Search

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

Background Patients with Crohn disease have debilitating psychological symptoms, mental fatigue, and poor quality of life. Psychological intervention may improve these symptoms. Methods We performed a randomized parallel-group physician-blinded trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) on quality of life and psychological symptoms in adults with mild-moderate Crohn disease. COBMINDEX was taught by social workers in one-on-one video conferences over 3 months; quotidian home practice was mandated. Results Fifty-five COBMINDEX and 61 waitlist control patients completed the study; mean age was 33 years and 65% of participants were women. At 3 months, COBMINDEX patients had significantly reduced disease activity (per Harvey-Bradshaw Index score, C-reactive protein level, and calprotectin level), increased quality of life (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score increased from baseline 41 to 50; P P Conclusions COBMINDEX was effective in increasing patients’ quality of life and reducing psychological symptoms and fatigue. Patients with severe baseline psychological symptoms benefited the most from COBMINDEX.

Background and Aims Capsule endoscopy (CE) is an important modality for Crohn's disease (CD) diagnosis and follow-up. Endoscopic severity of ulcers is of much significance for prediction of CD course. Deep learning has been proven accurate in detecting ulcers on CE. However, endoscopic classification of ulcers by deep learning has not been attempted. The aim of our study was to develop a deep learning algorithm for the automated grading of CD ulcers on CE. Methods We retrospectively collected CE images of CD ulcers from our CE database. In experiment 1, each ulcer severity was graded by 2 capsule readers based on PillCam CD classification (grade 1-3 from mild to severe), and the inter-reader variability was evaluated. In experiment 2, a consensus reading by 3 capsule readers was used to train an ordinal convolutional neural network (CNN) to automatically grade images of ulcers, and the resulting algorithm was tested against consensus reading. A pretraining stage included training the network on images of normal mucosa and ulcerated mucosa. Results Overall, our dataset included 17,640 CE images from 49 patients; 7391 images with mucosal ulcers and 10,249 normal images. A total of 2598 randomly picked pathological images were further graded from 1 to 3 according to the ulcer severity in the 2 different experiments. In experiment 1, the overall inter-reader agreement occurred in 31% of the images (345/1108). When, and for distinction of grade 1 and 3 - 76% (752/989). In experiment 2, the algorithm was trained on 1242 images. It achieved an overall agreement to consensus reading of 67% (166/248), and 91% (158/173) for distinction of grade 1 and 3. When testing for classification accuracy, the algorithm performance was 0.91 (95% CI, 0.867 - 0.954) for grade 1 versus grade 3 ulcers, 0.78 (95% CI, 0.716-0.844) for 2 versus 3 and 0.624 (95% CI, 0.547-0.701) for 1 versus 2. Conclusions CNN achieved high accuracy in detection of severe CD ulcerations. CNN-assisted CE reading in CD patients can potentially facilitate and improve diagnosis and monitoring these patients.

Main recommendations1. ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia. Strong recommendation, high quality evidence. ESGE/ESGAR do not recommend barium enema in this setting. Strong recommendation, high quality evidence.2. ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. The timing depends on an interdisciplinary decision including endoscopic and radiological factors. Strong recommendation, low quality evidence. ESGE/ESGAR suggests that, in centers with expertise in and availability of colon capsule endoscopy (CCE), CCE preferably the same or the next day may be considered if colonoscopy is incomplete. Weak recommendation, low quality evidence.3. When colonoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with alarm symptoms. Strong recommendation, high quality evidence. Because of lack of direct evidence, ESGE/ESGAR do not recommend CCE in this situation. Very low quality evidence. ESGE/ESGAR recommend CTC as an acceptable alternative to colonoscopy for patients with non-alarm symptoms. Strong recommendation, high quality evidence. In centers with availability, ESGE/ESGAR suggests that CCE may be considered in patients with non-alarm symptoms. Weak recommendation, low quality evidence.4. Where there is no organized fecal immunochemical test (FIT)-based population colorectal screening program, ESGE/ESGAR recommend CTC as an option for colorectal cancer screening, providing the screenee is adequately informed about test characteristics, benefits, and risks, and depending on local service- and patient-related factors. Strong recommendation, high quality evidence. ESGE/ESGAR do not suggest CCE as a first-line screening test for colorectal cancer. Weak recommendation, low quality evidence.5. ESGE/ESGAR recommend CTC in the case of a positive fecal occult blood test (FOBT) or FIT with incomplete or unfeasible colonoscopy, within organized population screening programs. Strong recommendation, moderate quality evidence. ESGE/ESGAR also suggest the use of CCE in this setting based on availability. Weak recommendation, moderate quality evidence.6. ESGE/ESGAR suggest CTC with intravenous contrast medium injection for surveillance after curative-intent resection of colorectal cancer only in patients in whom colonoscopy is contraindicated or unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in this setting. Very low quality evidence.7. ESGE/ESGAR suggest CTC in patients with high risk polyps undergoing surveillance after polypectomy only when colonoscopy is unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in post-polypectomy surveillance. Very low quality evidence.8. ESGE/ESGAR recommend against CTC in patients with acute colonic inflammation and in those who have recently undergone colorectal surgery, pending a multidisciplinary evaluation. Strong recommendation, low quality evidence. 9. ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp >= 6 mm detected at CTC or CCE. Follow-up CTC may be clinically considered for 6-9-mm CTC-detected lesions if patients do not undergo polypectomy because of patient choice, comorbidity, and/or low risk profile for advanced neoplasia. Strong recommendation, moderate quality evidence.Source and scopeThis is an update of the 2014-15 Guideline of the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR). It addresses the clinical indications for the use of imaging alternatives to standard colonoscopy. A targeted literature search was performed to evaluate the evidence supporting the use of computed tomographic colonography (CTC) or colon capsule endoscopy (CCE). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence.

Background and Aims Passable intestinal strictures are frequently detected on capsule endoscopy [CE]. Such strictures are a major component of inflammatory scores. Deep neural network technology for CE is emerging. However, the ability of deep neural networks to identify intestinal strictures on CE images of Crohn’s disease [CD] patients has not yet been evaluated. Methods We tested a state-of-the-art deep learning network for detecting CE images of strictures. Images of normal mucosa, mucosal ulcers, and strictures of Crohn’s disease patients were retrieved from our previously described CE image bank. Ulcers were classified as per degree of severity. We performed 10 cross-validation experiments. A clear patient-level separation was maintained between training and testing sets. Results Overall, the entire dataset included 27 892 CE images: 1942 stricture images, 14 266 normal mucosa images, and 11 684 ulcer images [mild: 7075, moderate: 2386, severe: 2223]. For classifying strictures versus non-strictures, the network exhibited an average accuracy of 93.5% [±6.7%]. The network achieved excellent differentiation between strictures and normal mucosa (area under the curve [AUC] 0.989), strictures and all ulcers [AUC 0.942], and between strictures and different grades of ulcers [for mild, moderate, and severe ulcers—AUCs 0.992, 0.975, and 0.889, respectively]. Conclusions Deep neural networks are highly accurate in the detection of strictures on CE images in Crohn’s disease. The network can accurately separate strictures from ulcers across the severity range. The current accuracy for the detection of ulcers and strictures by deep neural networks may allow for automated detection and grading of Crohn’s disease-related findings on CE.

