.78) Geboes-Crypt destruction 0.34 (0.24 0.47) 0.61 (0.54 0.69) Geboes-Erosion or ulceration 0.56 (0.45 0.67) 0.78 (0.73 0.84)

Development of the IBD Disk: A Visual Self-administered Tool for Assessing Disability in Inflammatory Bowel Diseases.

Background: The Inflammatory bowel disease (IBD) Disability Index is a validated tool that evaluates functional status; however, it is used mainly in the clinical trial setting. We describe the use of an iterative Delphi consensus process to develop the IBD Disk—a shortened, self-administered adaption of the validated IBD Disability Index—to give immediate visual representation of patient-reported IBD-related disability. Methods: In the preparatory phase, the IBD CONNECT group (30 health care professionals) ranked IBD Disability Index items in the perceived order of importance. The Steering Committee then selected 10 items from the IBD Disability Index to take forward for inclusion in the IBD Disk. In the consensus phase, the items were refined and agreed by the IBD Disk Working Group (14 gastroenterologists) using an online iterative Delphi consensus process. Members could also suggest new element(s) or recommend changes to included elements. The final items for the IBD Disk were agreed in February 2016. Results: After 4 rounds of voting, the following 10 items were agreed for inclusion in the IBD Disk: abdominal pain, body image, education and work, emotions, energy, interpersonal interactions, joint pain, regulating defecation, sexual functions, and sleep. All elements, except sexual functions, were included in the validated IBD Disability Index. Conclusions: The IBD Disk has the potential to be a valuable tool for use at a clinical visit. It can facilitate assessment of inflammatory bowel disease-related disability relevant to both patients and physicians, discussion on specific disability-related issues, and tracking changes in disease burden over time.

Cerebrovascular events in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents.

BACKGROUND AND AIMS Cerebrovascular accidents [CVA] have rarely been reported in inflammatory bowel disease [IBD] patients treated with anti-tumour necrosis alpha [anti-TNF alpha] agents. Our aim here was to describe the clinical course of CVA in these patients. METHODS This was a European Crohns and Colitis Organisation [ECCO] retrospective observational study, performed as part of the CONFER [COllaborative Network For Exceptionally Rare case reports] project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNF alpha agents. Clinical data were recorded in a standardised case report form and analysed for event association with anti-TNF alpha treatment. RESULTS A total of 19 patients were identified from 16 centres: 14 had Crohns disease, four ulcerative colitis and one IBD colitis unclassified [median age at diagnosis: 38.0 years, range: 18.6-62.5]. Patients received anti-TNF alpha for a median duration of 11.8 months [range: 0-62] at CVA onset; seven had previously been treated with at least one other anti-TNF alpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNF alpha was discontinued in 16/19 patients. However, recurrent CVA or neurological deterioration was not observed in any of the 11 patients who received anti-TNF alpha after CVA [eight resumed after temporary cessation, three continued without interruption] for a median follow-up of 39.8 months [range: 5.6-98.2]. CONCLUSION These preliminary findings do not unequivocally indicate a causal role of anti-TNF alpha in CVA complicating IBD. Resuming or continuing anti-TNF alpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent.

Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study.

Background: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). Methods: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral—if treated with antivirals alone; combined—if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. Results: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. Conclusions: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.