Background Mucosal healing has been associated with long-term response to therapy for Crohn disease (CD). However, little is known about the significance of terminal ileum (TI) transmural thickness in predicting clinical outcomes. Methods In this retrospective observational cohort study, we examined the association of an index ultrasonographic assessment of TI thickness during the maintenance phase and the subsequent clinical outcome of CD in a cohort of patients treated with infliximab (IFX). Treatment failure was defined as treatment discontinuation because of lack of efficacy, a need for dose escalation, or surgery. Clinical response was defined as treatment continuation in the absence of any of the aforementioned failure criteria. Results Sixty patients with CD receiving IFX therapy were included in the study. The patients were followed for a median of 16 months (5-24 months) after an index intestinal ultrasound. Thirty-eight patients (63.3%) maintained response to the therapy and 22 patients (36.6%) failed the treatment, with a mean follow up of 10.5 months (6.5-17 months) vs 9.25 months (1-10.25 months), respectively. On univariate analysis, the only variables differing between treatment response and failure were a TI thickness of 2.8 vs 5 mm (P < 0.0001) and an IFX trough level of 6.6 vs 3.9 µg/mL (P = 0.008). On multivariable analysis, only a small bowel thickness of ≥4 mm was associated with the risk of treatment failure (odds ratio, 2.9; 95% CI, 1.49-5.55; P = 0.002). Conclusions Our findings suggest that transmural thickness of ≥4 mm can predict subsequent treatment failure in patients with CD treated using IFX, indicating transmural thickness

Background Immunomodulators and anti tumor-necrosis-α antibodies (anti-TNFs) have been implicated in increased risk of Epstein–Barr virus (EBV)–driven B-cell lymphoproliferative disorders in inflammatory bowel disease (IBD) patients. However, the underlying mechanisms are poorly understood. Methods An in-vitro model of lymphoblastoid cell line (LCL) was established by co-incubation of EBV-infected human peripheral blood mononuclear cells (PBMC) with Cyclosporin-A (CSA). After 4 weeks, the resultant LCLs were analyzed by flow cytometry, telomerase activity assay, and next generation sequencing. Subsequently, LCLs were explored in the presence of therapeutic agents for IBD (anti-TNFs, vedolizumab, 6-Mercaptopurine [6MP], methotrexate). Epstein–Barr virus titers were quantitated by real-time polymerase chain reaction. Results In cultures of PBMC with EBV and CSA, LCLs were characterized as an expanded, long lived population of CD58+CD23hi B-cells with high telomerase activity and clonal expansion. Upon addition to the cell cultures, LCL percentages were higher with infliximab (median 19.21%, P = 0.011), adalimumab (median 19.85%, P = 0.003), and early washed-out 6MP (median 30.57%, P = 0.043) compared with PBMC with EBV alone (median 9.61%). However, vedolizumab had no such effect (median 8.97%; P = 0.435). Additionally, LCL expansion was accompanied by increase in intracellular, rather than extracellular, EBV viral copies. Compared with PBMC with EBV alone, high levels of LCL were subsequently observed after triple depletion of NK cells, CD4+ T cells, and CD8+ T cells (median 52.8% vs 16.4%; P = 0.046) but also in cultures depleted solely of CD4+ T cells (median 30.7%, P = 0.046). Conclusions These results suggest that both anti-TNFs and 6MP, but not vedolizumab, propagate EBV-driven lymphoblastoid transformation in an in vitro model of lymphoma. This model may prove useful for studying mechanisms underlying proneoplastic viral immune interactions of novel drugs in IBD therapy.

Extra-intestinal manifestations (EIM) are common in inflammatory bowel diseases (IBD) and may affect up to 40% of the patients during the course of the disease. Peripheral arthralgia (PA) is by far the most common EIM. To date, TNFα inhibitors are the most established treatment for EIMs in IBD. Infliximab (IFX) trough levels (TL) and anti-IFX antibodies (ATI) are correlated with multiple outcomes in IBD such as clinical response and remission, mucosal healing, fistular healing, and more. So far, a correlation between PA and IFX TL\ATI has not been evaluated. This retrospective study included IBD patients followed by the gastroenterology department of Sheba Medical Center. Patients with active PA at onset of IFX treatment were included. IFX TL and ATI were evaluated at week 6, 14, and 26 and correlated with PA persistence. Forty patients (37 Crohn’s and 3 ulcerative colitis) with IBD-related PA were included. The overall prevalence of PA was 55% (22/40), 42.5% (17/40), and 55% (22/40) after 6, 14, and 26 weeks, respectively. IFX trough drug levels were not associated with reported PA at week 6 [median, 11.8 μg/ml (IQR 6.6–15.5) vs 10.05 μg/ml (IQR 7.35–12.87), p = 0.56], week 14 [median, 4.7 μg/ml (IQR 2.3–7) vs 3.1 μg/ml (IQR 1.35–7.35), p = 0.55], and week 26 [median, 3 μg/ml (IQR 1.15–5.17) vs 3.4 μg/ml (IQR 0.13–6.75), p = 0.94]. Detectable ATI were significantly more prevalent in patients with PA than in patients without PA at week 26 [11/22 (50%) vs 3/18 (16.7%), p = 0.028]. In patients with IBD-related PA, ATI are associated with an increased risk of persistence of PA. No direct correlation was demonstrated between IFX TL and persistence of PA.

Patients with Crohn’s disease, an inflammatory bowel disease, struggle with chronic somatic symptoms that could bring about emotional distress. This study assessed the relative role of somatization, and depressive and anxiety symptoms in disease activity among 619 Crohn’s patients (18–79 years; 58.3% women). Structural equation modeling revealed that somatization was the only unique predictor of disease activity beyond depression and anxiety. In addition, the effect of somatization on disease activity was stronger in men compared to women. Findings suggest that somatization represents a distinct domain of psychological distress that may play a role in the health of patients with Crohn’s disease.

BACKGROUND: In Crohn's disease, higher adalimumab trough levels and negative anti-adalimumab-antibodies associate with better clinical and endoscopic outcomes. Intestinal ultrasound has become a relevant non-invasive method to monitor treatment. However, data on the association between adalimumab levels and bowel wall thickness measured with ultrasound is limited. OBJECTIVE: The purpose of this study was to examine the possible association between the sonographic transmural-thickness and adalimumab trough levels. METHODS: This prospective observational cohort study was conducted at Sheba Medical Center in 2014–2018. Crohn's disease patients on adalimumab maintenance therapy with intestinal ultrasound performed within

Background: The main factor that limits wider utilization of capsule endoscopy (CE) in Crohn's disease (CD) is the potential risk of retention. The aim of this systematic review was to evaluate capsule retention rates in adult and pediatric CD and determine if retention risk is reduced in established CD (ECD) with patency capsule (PC) or magnetic resonance/computed tomography (MR/CT) enterography. Methods: Studies of CD patients undergoing CE that reported retention were identified. Pooled estimates for retention rates and relative risk in ECD to suspected CD (SCD) were calculated. All hypothesis tests were 2-sided; statistical significance was set at a P value of

Infliximab and vedolizumab are effective treatments for inflammatory bowel disease (IBD), although associated with adverse events (AE). While low or non-existent drug levels and positive antidrug antibodies have been associated with therapeutic failure, there is no clear association between higher drug levels and AE. A cross-sectional study consisting of Crohn’s disease (CD) and ulcerative colitis (UC) patients receiving infliximab or vedolizumab at the Sheba Medical Center was performed. Patients completed a questionnaire regarding AEs related to biological therapy. Serum trough levels obtained on the same day were analyzed. Objective measures of outcomes were retrieved from medical records. Questionnaires were completed by infliximab (n = 169) and vedolizumab (n = 88)-treated therapy patients. Higher infliximab levels were only numerically associated with the occurrence of at least one AE (p = 0.08). When excluding fatigue and abdominal pain, higher infliximab levels were statistically associated with the occurrence of at least one AE (p = 0.03). Vedolizumab drug levels &gt, 18μg/mL were also linked with the occurrence of more AEs. No specific association was observed between the increased levels of either infliximab or vedolizumab and specific AEs (neurological symptoms, upper GI symptoms, infectious complications, and musculoskeletal symptoms). As significant AEs are very rare, additional multi-center studies are required.

Background and Study Aims: Deep learning (DL) for video capsule endoscopy (VCE) is an emerging research field. It has shown high accuracy for the detection of Crohn's disease (CD) ulcers. Non-steroidal anti-inflammatory drugs (NSAIDS) are commonly used medications. In the small bowel, NSAIDs may cause a variety of gastrointestinal adverse events including NSAID-induced ulcers. These ulcers are the most important differential diagnosis for small bowel ulcers in patients evaluated for suspected CD. We evaluated a DL network that was trained using CD VCE ulcer images and evaluated its performance for NSAID ulcers.Patients and Methods: The network was trained using CD ulcers and normal mucosa from a large image bank created from VCE of diagnosed CD patients. NSAIDs-induced enteropathy images were extracted from the prospective Bifidobacterium breve (BIf95) trial dataset. All images were acquired from studies performed using PillCam SBIII. The area under the receiver operating curve (AUC) was used as a metric. We compared the network's AUC for detecting NSAID ulcers to that of detecting CD ulcers.Results: Overall, the CD training dataset included 17,640 CE images. The NSAIDs testing dataset included 1,605 CE images. The DL network exhibited an AUC of 0.97 (95% CI 0.97–0.98) for identifying images with NSAID mucosal ulcers. The diagnostic accuracy was similar to that obtained for CD related ulcers (AUC 0.94–0.99).Conclusions: A network trained on VCE CD ulcers similarly identified NSAID findings. As deep learning is transforming gastrointestinal endoscopy, this result should be taken into consideration in the future design and analysis of VCE deep learning applications.

Background Ustekinumab [UST] is effective in Crohn’s disease (CD) in the UNITI studies. Several real-world experience (RWE) studies with UST have been published to date. Our aim was to summarize the available RWE data for UST effectiveness and safety. Methods A systematic review of the available RWE studies of UST for CD and pooled analysis of the available effectiveness and safety data was performed. Results Eight relevant studies of 6 RWE were included for analysis. Data from 578 patients were pooled for analysis. Most patients (97.7%) were anti-TNF experienced. Pooled clinical response rate was 60%, 62%, 49% at 12, 24 and 52 weeks respectively (95% CI (0.42–0.77), (0.48–0.75), (0.37–0.62)). Pooled remission rate was 39% (95% CI (0.18–0.65)) at 24 weeks and pooled endoscopic response rate was 63% (95% CI (0.53–0.72)) after approximately one year of UST; 134 adverse events (AE) were reported in total, pooled proportion 21% (95% CI (0.12–0.35)). Serious AE were reported in 19 patients, pooled proportion 5% (95% CI (0.03–0.08)). Infections were reported in 38, pooled proportion 6% (95% CI (0.04–0.11)). Conclusion Pooled analysis of the RWE data suggests that the real-world effectiveness and safety are comparable to that reported in the randomized control trials.

Background and study aims Nomenclature and descriptions of small bowel (SB) vascular lesions in capsule endoscopy (CE) are scarce in the medical literature. They are mostly based on the reader's opinion and thus differ between experts, with a potential negative impact on clinical care, teaching and research regarding SBCE. Our aim was to better define a nomenclature and to give a description of the most frequent vascular lesions in SBCE. Methods A panel of 18 European expert SBCE readers was formed during the UEGW 2016 meeting. Three experts constructed an Internet-based four-round Delphi consensus, but did not participate in the voting process. They built questionnaires that included various still frames of vascular lesions obtained with a third-generation SBCE system. The 15 remaining participants were asked to rate different proposals and description of the most common SB vascular lesions. A 6-point rating scale (varying from ‘strongly disagree’ to ‘strongly agree’) was used successive rounds. The consensus was reached when at least 80 % voting members scored the statement within the ‘agree’ or ‘strongly agree’. Results Consensual terms and descriptions were reached for angiectasia/angiodysplasia, erythematous patch, red spot/dot, and phlebectasia. A consensual description was reached for more subtle vascular lesions tentatively named “diminutive angiectasia” but no consensus was reached for this term. Conclusion An international group has reached a consensus on the nomenclature and descriptions of the most frequent and relevant SB vascular lesions in CE. These terms and descriptions are useful in daily practice, for teaching and for medical research purposes.

ispartof: JOURNAL OF CROHNS & COLITIS vol:13 issue:2 pages:144-+ ispartof: location:England status: published

Background Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. Methods A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. Results A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations. Conclusions These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab’s immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.

Background and aimAlthough recommended, the P-score used for assessing the pertinence / relevance of findings seen in small bowel (SB) capsule endoscopy (CE) is based on a low level of knowledge. The aim of this study was to evaluate the clinical relevance of the most frequent SBCE findings through an illustrated script questionnaire.Materials and MethodsSixteen types of SBCE findings were illustrated four times each in three different settings (occult and overt obscure gastrointestinal bleeding and suspected Crohn's disease), and with a variable number (n = 1/n = 2–5/n ≥ 6), thus providing a questionnaire with 192 scenarios and 576 illustrated questions. Fifteen international experts were asked to rate the finding's relevance for each question as very unlikely (−2) / unlikely (−1) / doubtful (0) / likely (+1) / very likely (+2). The median score (≤−0.75, between -0.75 and 0.75, or ≥0.75) obtained for each scenario determined a low (P0), intermediate (P1) or high (P2) relevance, respectively.Results8064 answers were analyzed. Participation and completion rates were 93% and 100%, respectively. In overt or occult OGIB, resultant P2 findings were 'typical angiectasia', 'deep ulceration', 'stenosis', and'blood', whatever their numbers, and 'superficial ulcerations' when multiple. While in suspected CD, consensus P2 lesions were 'deep ulceration' and 'stenosis' whatever their numbers, and 'aphthoid erosions' and 'superficial ulcerations' when multiple.ConclusionThis study establishes a guide for the evaluation of relevance of SBCE findings. It represents a step forward for SB-CE interpretation and is intended to be used as a tool for teaching and academic research.

Background Endoscopically defined mucosal healing in Crohn's disease is associated with improved outcomes. Panenteric capsule endoscopy enables a single non‐invasive assessment of small and large bowel mucosal inflammation. Aims and Methods This multicentre observational study of patients with suspected and established Crohn's disease examined the feasibility, safety and impact on patient outcomes of panenteric capsule endoscopy in routine clinical practice. The potential role in assessment of disease severity and extent by a comparison with existing clinical and biochemical markers is examined. Results Panenteric capsule endoscopy was performed on 93 patients (71 with established and 22 with suspected Crohn's disease). A complete examination occurred in 85% (79/93). Two cases (2.8%) of capsule retention occurred in patients with established Crohn's disease. Panenteric capsule resulted in management change in 38.7% (36/93) patients, including 64.6% (32/48) of those with an established diagnosis whose disease was active, and all three patients with newly diagnosed Crohn's disease. Montreal classification was upstaged in 33.8% of patients with established Crohn's disease and mucosal healing was demonstrated in 15.5%. Proximal small bowel disease upstaged disease in 12.7% and predicted escalation of therapy (odds ratio 40.3, 95% confidence interval 3.6–450.2). Raised C‐reactive protein and faecal calprotectin were poorly sensitive in detecting active disease (0.48 and 0.59 respectively). Conclusions Panenteric capsule endoscopy was feasible in routine practice and the ability to detect proximal small bowel disease may allow better estimation of prognosis and guide treatment intensification. Panenteric capsule endoscopy may be a suitable non‐invasive endoscopic investigation in determining disease activity and supporting management decisions., Key Summary Summarise the established knowledge on this subject Biochemical and clinical markers poorly predict active disease and need for treatment escalation;Panenteric capsule endoscope is feasible, safe and has the potential to non‐invasively assess patients with Crohn's Disease. What are the significant and/or new findings of this study? Panenteric capsule endoscope can upstage disease in one‐third of patients with a threefold increase in the identification of proximal small bowel disease;Identification of proximal small bowel disease predicted treatment intensification.

Background There are currently no nationwide data on the epidemiology of inflammatory bowel diseases (IBD) in Israel. We aimed to determine the population-based epidemiological trends of IBD in the diverse Israeli population. Methods Health-administrative data were retrieved from all 4 Israeli health maintenance organizations, insuring 98% of the population, using validated identification algorithms. National trends were determined using Joinpoint regression analysis calculating annual percent change and average annual percent change (AAPC). Results By 2019, there were 46,074 patients with IBD in Israel, corresponding to a national prevalence of 519/100,000 (0.52%), of whom 54.1% had Crohn disease (CD) and 45.9% had ulcerative colitis (UC). The number of Jewish patients doubled from 18,701 in 2005 (354/100,000) to 38,950 (589/100,000) in 2018 (AAPC, +4.0%; P < 0.05), and the number of Arab patients increased 3-fold from 1096 (102.1/100,000) to 3534 (240.7/100,000; AAPC, +6.8%; P < 0.05) during the same years. However, the increase rate has gradually decelerated over time (annual percent change during 2005-2008, 2009-2014, and 2005-2018 was +6.7%, +4.2%, and +2.3%, respectively; P < 0.05). Pediatric prevalence increased from 37.4 to 52.2/100,000, with CD predominating in both Jews and Arabs. The incidence of CD remained stable (from 15.9/100,000 to 14.9/100,000) and the incidence of UC decreased (15.4/100,000 to 10.5/100,000 (AAPC, –3.2%; P < 0.001)). In contrast, pediatric incidence of CD increased from 7.3/100,000 to 8.3/100,000 (AAPC, +1.9%; P < 0.05) and that of UC increased from 2.6 to 4.4/100,000 (AAPC, +5.8%; P < 0.05). Conclusions The IBD prevalence rate in Israel is still increasing but gradually decelerating, probably due to the decreasing overall IBD incidence. Nonetheless, incidence rate in children is still increasing. Ongoing narrowing in the rates between Jews and Arabs over time may indicate shared environmental factors.

INTRODUCTION: Capsule endoscopy is an important modality for monitoring of Crohn’s disease. Recently, a novel panenteric capsule, PillCam Crohn’s (Medtronic, USA), was approved for use. No quantitative index of inflammation for this method is currently available. This sub-study of a prospective randomized controlled Comprehensive individUalized pRoactive ThErapy of Crohn’s Disease trial (CURE-CD) which aimed to compare the correlation and reliability of the novel PillCam Crohn’s score with the existing small bowel capsule Lewis inflammatory score. METHODS: The study cohort included Crohn’s disease patients in remission who were evaluated with PillCam Crohn’s. Each result was independently reviewed by two experienced readers. Inflammation was scored in all studies using Lewis inflammatory score and PillCam Crohn’s score (comprised of a sum of scores for most common and most severe lesions multiplied by percentage of segmental involvement + stricture score). RESULTS: Fifty-four PillCam Crohn’s studies from 41 patients were included. The median Lewis inflammatory score was 225 for both readers. The median PillCam Crohn’s score was six (0–14) and four (3–15) for readers 1 and 2, respectively. There was a high inter-rater reliability coefficient between the two readers for Lewis inflammatory and PillCam Crohn’s score (0.9, p

Background: In the medical literature, the nomenclature and descriptions (ND) of small bowel (SB) ulcerative and inflammatory (U-I) lesions in capsule endoscopy (CE) are scarce and inconsistent. Inter-observer variability in interpreting these findings remains a major limitation in the assessment of the severity of mucosal lesions, which can impact negatively on clinical care, training and research on SB-CE. Objective: Focusing on SB-CE in Crohn’s disease (CD), our aim is to establish a consensus on the ND of U-I lesions. Methods: An international panel of experienced SB-CE readers was formed during the 2016 United European Gastroenterology Week meeting. A core group of five CE and inflammatory bowel disease (IBD) experts established an Internet-based, three-round Delphi consensus but did not participate in the voting process. The core group built illustrated questionnaires, including SB-CE still frames of U-I lesions from patients with documented CD. Twenty-seven other experts were asked to rate and comment on the different proposals for the ND of the most frequent SB U-I lesions. For each round, we used a 6-point rating scale (varying from ‘strongly disagree’ to ‘strongly agree’). The consensus was reached when at least 80 % of the voting members scored the statement within the ‘agree’ or ‘strongly agree’ categories. Results: A 100% participation rate was obtained for all the rounds. Consensual ND were reached for the following seven U-I lesions: aphthoid erosion, deep ulceration, superficial ulceration, stenosis, edema, hyperemia and denudation. Conclusion: Considering the most frequent SB U-I lesions seen in CE in CD, a consensual ND was reached by the international group of experts. These descriptions and names are useful not only for daily practice and medical education, but also for medical research.

INTRODUCTION: Ustekinumab is an effective treatment of Crohn’s disease (CD). Real-world data addressing the efficacy and safety of ustekinumab are scarce. AIM: Our aim was to assess the safety and efficacy of ustekinumab in a large national patient cohort. METHODS: A prospective multicenter study, in which we followed patients with active CD treated with ustekinumab for 24 weeks. Induction dose was intravenous ranging from 260 to 520 mg, according to body weight, followed by 90 mg doses given subcutaneously every 8 weeks. Clinical response was defined as a reduction of at least 1 severity category, as defined by Harvey–Bradshaw index (HBI). Patients with HBI

Current guidelines state that systemic inflammation, together with endothelial dysfunction, calcification, and hypercoagulability, predispose to premature atherosclerosis in patients with inflammatory bowel disease (IBD). We assessed whether IBD can affect aortic stiffness, a well-recognized vascular biomarker and an independent risk factor for cardiovascular (CV) disease (CVD) in several populations. Recent studies reported that aortic stiffness is increased in adults with IBD compared with matched controls. This association is dependent on inflammatory burden and disease duration, and is reduced by antitumor necrosis factor therapy. Considered together, current findings suggest that increased aortic stiffness is an extraintestinal manifestation of IBD. This is clinically relevant since measuring aortic stiffness in patients with IBD could improve risk assessment, especially in those without established CVD. Moreover, effective control of inflammation could lower CV risk in patients with IBD by reducing aortic stiffness. Further longitudinal studies are needed to better clarify (i) the relationship between disease duration and irreversible changes of the arterial wall, (ii) the clinical characteristics of patients with IBD that have an increased arterial stiffness at least in part reversible, and (iii) whether arterial stiffness is useful to evaluate the efficacy of immunosuppressive therapy.

Mira Y Friedman,1,2 Maya Leventer-Roberts,3 Joseph Rosenblum,4 Nir Zigman,4 Iris Goren,4 Vered Mourad,4 Natan Lederman,5 Nurit Cohen,5 Eran Matz,6 Doron Z Dushnitzky,6 Nirit Borovsky,6 Moshe B Hoshen,3 Gili Focht,1 Malka Avitzour,1 Yael Shachar,1 Yehuda Chowers,7 Rami Eliakim,8 Shomron Ben-Horin,8 Shmuel Odes,9 Doron Schwartz,9 Iris Dotan,10 Eran Israeli,11 Zohar Levi,10 Eric I Benchimol,12–14 Ran D Balicer,3 Dan Turner1 On behalf of the Israeli IBD Research Nucleus (IIRN) 1The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; 2Braun School of Public and Community Medicine, The Hebrew University– Hadassah Medical Center, Jerusalem, Israel; 3Clalit Research Institute, Chief’s Office, Clalit Health Services, Tel Aviv, Israel; 4Maccabi Healthcare Services, Tel Aviv, Israel; 5Meuhedet Health Services, Tel Aviv, Israel; 6Leumit Health Services, Tel Aviv, Israel; 7Department of Gastroenterology, Rambam Health Care Campus, Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel; 8Department of Gastroenterology, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 9Department of Gastroenterology and Hepatology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel; 10Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel; 11Institute of Gastroenterology and Liver Diseases, Hadassah Medical Center, Hebrew University, Jerusalem, Israel; 12CHEO Inflammatory Bowel Disease Centre, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; 13Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada; 14Institute for Clinical Evaluative Sciences, Ottawa, ON, Canada Background: Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn’s disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. Methods: Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. Results: The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2–5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). Conclusion: The application of the validated algorithms to Israel’s administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies. Keywords: inflammatory bowel diseases, Crohn’s disease, ulcerative colitis, search algorithms, validation, case ascertainment, Israel, administrative database research

Distinguishing between fibrotic and inflammatory strictures in Crohn’s disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD. Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation. A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (

Background Several studies have reported the surgical outcomes of inflammatory bowel disease (IBD) patients exposed to vedolizumab (VDZ) preoperatively, with conflicting results. This meta-analysis aims to evaluate the risk of postoperative complications in IBD patients preoperatively exposed to VDZ in comparison with patients exposed to anti-tumor necrosis factor (anti-TNF) treatment or no biologic therapy. Methods A systematic review with a meta-analysis of the existing literature was conducted. The main outcomes included the odds of developing overall postoperative complications, infectious complications, surgical site infections, need for repeat surgery, and major postoperative complications, as defined by the Clavien-Dindo criteria. Results Four studies were included in the meta-analysis. The risk of all postoperative complications was not significantly different between IBD patients exposed preoperatively to VDZ vs anti-TNFs (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.21-1.88). In patients with ulcerative colitis (UC), the OR for complications was significantly lower in VDZ-exposed as opposed to anti-TNF-exposed patients (OR, 0.35; 95% CI, 0.14-0.85); the comparison was insignificant in Crohn's disease. There were no significant differences in the risk of infectious complications, surgical site infections, need for reoperation, or major surgical complications in patients exposed to VDZ vs anti-TNFs. There were no significant differences in outcomes when comparing patients exposed to VDZ with those not given biologic therapy. Conclusions This meta-analysis did not detect an increased risk of postoperative complications with preoperative VDZ exposure; the risk of overall complications may be lower in UC patients in comparison with those with anti-TNF exposure. These results merit further verification in future studies.

Background and aims Capsule endoscopy [CE] and magnetic resonance enterography [MRE] are prime modalities for evaluation of the small bowel in Crohn's disease [CD]. Detection of proximal small bowel [SB] inflammation in CD by MRE is challenging. Currently available quantitative MRE scores do not incorporate proximal SB data. The MRE global score [MEGS] was designed for quantitative evaluation of the entire digestive tract; its accuracy in the proximal SB has not previously been evaluated. This study compared the evaluation of the small bowel inflammation by MEGS and CE-derived quantitative score (the Lewis score[LS]). Methods CD patients in stable clinical remission were prospectively recruited and underwent MRE and CE; faecal calprotectin [FC] levels were obtained. MEGS was calculated for each SB segment and the entire SB [SBMEGS]. SB inflammation on CE was quantified using LS. A cumulative Lewis score [C-LS] was calculated based on summation of three tertiles scores. Results Fifty patients were included. There was a significant correlation of SBMEGS with LS and C-LS [r = 0.61 and 0.71, both p = 0.001]. The correlation with FC was stronger for MEGS than for LS or C-LS [r = 0.68 vs r = 0.46 vs r = 0.53, all p = 0.001]. The correlation between the proximal LS and MEGS was significant [r = 0.55, p = 0.001]; median MEGS was significantly different in patients, with LS values consistent with mucosal healing, mild and moderate-to-severe inflammation. Conclusions MEGS provides accurate evaluation of the SB and strongly correlates with FC; the main advantage of MEGS is the accurate quantification of proximal SB inflammation unavailable for alternative MRE scores.

BACKGROUND Certain Enterobacteriaceae strains have been associated with the development of ulcerative colitis (UC). Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are the most commonly found multi-drug-resistant (MDR) bacteria colonizing the gut in UC patients and might trigger a more severe disease activity in UC patients. OBJECTIVE The aim of this study was to evaluate whether disease activity is higher in UC patients with gut colonization with ESBL-producing Enterobacteriaceae. MATERIALS AND METHODS A cross-sectional, pilot study was carried out in a tertiary medical center in Latvia. Demographic data were collected; UC disease activity and extent were evaluated according to the full Mayo score, Montreal classification, and adapted Truelove and Witt's index. Rectal swabs with fecal biomaterial were collected, ESBL-producing Enterobacteriaceae were isolated, and bacterial plasmid genes responsible for ESBL production, blaCTX-M, blaTEM, and blaSHV, were detected. UC disease activity was compared in patients with and without gut colonization with ESBL-producing Enterobacteriaceae. RESULTS A total of 65 patients with UC were included in the initial analysis. Gut colonization with ESBL-producing Enterobacteriaceae was found in seven (11%) patients - mostly Escherichia coli [5 (71%)] containing the blaCTX-M bacterial plasmid gene. Patients with gut colonization with ESBL-producing Enterobacteriaceae had more severe disease compared with patients without gut colonization according to the full Mayo score (5.86 vs. 3.40; P=0.015), Montreal classification (moderate disease vs. clinical remission; P=0.031), and adapted Truelove and Witt's index (moderate disease vs. mild disease; P=0.008). CONCLUSION Gut colonization with ESBL-producing Enterobacteriaceae may increase UC disease activity. Further research is needed to analyze the possible confounding factors that could contribute toward this outcome.

Background Anastomotic recurrence is frequent in patients with Crohn’s disease (CD) following ileocecal resection. The degree of endoscopic recurrence, quantified by the Rutgeerts score (RS), is correlated with the risk of clinical and surgical recurrence. Noninvasive modalities such as capsule endoscopy (CE), magnetic resonance enterography (MRE), and intestinal ultrasound (US) may yield similar information without the need for ileocolonoscopy (IC). The aim of our meta-analysis was to evaluate the accuracy of those modalities for detection of endoscopic recurrence in postoperative CD patients. Methods We performed a systematic literature search for studies comparing the accuracy of CE, MRE, and US with IC for detection of postoperative recurrence in CD. We calculated pooled diagnostic sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) for each comparison. Results A total of 135 studies were retrieved; 14 studies were eligible for analysis. For CE, the pooled sensitivity was 100% (95% CI, 91%–100%), specificity was 69% (95% CI, 52%–83%), DOR was 30.8 (95% CI, 6.9–138), and AUC was 0.94. MRE had pooled sensitivity of 97% (95% CI, 89%–100%), specificity of 84% (95% CI, 62%–96%), DOR of 129.5 (95% CI, 16.4–1024.7), and AUC of 0.98. US had pooled sensitivity of 89% (95% CI, 85%–92%), specificity of 86% (95% CI, 78%–93%), DOR of 42.3 (95% CI, 18.6–96.0), and AUC 0.93. Conclusions CE, MRE, and US provide accurate assessment of postoperative endoscopic recurrence in CD. These modalities should gain wider use for detection of postoperative recurrence; the prognostic value of those diagnostic findings merits evaluation in further prospective studies.

Background Biologic treatments are inherently associated with an increased risk of infections, and recipients are intuitively considered at-risk for a more severe course of COVID-19. However, the actual risks are not fully described, neither are the appropriate adjustments needed to mitigate such risks. Methods Nation-wide registry was set up by Israeli IBD Section, to characterize course of COVID-19 in IBD patients who contacted SARS-CoV-2 infection while on biologics. We prospectively collected demographic and clinical data, and analyzed COVID-19 outcomes with regard to the specific treatments. Results Between Apr and Oct 2020, 144 patients with an established IBD diagnosis and confirmed COVID-19 were enrolled at 20 IBD referral centers. The majority of patients was under the age of 40 (113, 78%), 9 (6%) were younger than 18, only 4 patients (3%) over the age of 70. 94 patients received biologics, as monotherapy (76, 52.8%), combined with immunomodulators (9, 10%) or concomitant corticosteroids (9, 10%). 37 patients (26%) were reported with moderate and severe COVID-19 course, third of them (13) on biologics. 24 patents (17%) were admitted for hospitalization, the rest managed in home setting (114, 79%) and hotels converted into makeshift healthcare facilities (6, 4%). Fifteen patients (10%) required non-invasive ventilation and oxygen support, 3 patients (2%) went on mechanical ventilation. All patients recovered uneventfully, with no mortalities reported. Age was the most significant factor associated with moderate and severe disease. We found no correlation between bowel disease activity and the severity of COVID-19 course. The rate of serious COVID-19 for the 94 patients who had received biologics was significantly lower than that of 50 patients who were not treated with biologics (13/94 vs 24/50; RR 0.29 [95% CI, 0.161–0.515]; p < 0.0001). On adjusting for age, gender, comorbidities, IBD phenotype and activity, the surprising ameliorating effect associated with biologics was profound and significant (OR, 0.082 [95% CI 0.009-0.621], p =0.013) in all age categories. Conclusion Our results are reassuring and encouraging, and do not suggest that therapeutic immune suppression renders IBD patients particularly vulnerable for more severe course of the COVID-19. Adjusted odds for severe COVID-19 course actually decreased significantly in patients treated with biologics. It could be speculated that cytokine inhibition may mitigate progression of the infection to a devastating hyperinflammatory state. Continuing necessary maintenance immune suppression seems to be appropriate and safe approach, despite the COVID-19 pandemic.

Background & Aims The early stages of Crohn's disease (CD) course are heterogeneous, and it is a challenge to predict the course of disease in patients with new diagnosis. Methods We performed an observational longitudinal study of 156 adults (79 male; median age, 27.7 years; 57 treatment naive) with newly diagnosed CD (within 6 months of enrollment), referred from medical centers and community clinics in Israel from 2013 through 2017. Study participants each received semi-annual scheduled evaluations. Indolent disease was defined as a disease course without need for strict interventions to control complicated course of CD (hospitalization or surgery, or decision to start steroid, immunomodulator, or biologic therapy). Cox regression and receiver operating characteristic analyses were used to identify factors associated with early indolent or complicated course of CD. We validated our findings in an independent cohort of patients with CD from a separate medical center in Israel in 2018. Results Over a median follow-up period of 17.2 months (interquartile range, 8.8–23.8 months), 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. The median time to first intervention was 3.4 months (95% CI, 2.4–4.4). We developed a model based on clinical factors that identified 4 factors associated with complicated course in treatment-naive patients: body mass index Conclusions In an observational longitudinal study of 156 patients with newly diagnosed CD, we found that one third have an early indolent course of disease. We identified factors that can be measured at diagnosis to identify patients at risk for an early complicated course—these might be used in patient management and selection of treatment.

Background Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. Aim To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. Methods A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay. Results Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 μg/mL vs 13.5, 9.5 μg/mL, P = .0019, P 4.3 μg/mL-eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. Conclusions Infliximab levels below 6.8 μg/mL and antibodies to infliximab levels above 4.3 μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.

Background Vedolizumab [VDZ] is an anti-integrin monoclonal antibody effective in ulcerative colitis [UC] and Crohn's disease [CD]. Several real-world experience [RWE] studies with VDZ have been published to date. The aim of this systematic review was to summarise the available real-life experience with VDZ. Methods We performed a systematic review of the available RWE studies of VDZ in CD and UC. We performed a pooled analysis of the available efficacy and safety data for induction and maintenance treatment in adult cohorts. A narrative review of VDZ use in special clinical settings was also performed. Results Nine studies including 1565 [571 UC, 994 CD] adult patients were identified. In CD, clinical response and remission were achieved in 54% (95% confidence interval [CI] 41-66%) and 22% [95% CI 13-35%] by Week 6 and in 49% [95% CI 37-51%] and 32% [95% CI 23-42%] by Week 14; at Week 52, 45% [95% CI 28-64%] and 32% [95% CI 12-62] of the patients responded, and were in clinical remission, respectively. In UC, clinical response and remission were achieved in 43% [95% CI 37-49] and 25% [95% CI 12-45] by Week 6, respectively, and in 51% [95% CI 43-61%]and 30% [95% CI 24-36%] by Week 14/22, respectively; at week 52, clinical response and remission were achieved in 48% and 39% of the patients, respectively. Adverse effects were mostly minor and occurred in 30.6% of the patients; infections were reported in 3.4% of the patients. Conclusions VDZ is efficacious in CD and UC and has a favourable safety profile in RWE studies.

Studies have confirmed an increased risk of colorectal cancer in patients with ulcerative colitis; hence, surveillance is recommended. Optional modalities include white light endoscopy (WLE) or dye-spray chromoendoscopy. However, narrow-band imaging (NBI) is still not considered comparable to chromoendoscopy. The aim of this study was to compare the diagnostic yield (DY) of WLE, chromoendoscopy, NBI for detection of neoplasia in patients with inflammatory bowel disease (IBD) by performing a meta-analysis of the existing literature. We searched databases for prospective studies. For each modality, we performed comparative per-lesion analysis (any neoplasia detection) and per-patient analysis (patient with neoplastic lesions). Meta-analysis was performed using fixed-effect model unless heterogeneity was high. Odds ratios (ORs) with 95% CIs were calculated and pooled. Five studies compared chromoendoscopy to WLE. Chromoendoscopy (n = 361) was superior to WLE (n = 358) with per-patient analysis OR 2.05 (95% CI 1.26, 3.35) and per-lesion analysis OR 2.79 (95% CI 2.08, 3.73). High-definition (HD) chromoendoscopy was superior to HD-WLE with per-lesion analysis OR 2.48 (95% CI 1.55, 3.97). In four studies comparing NBI to WLE (n = 305), no difference was found in per-patient analysis OR 0.97 (95% CI 0.62, 1.53) and per-lesion analysis OR 0.94 (95% CI 0.63, 1.4). In two studies comparing CE to NBI (n = 104), no difference was found in per-patient analysis OR 1.0 (95% CI 0.51, 1.95) and per-lesion analysis OR 1.29 (95% CI 0.69, 2.41). Chromoendoscopy is superior to WLE for detection of dysplasia in IBD, even with HD endoscopy. No difference in DY could be demonstrated for NBI in comparison with other modalities.

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.

Crohn’s disease (CD) is a chronic inflammatory disease, in most patients involving the small and large bowel. In recent years, with the use of small bowel video capsule endoscopy (SBCE), it has become clear that in 50% or more of adults with established CD there is not only distal but also proximal small bowel involvement that suggests poor prognosis. A great deal of effort has been put into early diagnosis and stratification of patients into low versus high risk, thus directing treatment from step-up, or accelerated step-up, to top-down therapies. SBCE has been used for assessment of small bowel pathologies for over 15 years, mainly for occult gastrointestinal bleeding and suspected CD. In recent years, a colonic capsule, with cameras on both sides and a wider angle of view, has been developed and is used by some to survey both small and large bowel. Recently the same capsule, with adjustments, has been released in Europe, concentrating (with specialized software) on inflammatory bowel disease. In this review I summarize the new data regarding the use of SBCE as well as the small bowel colon (SBC) versions of capsule endoscopy in established CD and the ways these could alter the management of such patients.

Crohn's disease is associated with accumulation of progressive structural bowel damage (SBD) leading to the development of stenotic and penetrating complications. The data pertaining to the course of progression of SBD is scarce. The Lemann index (LI) is a novel tool for evaluation of SBD that incorporates pan-enteric clinical, endoscopic and imaging data.To evaluate the progression of SBD in quiescent CD patients.Patients with known quiescent small bowel Crohn's disease (CD) for at least 3 months (CDAI220) were prospectively recruited and underwent repeated magnetic resonance enterographies (MRE) and video capsule endoscopies (VCE). Patients were assessed for SBD on initial and follow-up evaluation using relevant clinicopathological data, MRE and VCE results. Significant structural bowel damage (SBD) was identified as LI4.8, and progression of SBD as LI0.3.Sixty one patients were enrolled in the study. Significant SBD was detected 13 (21.4%) on enrollment. Duration of disease (p=0.036) and history of CD-related surgery (p=0.0001) were associated with significant BD. Forty one patients underwent a follow-up MRE (14.8±2.5 months apart). LI was similar at baseline and follow-up. There was a negligible change in LI between the evaluations.In patients with quiescent Crohn's disease, structural bowel damage was stable over a median of 14 months follow-up.

BACKGROUND Vedolizumab (VDZ) is an anti-integrin monoclonal antibody effective in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to examine the "real world" efficacy and safety of VDZ in a large national patient cohort. METHODS Patients with inflammatory bowel disease treated with VDZ were prospectively followed for 14 weeks. Patients who completed the induction protocol (week 0/2/6/14) or discontinued the treatment before week 14 for adverse events (AEs) or primary nonresponse were included. The primary outcome was induction of clinical remission at week 14; secondary outcomes included clinical response and corticosteroid-free clinical remission. RESULTS A total of 204 patients (CD-130, UC-69, inflammatory bowel disease-unclassified-5) from 8 centers in Israel were included. Fifteen (7.4%) of the patients were anti-tumor necrosis factor naive and 46 (35.4%) had a previous surgery. For patients with CD, 69/130 (53.1%) responded to treatment; 45 (34.6%) achieved clinical remission; and 38 (29.2%) achieved corticosteroid-free remission at week 14. Fourteen (10.7%) patients discontinued VDZ before week 14 due to primary nonresponse or AEs. For UC, 32/74 (43.2%) responded to treatment; 20 (28.4%) achieved clinical remission, and 18 (24.3%) achieved corticosteroid-free remission at week 14. Fifteen (20.3%) patients with UC did not complete the induction due to primary nonresponse or AEs. AEs were reported by 29 (14.2%) patients (CD and UC combined), most common being nasopharyngitis and skin eruptions. CONCLUSIONS In a large real-world Israeli cohort of anti-tumor necrosis factor-experienced patients with inflammatory bowel disease, VDZ was effective and safe in induction of clinical remission and steroid-free clinical remission.

Background Capsule endoscopy (CE) is an important modality for monitoring of Crohn’s disease (CD). We recently established that small bowel (SB) inflammation on CE quantified by a Lewis score >350 accurately predicts risk of relapse within 2 years in CD patients in clinical remission. Recently, a novel pan-enteric capsule (PillCam Crohn’s (PCCE), Medtronic, USA) was approved for use. However, no quantitative index for pan-enteric PCCE is currently available. The current study was undertaken as a sub-study of a prospective randomised controlled CURE-CD trial aiming to optimise treatment of CD patients in remission using a PCCE- based treat-to-target approach; the aim of this ancillary study was to compare the correlation and reliability of the novel PCCE inflamatory score (Eliakim score) with the Lewis score as performed by 2 independent experienced CE readers. Methods The study cohort includes CD patients in clinical remission (CDAI Results Forty PCCE exams were included. The median LS was 225 for both readers (interquartile range (IQR)—157–815 for reader 1, 33- 1125 for reader 2). Both readers identified significant SB inflammation (LS>350) in 17/40 (42.5%) of the patients with strong agreement between the readers (Spearman’s r = 0.87, p < 0.0001). The median PCCE score was 6 (4–14.75) and 4 (2–14.75) for reader 1 and 2, respectively. There was a high IRC between the two readers for LS (0.88, p < 0.0001 for absolute agreement) and PCCE score (0.91, p < 0.0001). For the small bowel, the correlation between LS and PCCE was moderate for reader 1 (Pearson’s r = 0.72, p < 0.0001 and strong for reader 2 Pearson’s r = 0.84, p < 0.0001). Conclusion There is a need for a quantitative pan-enteric score for the novel Pillcam Crohns capsule. The presently proposed score, while mandating further clinical validation, has strong inter-reader reliability and moderate-to-strong correlation with the validated small bowel capsule score (LS)

Background Previous studies have shown inconclusive associations between vedolizumab trough levels and therapy outcomes. A near-complete occupancy of blood and intestinal α4β7 was exerted by vedolizumab through a wide-range of drug levels, regardless of clinical outcomes. However, these observations were not conducted specifically at the time of trough drug levels, did not include α4β7 highly expressing eosinophils and did not establish whether occupancy is in fact due to fully internalised VDZ- α4β7 complex in the target T-cell. Methods Peripheral blood (PB) and intestinal lamina propria (LP) were collected from IBD patients undergoing lower endoscopies on the day of vedolizumab infusion (trough time-point). Clinical and endoscopic scores were prospectively recorded. FACS analysis was performed using fluorescent conjugated-vedolizumab to investigate α4β7 occupancy on effector-memory T cells (CD3+CD45RO+ cells) and on eosinophils (CD49d+CD294+) in PB. Using a newly-developed dissociation assay, we also assessed the degree of membrane-bound VDZ-mediated blocked- α4β7. Results Forty-five IBD patients (16, 35% Crohn’s patients, 18, 40% in endoscopic remission) underwent clinical and endoscopic assessment just before their scheduled vedolizumab infusions. The median percentage of free α4β7 receptors at trough was 1.3% (IQR 0.5–3.7%) for PB T cells and 7.2% (IQR 3.6–23.4%) for LP T cells. No statistically significant difference was detected in α4β7 receptor saturation between patients with and without mucosal healing, both for PB (free α4β7 receptors: median 0.5%, 1.46%, IQR 0.3–1.4%, 0.9–3.5% respectively, p = 0.15) and for LP (free α4β7 receptors, median: 11.5%, 7%, IQR 3.5–24.2%, 5.8–20.9%, p = 0.88). Similarly, almost complete α4β7 receptor saturation at trough was detected among PB eosinophils (1.5% free α4β7 receptors, IQR 0.9–2.6%). Upon dissociation assay, a significant number of membrane-bound α4β7 receptors became detectable both on PB and LP T cells, with medians of 31% (IQR 24–41%), 22.2% (IQR 15–31%) respectively, and also for eosinophils, with a median of 83% (IQR 67–89%). When compared with values before dissociation, the proportion of unbound receptors was considerably lower (p < 0.001 for all analyses, respectively). Conclusion Even at trough, almost complete α4β7 receptor saturation is reached, both for PB and LP T cells, as well as for PB eosinophils, regardless of endoscopic activity status. This receptor occupancy is unrelated to receptor-internalisation and reflects a complete and continuous antigen-binding at the membranal level.

Background Intestinal ultrasound (IUS) is as an accurate bedside tool for monitoring Crohn’s disease (CD). However, there is no validated quantitative ultrasonographic score for evaluation of the activity of intestinal inflammation in CD. Such a score may facilitate the use of IUS-based monitoring in clinical practice and in clinical trials in CD. For magnetic resonance enterography (MRE), the magnetic resonance index of activity (MaRIA) is most commonly used. Thus, the aim of our study was to correlate IUS data for the terminal ileum with segmental MARIA score for the terminal ileum in order to devise a quantitative inflammatory index for IUS. Methods In this retrospective cohort study, the data of CD patients who were followed in the Gastroenterology Department at Sheba medical centre between January 2016 and December 2018 were extracted. Inclusion criteria were age >18 and an interval Results Forty-two patients with established Crohn’s disease were included. A stepwise multiple regression model was constructed to predict MaRIA score using US features. Two variables were found to be independently significant in the explanatory model, terminal ileum thickness (r = 0.68, p = 0.001) and US fat proliferation (r = 0.45, p = 0.019). A model was constructed as follows: MaRIA = 7 + 2.5 * TI US thickness (mm) + 7 * US fat proliferation (0 = no, 1 = yes). This model has an R2 of 0.51 for explaining the variability in the results. Conclusion Quantitative IUS measurements are significantly correlated with segmental MaRIA score in the terminal ileum; a simple computational model for prediction can be constructed; however,, the accuracy of such model to predict segmental MaRIA was moderate. Additional work to develop quantitative IUS parameters in CD is merited.

Background:Matrix metalloproteinase-9 (MMP-9) is a novel marker of intestinal inflammation. The aim of this study was to assess if serum MMP-9 levels predict clinical flare in patients with quiescent Crohn’s disease (CD).Methods:This study was a post hoc analysis of a prospective observational study in which quiescent CD patients were included and followed until clinical relapse or the end of a 2-year follow-up period. Serial C-reactive protein (CRP) and fecal calprotectin (FC) levels were measured, and the patients underwent repeated capsule endoscopies (CEs) every 6 months. Small bowel inflammation was quantified by Lewis score (LS) for CE. A baseline magnetic resonance enterography was also performed, and MaRIA score was calculated. Serum MMP-9 levels in baseline blood samples were quantified by ELISA.Results:Out of 58 eligible enrolled patients, 16 had a flare. Higher levels of baseline MMP-9 were found in patients who developed subsequent symptomatic flare compared with patients who did not [median 661 ng/ml, 25–75 interquartile range (IQR; 478.2–1441.3) versus 525.5 ng/ ml (339–662.7), respectively, p = 0.01]. Patients with serum MMP-9 levels of 945 ng/ ml or higher were at increased risk for relapse within 24 months [area under the curve (AUC) of 0.72 [95% confidence interval (CI): 0.56–0.88]; hazard ratio 8.1 (95% CI 3.0–21.9, p Conclusions:Serum MMP-9 may be a promising biomarker for prediction of clinical flare in CD patients with quiescent disease.

BACKGROUND Inflammatory bowel diseases (IBD) is a heterogenous, lifelong disease, with an unpredictable and potentially progressive course, that may impose negative psychosocial impact on patients. While informed patients with chronic illness have improved adherence and outcomes, previous research showed that the majority of IBD patients receive insufficient information regarding their disease. The large heterogeneity of IBD and the wide range of information topics makes a one-size fits all knowledge resource overwhelming and cumbersome. We hypothesized that different patient profiles may have different and specific information needs, the identification of which will allow building personalized computer-based information resources in the future. AIM To evaluate the scope of disease-related knowledge among IBD patients and determine whether different patient profiles drive unique information needs. METHODS We conducted a nationwide survey addressing hospital-based IBD clinics. A Total of 571 patients completed a 28-item questionnaire, rating the amount of information received at time of diagnosis and the importance of information, as perceived by participants, for a newly diagnosed patient, and for the participants themselves, at current time. We performed an exploratory factor analysis of the crude responses aiming to create a number of representative knowledge domains (factors), and analyzed the responses of a set of 15 real-life patient profiles generated by the study team. RESULTS Participants gave low ratings for the amount of information received at disease onset (averaging 0.9/5) and high ratings for importance, both for the newly diagnosed patients (mean 4.2/5) and for the participants themselves at current time (mean 3.5/5). Factor analysis grouped responses into six information-domains. The responses of selected profiles, compared with the rest of the participants, yielded significant associations (defined as a difference in rating of > 0.5 points with a P < 0.05). Patients with active disease showed a higher interest in work-disability, stress-coping, and therapy-complications. Patients newly diagnosed at age > 50, and patients with long-standing disease (> 10 years) showed less interest in work-disability. Patients in remission with mesalamine or no therapy showed less interest in all domains except for nutrition and long-term complications. CONCLUSION We demonstrate unmet patient information needs. Analysis of various patient profiles revealed associations with specific information topics, paving the way for building patient-tailored information resources.

The optimal monitoring strategy for predicting disease course in Crohn's disease remains undefined. We aimed to evaluate the accuracy, safety, and tolerability of an intensive monitoring strategy designed to predict the future course of Crohn's disease in patients with quiescent disease.In a prospective observational cohort study, we recruited patients older than 18 years with quiescent (for 3-24 months) Crohn's disease involving the small bowel with confirmed small bowel patency from three tertiary medical centres in Israel. Enrolled patients underwent baseline magnetic resonance enterography (MRE) and patency capsule, clinical or biomarker assessment every 3 months, and video capsule endoscopy (VCE) at baseline and every 6 months for 2 years or until a clinical flare (the primary outcome, defined as an increase in the Crohn's disease activity index score by 70 points or more) or disease worsening necessitating treatment intensification. We assessed the ability of the different Crohn's disease monitoring methods used to predict the occurrence of a flare during the 24-month follow-up period.Of 90 screened patients, 29 were excluded (17 because of non-patent small bowel). Of the 61 patients enrolled between July 3, 2013, and Feb 1, 2015, 17 (28%) had a flare during the 24-month follow-up. No clinicodemographic parameter predicted future flare. A baseline VCE Lewis score of 350 or more identified patients with future flare (area under the curve [AUC] 0·79, 95% CI 0·66-0·88; p0·0001; hazard ratio 10·7, 3·8-30·3). C-reactive protein at baseline had an AUC of 0·73 (0·6-0·84; p=0·0013) for predicting flare. The AUC of baseline faecal calprotectin for the prediction of flare occurring within 2 years was 0·62 (0·49-0·74; p=0·17), but progressively improved for shorter timespans and reached an AUC of 0·81 (0·76-0·85) for the prediction of flare occurring within 3 months. Of four MRE-based indices, only MRE global score correlated with 2-year flare risk (AUC 0·71, 0·58-0·82; p=0·024). During follow-up, a Lewis score increase of 383 points or more from baseline predicted imminent disease exacerbation within 6 months (AUC 0·79, 0·65-0·89; p=0·011). The safety and tolerability of the 231 VCEs ingested was excellent, with none being retained.In patients with quiescent Crohn's disease involving the small bowel, faecal calprotectin predicts short-term flare risk, whereas VCE predicts both short-term and long-term risk of disease exacerbation. If corroborated by additional studies, protocols incorporating VCE could expand the scope of available methods for monitoring disease activity and predicting outcomes in small bowel Crohn's disease.The Leona MHarry B Helmsley Charitable Trust.

OBJECTIVES Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. METHODS We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. RESULTS Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3-42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. DISCUSSION Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.

Background Lynch syndrome carries an increased risk of colorectal neoplasia, hence annual surveillance colonoscopy is recommended. This study aimed to compare the diagnostic yields of image enhancement modalities for colorectal neoplasia in patients with Lynch syndrome. Methods Meta-analysis of pooled ratios of lesion detection rates (RRs) and odds ratios (ORs) with 95% confidence intervals (CIS), comparing white light endoscopy (WLE) and chromoendoscopy (ChE). Results Four studies comparing WLE to ChE were analyzed. ChE fared better than WLE in overall lesion detection (RR 1.97, 95% CI 1.63–2.38) and detection of adenomas (RR 1.53, 95% CI 1.07–2.17), flat lesions (RR 3.4, 95% CI 2.47–4.67) and proximally-located lesions (RR 2.93, 95% CI 1.91–4.5). The odds of a patient having any lesion found were higher in ChE compared to WLE (OR 2.42, 95% CI 1.56–3.75). The odds of a patient having adenoma(s) found on endoscopy were not significantly higher in chromoendoscopy compared to white light endoscopy (OR 1.81, 95% CI 0.65–5.01). Conclusion Using standard definition technology, ChE allows detection of more lesions, especially adenomas, flat lesions and proximal lesions in Lynch syndrome patients, compared to WLE. The results show that surveillance colonoscopy of Lynch syndrome patients should be performed using ChE.

Background The serum metabolome contains potential disease biomarkers, some of which are produced endogenously, and some are generated by the gut microbiome. We recently found that Crohn’s Disease (CD) patients in remission still show significantly reduced gut microbial richness and increased dysbiosis compared to healthy controls (PMID: 30741738). Methods Serum untargeted metabolomics, fecal V4 16S microbial characterization, and fecal calprotectin were longitudinally tested in CD patients enrolled in remission. Metabolomics was performed on 139 samples (25 CD and 12 controls) by liquid chromatography coupled with Q-Exactive Orbitrap Mass Spectrometer (LC/MS), and Thermo Xcalibur was used for data acquisition. PERMANOVA on beta diversity was used to define factors affecting serum metabolome. Multivariate analyses in MaAsLin were applied for specific metabolites differential abundance (FDR Results During 24-months of prospective follow-up, 11/25 of the CD patients, who started in remission, flared. PERMANOVA on the serum metabolomic data indicated subject-specific signals. Despite this, using multivariate analyses and controlling for age, gender, and subject, we identified specific metabolites that were significantly different between CD and controls. CD samples were significantly enriched for purine derivatives, simple sugars, histidine and oxalate, compared to healthy controls. In contrast, amino-acids, TCA cycle-related metabolites, saturated fatty acids and acylcarnitines were consistently downregulated in CD. Interestingly, most of those CD-associated metabolic signatures were similar between CD patients with mucosal healing (calprotectin 100, Median 197; IQR 143,300). Interestingly, α-ketoglutarate (aKG) and decanoic-acid were further downregulated in active samples compared to remission (q= 0.2 and 0.16, respectively). Looking into those metabolites in samples prior to the flare, flared patients showed a negative trend in aKG, and a significant reduction in decanoic acid pre-flare (p Conclusion CD patients in remission exhibit a distinct serum metabolic signature, which may be linked in part with the gut microbial diversity and composition. Several metabolite signals may precede disease flare.